Wikiversity enwikiversity https://en.wikiversity.org/wiki/Wikiversity:Main_Page MediaWiki 1.39.0-wmf.21 first-letter Media Special Talk User User talk Wikiversity Wikiversity talk File File talk MediaWiki MediaWiki talk Template Template talk Help Help talk Category Category talk School School talk Portal Portal talk Topic Topic talk Collection Collection talk Draft Draft talk TimedText TimedText talk Module Module talk Gadget Gadget talk Gadget definition Gadget definition talk 4 28 2408125 2407969 2022-07-20T05:15:50Z Koavf 147 Reverted edits by [[Special:Contributions/41.114.38.24|41.114.38.24]] ([[User_talk:41.114.38.24|talk]]) to last version by [[User:Xeno (WMF)|Xeno (WMF)]] using [[Wikiversity:Rollback|rollback]] wikitext text/x-wiki {{Wikiversity:Colloquium/Header}} <!-- MESSAGES GO BELOW --> == Warning templates == We do not have any warning templates here at Wikiversity yet. Why not import them? [[User:Lightbluerain|Lightbluerain]] ([[User talk:Lightbluerain|discuss]] • [[Special:Contributions/Lightbluerain|contribs]]) 17:40, 13 May 2022 (UTC) :@[[User:Lightbluerain|Lightbluerain]]: I'm not sure which warnings you are looking for, but see [[Wikiversity:Import]] to add you request(s). Thanks! -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 23:38, 13 May 2022 (UTC) :We do have a couple of templates in [[:Category:User warning templates]]. --[[User:Mu301|mikeu]] ^{[[User talk:Mu301|talk]]} 21:40, 17 June 2022 (UTC) == Next steps on the Universal Code of Conduct (UCoC) Enforcement guidelines == Hey all - I have an update on the [[m:Special:MyLanguage/Universal Code of Conduct/Project|Universal Code of Conduct (UCoC) project]]. [[m:Special:MyLanguage/Universal Code of Conduct/Enforcement guidelines/Voting/Report|'''A report is available on Meta-Wiki''']]. about the [[m:Special:MyLanguage/Universal Code of Conduct/Enforcement guidelines/Vote|2022 March ratification vote]] on the [[m:Special:MyLanguage/Universal Code of Conduct/Enforcement guidelines|UCoC Enforcement guidelines]]. Voters cast votes from at least 137 communities. At least 650 participants added comments with their vote. ''([[m:Special:MyLanguage/Universal Code of Conduct/Enforcement guidelines/Voting/Report/Announcement|See full announcement]])'' Following the vote, the [[m:Special:MyLanguage/Wikimedia Foundation Community Affairs Committee|Community Affairs committee (CAC)]] of the Wikimedia Foundation Board of Trustees [https://lists.wikimedia.org/hyperkitty/list/wikimedia-l@lists.wikimedia.org/thread/JAYQN3NYKCHQHONMUONYTI6WRKZFQNSC/ asked that several areas be reviewed for improvements]. A [[m:Special:MyLanguage/Universal Code of Conduct/Drafting committee#Revisions Committee|Revision Drafting Committee]] will refine the enforcement guidelines based on community feedback. To help the Revisions committee, input from the community is requested. Visit the Meta-wiki pages ([[m:Special:MyLanguage/Universal_Code_of_Conduct/Enforcement_guidelines/Revision_discussions|Enforcement Guidelines revision discussions]], [[m:Special:MyLanguage/Universal_Code_of_Conduct/Policy text/Revision_discussions|Policy text revision discussions]]) to provide thoughts for the new drafting committee. ''([[m:Universal Code of Conduct/Enforcement guidelines/Revision discussions/Announcement|See full announcement]])'' Let me know if you have any questions about these next steps. [[User:Xeno (WMF)|Xeno (WMF)]] ([[User talk:Xeno (WMF)|discuss]] • [[Special:Contributions/Xeno (WMF)|contribs]]) 02:23, 2 June 2022 (UTC) == Chris Tolworthy == A blogger by the name of [https://answersanswers.com/index.html Chris Tolworthy] has written a lot of essays about the Bible and other subjects. Personally, I think that while some of these essays are pretty much just drivel, others might be worth including on Wikiversity. However, I don't know what kind of license Tolworthy uses on his work- the main page just says, "If you find these pages useful please share and copy them." How that would be expressed in the form of a Creative Commons license, I'm not entirely sure. Also, if we did include Tolworthy's works, he has [https://www.facebook.com/HeyLookThatsMe/ a Facebook account], which would satisfy criteria no. 3 on the [[Help:Essay]] page. What do you think? --[[User:Lizardcreator|Lizardcreator]] ([[User talk:Lizardcreator|discuss]] • [[Special:Contributions/Lizardcreator|contribs]]) 23:34, 15 June 2022 (UTC) :@[[User:Lizardcreator|Lizardcreator]] You are welcome to link to these resources and create learning projects around them. You cannot copy them and host them at Wikiversity. Only Chris Tolworthy can do that. Any resource that doesn't explicitly include a Creative Commons or other open license isn't licensed for sharing on Wikiversity. [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 13:57, 16 June 2022 (UTC) == Desktop Improvements update == [[File:Table of contents shown on English Wikipedia 02.webm|thumb]] ; Making this the new default Hello. I wanted to give you an update about the [[mw:Special:MyLanguage/Reading/Web/Desktop_Improvements|Desktop Improvements]] project, which the Wikimedia Foundation Web team has been working on for the past few years. Our work is almost finished! 🎉 We would love to see these improvements become the default for readers and editors across all wikis. <span style="background-color:#fc3;">In the coming weeks, we will begin conversations on more wikis, including yours. 🗓️</span> We will gladly read your suggestions! The goals of the project are to make the interface more welcoming and comfortable for readers and useful for advanced users. The project consists of a series of feature improvements which make it easier to read and learn, navigate within the page, search, switch between languages, use article tabs and the user menu, and more. The improvements are already visible by default for readers and editors on more than 30 wikis, including Wikipedias in [[:fr:|French]], [[:pt:|Portuguese]], and [[:fa:|Persian]]. The changes apply to the [{{fullurl:{{FULLPAGENAMEE}}|useskin=vector}} Vector] skin only, although it will always be possible to revert to the previous version on an individual basis. [{{fullurl:{{FULLPAGENAMEE}}|useskin=monobook}} Monobook] or [{{fullurl:{{FULLPAGENAMEE}}|useskin=timeless}} Timeless] users will not notice any changes. ; The newest features * [[mw:Special:MyLanguage/Reading/Web/Desktop_Improvements/Features/Table of contents|Table of contents]] - our version is easier to reach, gain context of the page, and navigate throughout the page without needing to scroll. It is currently tested across our pilot wikis. It is also available for editors who have opted into the Vector 2022 skin. * [[mw:Special:MyLanguage/Reading/Web/Desktop_Improvements/Features/Page tools|Page tools]] - now, there are two types of links in the sidebar. There are actions and tools for individual pages (like [[Special:RecentChangesLinked|Related changes]]) and links of the wiki-wide nature (like [[Special:RecentChanges|Recent changes]]). We are going to separate these into two intuitive menus. ; How to enable/disable the improvements [[File:Desktop Improvements - how to enable globally.png|thumb|[[Special:GlobalPreferences#mw-prefsection-rendering|{{int:globalpreferences}}]]]] * It is possible to opt-in individually [[Special:Preferences#mw-prefsection-rendering|in the appearance tab within the preferences]] by selecting "{{int:skinname-vector-2022}}". Also, it is possible to opt-in on all wikis using the [[Special:GlobalPreferences#mw-prefsection-rendering|global preferences]]. * On wikis where the changes are visible by default for all, logged-in users can always opt-out to the Legacy Vector. There is an easily accessible link in the sidebar of the new Vector. ; Learn more and join our events If you would like to follow the progress of our project, you can [[mw:Special:Newsletter/28/subscribe|subscribe to our newsletter]]. You can read the [[mw:Special:MyLanguage/Reading/Web/Desktop_Improvements|pages of the project]], check [[mw:Special:MyLanguage/Reading/Web/Desktop_Improvements/Frequently_asked_questions|our FAQ]], write on the [[mw:Talk:Reading/Web/Desktop_Improvements|project talk page]], and [[mw:Special:MyLanguage/Reading/Web/Desktop Improvements/Updates/Talk to Web|join an online meeting with us]]. Thank you! [[User:SGrabarczuk (WMF)|SGrabarczuk (WMF)]] ([[User talk:SGrabarczuk (WMF)|talk]]) 16:59, 21 June 2022 (UTC) <!-- Message sent by User:SGrabarczuk (WMF)@metawiki using the list at https://meta.wikimedia.org/w/index.php?title=User:SGrabarczuk_(WMF)/sandbox/MM/En_fallback&oldid=23430301 --> == TemplateScripts = Templates + JavaScript == Hi! I'd like to propose enabling [[c:Help:TemplateScripts|TemplateScripts]] on the English Wikiversity. It's not a MediaWiki extension, but a few lines of JavaScript added to [[MediaWiki:Common.js]] that basically allow to run JavaScript from templates, '''as long as the code is on the MediaWiki namespace and with the "TemplateScript-" prefix''', which requires an authorized user and community consensus to get there. The system is enabled on the Spanish Wikipedia where it's used for easy signing of polls and projects (see blue button [[:es:Wikiproyecto:Veganismo/participantes|here]]), for navigating [[Template:Excerpt#Excerpt trees|excerpt trees]] (see box with tree icon [[:es:Discusión:Ciencia|here]]), for injecting interactive widgets on some articles ([[:es:Hormiga de Langton|here]] and [[:es:Juego de la vida|here]]) and more recently for creating interactive forms that inject content into other pages (see template [[:es:Plantilla:Formulario|here]], soon to be used on admin boards). My immediate goal on Wikiversity is to use it to develop a tool to make [[Wikidebate|wikidebates]] more friendly. However I believe some of the existing scripts, particularly the ones for creating forms and signing pages, can be very useful on Wikiversity overall, as well as in some specific projects like [[Automata theory]] and [[Conway's Game of Life]]. So what do you think? [[User:Sophivorus|Sophivorus]] ([[User talk:Sophivorus|talk]]) 21:12, 29 June 2022 (UTC) == Results of Wiki Loves Folklore 2022 is out! == <div lang="en" dir="ltr" class="mw-content-ltr"> {{int:please-translate}} [[File:Wiki Loves Folklore Logo.svg|right|150px|frameless]] Hi, Greetings The winners for '''[[c:Commons:Wiki Loves Folklore 2022|Wiki Loves Folklore 2022]]''' is announced! We are happy to share with you winning images for this year's edition. This year saw over 8,584 images represented on commons in over 92 countries. Kindly see images '''[[:c:Commons:Wiki Loves Folklore 2022/Winners|here]]''' Our profound gratitude to all the people who participated and organized local contests and photo walks for this project. We hope to have you contribute to the campaign next year. '''Thank you,''' '''Wiki Loves Folklore International Team''' --[[User:MediaWiki message delivery|MediaWiki message delivery]] ([[User talk:MediaWiki message delivery|discuss]] • [[Special:Contributions/MediaWiki message delivery|contribs]]) 16:12, 4 July 2022 (UTC) </div> <!-- Message sent by User:Tiven2240@metawiki using the list at https://meta.wikimedia.org/w/index.php?title=Distribution_list/Non-Technical_Village_Pumps_distribution_list&oldid=23454230 --> == Wikiversity == What can i do with wikiversity --[[User:Goku Sakaki|Goku Sakaki]] ([[User talk:Goku Sakaki|discuss]] • [[Special:Contributions/Goku Sakaki|contribs]]) 16:58, 10 July 2022 (UTC) :@[[User:Goku Sakaki|Goku Sakaki]] Welcome! Start with [[What is Wikiversity?]]. Then look around and see what interests you. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 01:06, 11 July 2022 (UTC) == How to graphically design a park == How do I design a park {{unsigned|Darelle Meyer}} :That would be a pretty involved process and I don't think that Wikiversity or our sister project [[:b:en:|Wikibooks]] has a resource on that yet. —[[User:Koavf|Justin (<span style="color:grey">ko'''a'''vf</span>)]]<span style="color:red">❤[[User talk:Koavf|T]]☮[[Special:Contributions/Koavf|C]]☺[[Special:Emailuser/Koavf|M]]☯</span> 21:36, 11 July 2022 (UTC) == Wikimedia Foundation Board of Trustees Election: Propose statements for the 2022 Election Compass == <section begin="announcement-content" /> :''[[m:Special:MyLanguage/Wikimedia Foundation elections/2022/Announcement/Propose statements for the 2022 Election Compass| You can find this message translated into additional languages on Meta-wiki.]]'' :''<div class="plainlinks">[[m:Special:MyLanguage/Wikimedia Foundation elections/2022/Announcement/Propose statements for the 2022 Election Compass|{{int:interlanguage-link-mul}}]] • [https://meta.wikimedia.org/w/index.php?title=Special:Translate&group=page-{{urlencode:Wikimedia Foundation elections/2022/Announcement/Propose statements for the 2022 Election Compass}}&language=&action=page&filter= {{int:please-translate}}]</div>'' Hi all, Community members in the [[m:Special:MyLanguage/Wikimedia Foundation elections/2022|2022 Board of Trustees election]] are invited to '''[[m:Special:MyLanguage/Wikimedia_Foundation_elections/2022/Community_Voting/Election_Compass|propose statements to use in the Election Compass.]]''' An Election Compass is a tool to help voters select the candidates that best align with their beliefs and views. The community members will propose statements for the candidates to answer using a Lickert scale (agree/neutral/disagree). The candidates’ answers to the statements will be loaded into the Election Compass tool. Voters will use the tool by entering in their answer to the statements (agree/disagree/neutral). The results will show the candidates that best align with the voter’s beliefs and views. {{collapse|heading=Timeline for the Election Compass|content= July 8 - 20: Community members propose statements for the Election Compass July 21 - 22: Elections Committee reviews statements for clarity and removes off-topic statements July 23 - August 1: Volunteers vote on the statements August 2 - 4: Elections Committee selects the top 15 statements August 5 - 12: candidates align themselves with the statements August 15: The Election Compass opens for voters to use to help guide their voting decision }} The Elections Committee will select the top 15 statements at the beginning of August. The Elections Committee will oversee the process, supported by the Movement Strategy and Governance team. MSG will check that the questions are clear, there are no duplicates, no typos, and so on. Best, Movement Strategy and Governance ''This message was sent on behalf of the Board Selection Task Force and the Elections Committee''<br /><section end="announcement-content" /> [[User:Xeno (WMF)|Xeno (WMF)]] ([[User talk:Xeno (WMF)|discuss]] • [[Special:Contributions/Xeno (WMF)|contribs]]) 17:00, 11 July 2022 (UTC) == Movement Strategy and Governance News – Issue 7 == <section begin="msg-newsletter"/> <div style = "line-height: 1.2"> <span style="font-size:200%;">'''Movement Strategy and Governance News'''</span><br> <span style="font-size:120%; color:#404040;">'''Issue 7, July–⁠September 2022'''</span><span style="font-size:120%; float:right;">[[m:Special:MyLanguage/Movement Strategy and Governance/Newsletter/7|'''Read the full newsletter''']]</span> ---- Welcome to the 7th issue of Movement Strategy and Governance News! The newsletter distributes relevant news and events about the implementation of Wikimedia's [[:m:Special:MyLanguage/Movement Strategy/Initiatives|Movement Strategy recommendations]], other relevant topics regarding Movement governance, as well as different projects and activities supported by the Movement Strategy and Governance (MSG) team of the Wikimedia Foundation. The MSG Newsletter is delivered quarterly, while the more frequent [[:m:Special:MyLanguage/Movement Strategy/Updates|Movement Strategy Weekly]] will be delivered weekly. Please remember to subscribe [[m:Special:MyLanguage/Global message delivery/Targets/MSG Newsletter Subscription|here]] if you would like to receive future issues of this newsletter. </div><div style="margin-top:3px; padding:10px 10px 10px 20px; background:#fffff; border:2px solid #808080; border-radius:4px; font-size:100%;"> * '''Movement sustainability''': Wikimedia Foundation's annual sustainability report has been published. ([[:m:Special:MyLanguage/Movement Strategy and Governance/Newsletter/7#A1|continue reading]]) * '''Improving user experience''': recent improvements on the desktop interface for Wikimedia projects. ([[:m:Special:MyLanguage/Movement Strategy and Governance/Newsletter/7#A2|continue reading]]) * '''Safety and inclusion''': updates on the revision process of the Universal Code of Conduct Enforcement Guidelines. ([[:m:Special:MyLanguage/Movement Strategy and Governance/Newsletter/7#A3|continue reading]]) * '''Equity in decisionmaking''': reports from Hubs pilots conversations, recent progress from the Movement Charter Drafting Committee, and a new white paper for futures of participation in the Wikimedia movement. ([[:m:Special:MyLanguage/Movement Strategy and Governance/Newsletter/7#A4|continue reading]]) * '''Stakeholders coordination''': launch of a helpdesk for Affiliates and volunteer communities working on content partnership. ([[:m:Special:MyLanguage/Movement Strategy and Governance/Newsletter/7#A5|continue reading]]) * '''Leadership development''': updates on leadership projects by Wikimedia movement organizers in Brazil and Cape Verde. ([[:m:Special:MyLanguage/Movement Strategy and Governance/Newsletter/7#A6|continue reading]]) * '''Internal knowledge management''': launch of a new portal for technical documentation and community resources. ([[:m:Special:MyLanguage/Movement Strategy and Governance/Newsletter/7#A7|continue reading]]) * '''Innovate in free knowledge''': high-quality audiovisual resources for scientific experiments and a new toolkit to record oral transcripts. ([[:m:Special:MyLanguage/Movement Strategy and Governance/Newsletter/7#A8|continue reading]]) * '''Evaluate, iterate, and adapt''': results from the Equity Landscape project pilot ([[:m:Special:MyLanguage/Movement Strategy and Governance/Newsletter/7#A9|continue reading]]) * '''Other news and updates''': a new forum to discuss Movement Strategy implementation, upcoming Wikimedia Foundation Board of Trustees election, a new podcast to discuss Movement Strategy, and change of personnel for the Foundation's Movement Strategy and Governance team. ([[:m:Special:MyLanguage/Movement Strategy and Governance/Newsletter/7#A10|continue reading]]) </div><section end="msg-newsletter"/> [[User:Xeno (WMF)|Xeno (WMF)]] ([[User talk:Xeno (WMF)|discuss]] • [[Special:Contributions/Xeno (WMF)|contribs]]) 00:29, 17 July 2022 (UTC) 6cd0lq7gd3596ewvupvayqz2bee23nv 0 34381 2408141 2365591 2022-07-20T08:54:35Z 119.160.69.95 Xhdudhhd wikitext text/x-wiki {{RoundBoxTop|theme=16}} == Introduction == This course is an introduction for non-computer science students (see [[Introduction_to_Computer_Science|Introduction to Computer Science]] for computer science students). Instead this course is a gentler, lighter survey course without delving too much into technical details. It will also examine computers from the perspective on how they influence society. {{RoundBoxBottom|theme=16}} [https://lokynews.blogspot.com/]{{RoundBoxTop|theme=16}} == Prerequisites == Prerequisites are courses it is suggested you understand before you attempt this course. If you're having a hard time understanding the material in this course, make sure you understand these prerequisites first. * There are no prerequisites! (You should be able to follow along no matter how little experience you have in this subject.) {{RoundBoxBottom|theme=16}} [https://lokynews.blogspot.com/]{{RoundBoxTop|theme=16}} == Lessons == # {{100Percent}} Introduction #* {{100Percent}} [[Introduction_to_Computers/What is a computer|What is a computer?]] #* {{100Percent}} [[Introduction_to_Computers/History|History of computers]] #* {{100Percent}} [[Introduction_to_Computers/Computer types|Computer types]] #* {{100Percent}} [[Introduction_to_Computers/Hardware and software|Hardware and software]] #* {{100Percent}} [[Introduction_to_Computers/Basic operations|Basic operations]] #* {{100Percent}} [[Introduction_to_Computers/Data sizes and speeds|Data sizes and speeds]] # {{100Percent}} Inside a computer case #* {{100Percent}} [[Introduction_to_Computers/Motherboard|Motherboard]] #* {{100Percent}} [[Introduction_to_Computers/Processor|Processor]] #* {{100Percent}} [[Introduction_to_Computers/Memory|Memory]] #* {{100Percent}} [[Introduction_to_Computers/Disks|Disks]] # {{50Percent}} Peripherals #* {{75Percent}} [[Introduction_to_Computers/Input Devices|Input Devices]] #* {{75Percent}} [[Introduction_to_Computers/Output Devices|Output Devices]] #* {{25Percent}} [[Introduction_to_Computers/Future Peripherals|Future Peripherals]] # {{100Percent}} [[Introduction_to_Computers/System software|System software]] # {{100Percent}} [[Introduction_to_Computers/Application software|Application software]] # {{100Percent}} [[Introduction_to_Computers/Personal|Personal]] # {{100Percent}} [[Introduction_to_Computers/Networks|Networks]] # {{100Percent}} [[Introduction_to_Computers/Security|Security]] # {{100Percent}} [[Introduction_to_Computers/Internet|Internet]] # {{100Percent}} [[Introduction_to_Computers/Development|Development]] # {{100Percent}} [[Introduction_to_Computers/Databases|Databases]] # {{100Percent}} [[Introduction_to_Computers/AI|Artificial intelligence]] {{RoundBoxBottom|theme=16}} {{RoundBoxTop|theme=16}} == What Next? == Once you have completed this course, you have learned enough to take these courses: * [[Computer Skills]] * [[IC3 | Internet and Computing Core Certification (IC³)]] * [[IT Fundamentals]] * [[Introduction to Computer Science]] {{RoundBoxBottom|theme=16}} __NOTOC__ [[Category:Computing]] n3fll60q9ept2vk5bi90vam8r6eamys 0 109135 2408037 2266240 2022-07-19T17:43:15Z 154.158.128.68 when Jioni time description wikitext text/x-wiki == Numbers == === 1-10 === 1 = Moja (adj. -moja)<br> 2 = Mbili (adj. -wili) <br> 3 = Tatu (adj. -tatu) <br> 4 = Nne (adj. -nne) <br> 5 = Tano (adj. -tano) <br> 6 = Sita <br> 7 = Saba <br> 8 = Nane <br> 9 = Tisa/Kenda<br> Kenda is used in a different dialect mostly from Burundi, Rwanda and D.R.C but Tisa is used by Tanzania and Kenya more often. 10 = Kumi <br> === 10-20 === 11 = Kumi na moja (Na = And -> Kumi na moja = Ten and One) <br> 12 = Kumi na mbili <br> 13 = Kumi na tatu <br> ... 20 = Ishirini <br> (21 = Ishirini na moja... ) <br> === Tens === 30 = Thelathini <br> 40 = Arobaini <br> 50 = Hamsini <br> 60 = Sitini <br> 70 = Sabini <br> 80 = Themanini <br> 90 = Tisini <br> === 100+ === 100 = Mia moja <br> (101 = Mia moja na moja... ) <br> 200 = Mia mbili <br> ... 1,000 = Elfu == Time == Swahili time is expressed very differently from standard time in other parts of the world. Instead of midnight and noon, Swahili time is based on sunset and sunrise. As most Swahili-speaking countries are located near the equator, sunset and sunrise are mostly constant year-round, and defined to be 6:00 P.M. and 6:00 A.M., respectively in standard time. Hence, 6:00 P.M. is the zero hour (0:00 or 12:00) in Swahili time, 7:00 P.M. is the first hour (1:00 in the evening) and so on. An easy translation to Swahili time is to subtract six hours from the standard clock time, which is how many natives adjust. For example, 11:30 A.M. in standard time is 5:30 in the morning in Swahili time. Instead of A.M. and P.M., Swahili time expresses the hour followed by the portion of the day. <br> * ''Alfajiri'' = early morning, before the sun has fully risen <br> * ''Asubuhi'' = morning, roughly between sunrise and noon <br> * ''Mchana'' = daytime, between sunrise 6:A.M. and sunset 6:00 P.M. <br> * ''Jioni'' = evening, between sunset 6:P.M. and sunrise 6:00 A.M. <br> * ''Usiku'' = night time, from sunset until early morning again <br> As with standard time, the hour (''saa'') is expressed first, followed by the minutes (''dakika''). There are also abbreviations for half past (''nusu'', half) and others (''kasorobo'', less a quarter). Here are some examples of time-telling to help you understand how it is done. {| class="wikitable" |- ! Standard Time !! Swahili Time !! Translation !! Note |- | 12:00 A.M.|| 6:00 at night || ''saa sita usiku'' || literally hour six night |- | 3:00 P.M.|| 9:00 in the afternoon || ''saa tisa mchana'' || |- | 7:30 P.M.|| 1:30 in the evening || ''saa moja na nusu jioni'' || literally hour one and a half evening |- | 1:05 P.M.|| 7:05 in the afternoon || ''saa saba na dakika tano mchana'' || literally hour seven and minutes five afternoon |- | A quarter to 8:00 A.M.(7.45 A.M.)|| A quarter to 2:00 in the morning || ''saa mbili kasorobo asubuhi'' || literally hour two less one quarter morning |- | Almost 11:00 A.M.|| Almost 5:00 in the morning || ''saa tano kasoro asubuhi. (Karibu saa tano)'' || literally hour five less morning (Literally almost hour five) |} == Advice == You should make flashcards for these with the actual digits on one side and the Swahili word on the other and quiz yourself, looking at both sides and saying, aloud, what is on the other. === Exercises === [[/Exercises/]] fuol6mi5djo9jqpum1pja12dy2ovsz3 0 138773 2408115 2277657 2022-07-20T04:32:53Z 148.64.7.123 /* Readings */ wikitext text/x-wiki {{TOCright}} Wireshark is a free and open source packet analyzer used for network troubleshooting and analysis. These activities will show you how to use Wireshark to capture and filter network traffic using a display filter. == Readings == # [https://gitlab.com/wireshark/wireshark/-/wikis/DisplayFilters Wireshark: Display Filters] 172.20.192.71 == Multimedia == # [https://www.youtube.com/watch?v=N-HpD0bUSO4 YouTube: Wireshark 101: Display Filters and Filter Options, HakTip 122] == Preparation == To prepare for this activity: # Start your system Linux or Windows. # Log in if necessary. # [[Wireshark/Install | Install Wireshark]]. == Activity 1 - Capture Network Traffic == To capture network traffic: # [[Wireshark/Start | Start a Wireshark capture]]. # Use [[Ping/Host | ping 8.8.8.8]] to ping an Internet host by IP address. # [[Wireshark/Stop | Stop the Wireshark capture]]. == Activity 2 - Use a Display Filter == To use a display filter: # Type '''ip.addr == 8.8.8.8''' in the Filter box and press '''Enter.''' # Observe that the Packet List Pane is now filtered so that only traffic to (destination) or from (source) IP address 8.8.8.8 is displayed. # Click '''Clear''' on the Filter toolbar to clear the display filter. # Close Wireshark to complete this activity. '''Quit without Saving''' to discard the captured traffic. == References == * [http://www.wireshark.org/docs/wsug_html_chunked/ Wireshark: User's Guide] * [https://gitlab.com/wireshark/wireshark/-/wikis/home Wireshark Wiki] *[http://www.admin-magazine.com/Articles/Wireshark Admin Magazine: Wireshark] [[Category:Wireshark]] [[Category:Activities]] 7on7bqtloqva55s3v9r2f9vruhkv1c3 0 139384 2408008 2407060 2022-07-19T14:40:34Z Young1lim 21186 /* Adder */ wikitext text/x-wiki {{nocat}} == Adder == * Binary Adder Architecture Exploration ( [[Media:adder.20131113.pdf |pdf]] ) {| class="wikitable" |- ! Adder type !! Overview !! Analysis !! VHDL Level Design !! CMOS Level Design |- | '''1. Ripple Carry Adder''' || [[Media:VLSI.Arith.1A.RCA.20211108.pdf |pdf]] || || [[Media:adder.rca.20140313.pdf |pdf]] || [[Media:VLSI.Arith.1D.RCA.CMOS.20211108.pdf |pdf]] |- | '''2. Carry Lookahead Adder''' || [[Media:VLSI.Arith.1.A.CLA.20211106.pdf |pdf]] || || [[Media:adder.cla.20140313.pdf |pdf]] || |- | '''3. Carry Save Adder''' || [[Media:VLSI.Arith.1.A.CSave.20151209.pdf |pdf]] || || || |- || '''4. Carry Select Adder''' || [[Media:VLSI.Arith.1.A.CSelA.20191002.pdf |pdf]] || || || |- || '''5. Carry Skip Adder''' || [[Media:VLSI.Arith.5A.CSkip.20211111.pdf |pdf]] || || || [[Media:VLSI.Arith.5D.CSkip.CMOS.20211108.pdf |pdf]] |- || '''6. Carry Chain Adder''' || [[Media:VLSI.Arith.6A.CCA.20211109.pdf |pdf]] || || [[Media:VLSI.Arith.6C.CCA.VHDL.20211109.pdf |pdf]], [[Media:adder.cca.20140313.pdf |pdf]] || [[Media:VLSI.Arith.6D.CCA.CMOS.20211109.pdf |pdf]] |- || '''7. Kogge-Stone Adder''' || [[Media:VLSI.Arith.1.A.KSA.20140315.pdf |pdf]] || || [[Media:adder.ksa.20140409.pdf |pdf]] || |- || '''8. Prefix Adder''' || [[Media:VLSI.Arith.1.A.PFA.20140314.pdf |pdf]] || || || |- || '''9. Variable Block Adder''' || [[Media:VLSI.Arith.1.A.VBA.20220718.pdf |pdf]] || || || |} </br> === Adder Architectures Suitable for FPGA === * FPGA Carry-Chain Adder ([[Media:VLSI.Arith.1.A.FPGA-CCA.20210421.pdf |pdf]]) * FPGA Carry Select Adder ([[Media:VLSI.Arith.1.B.FPGA-CarrySelect.20210522.pdf |pdf]]) * FPGA Variable Block Adder ([[Media:VLSI.Arith.1.C.FPGA-VariableBlock.20220125.pdf |pdf]]) * FPGA Carry Lookahead Adder ([[Media:VLSI.Arith.1.D.FPGA-CLookahead.20210304.pdf |pdf]]) * Carry-Skip Adder </br> == Barrel Shifter == * Barrel Shifter Architecture Exploration ([[Media:bshift.20131105.pdf |bshfit.vhdl]], [[Media:bshift.makefile.20131109.pdf |bshfit.makefile]]) </br> '''Mux Based Barrel Shifter''' * Analysis ([[Media:Arith.BShfiter.20151207.pdf |pdf]]) * Implementation </br> == Multiplier == === Array Multipliers === * Analysis ([[Media:VLSI.Arith.1.A.Mult.20151209.pdf |pdf]]) </br> === Tree Mulltipliers === * Lattice Multiplication ([[Media:VLSI.Arith.LatticeMult.20170204.pdf |pdf]]) * Wallace Tree ([[Media:VLSI.Arith.WallaceTree.20170204.pdf |pdf]]) * Dadda Tree ([[Media:VLSI.Arith.DaddaTree.20170701.pdf |pdf]]) </br> === Booth Multipliers === * [[Media:RNS4.BoothEncode.20161005.pdf |Booth Encoding Note]] * Booth Multiplier Note ([[Media:BoothMult.20160929.pdf |H1.pdf]]) </br> == Divider == * Binary Divider ([[Media:VLSI.Arith.1.A.Divider.20131217.pdf |pdf]])</br> </br> </br> go to [ [[Electrical_%26_Computer_Engineering_Studies]] ] [[Category:Computer architecture]] 2l42szpt02kkyyz168lo832a2i38zgg 2408013 2408008 2022-07-19T14:42:48Z Young1lim 21186 /* Adder */ wikitext text/x-wiki {{nocat}} == Adder == * Binary Adder Architecture Exploration ( [[Media:adder.20131113.pdf |pdf]] ) {| class="wikitable" |- ! Adder type !! Overview !! Analysis !! VHDL Level Design !! CMOS Level Design |- | '''1. Ripple Carry Adder''' || [[Media:VLSI.Arith.1A.RCA.20211108.pdf |pdf]] || || [[Media:adder.rca.20140313.pdf |pdf]] || [[Media:VLSI.Arith.1D.RCA.CMOS.20211108.pdf |pdf]] |- | '''2. Carry Lookahead Adder''' || [[Media:VLSI.Arith.1.A.CLA.20211106.pdf |pdf]] || || [[Media:adder.cla.20140313.pdf |pdf]] || |- | '''3. Carry Save Adder''' || [[Media:VLSI.Arith.1.A.CSave.20151209.pdf |pdf]] || || || |- || '''4. Carry Select Adder''' || [[Media:VLSI.Arith.1.A.CSelA.20191002.pdf |pdf]] || || || |- || '''5. Carry Skip Adder''' || [[Media:VLSI.Arith.5A.CSkip.20211111.pdf |pdf]] || || || [[Media:VLSI.Arith.5D.CSkip.CMOS.20211108.pdf |pdf]] |- || '''6. Carry Chain Adder''' || [[Media:VLSI.Arith.6A.CCA.20211109.pdf |pdf]] || || [[Media:VLSI.Arith.6C.CCA.VHDL.20211109.pdf |pdf]], [[Media:adder.cca.20140313.pdf |pdf]] || [[Media:VLSI.Arith.6D.CCA.CMOS.20211109.pdf |pdf]] |- || '''7. Kogge-Stone Adder''' || [[Media:VLSI.Arith.1.A.KSA.20140315.pdf |pdf]] || || [[Media:adder.ksa.20140409.pdf |pdf]] || |- || '''8. Prefix Adder''' || [[Media:VLSI.Arith.1.A.PFA.20140314.pdf |pdf]] || || || |- || '''9. Variable Block Adder''' || [[Media:VLSI.Arith.1.A.VBA.20220719.pdf |pdf]] || || || |} </br> === Adder Architectures Suitable for FPGA === * FPGA Carry-Chain Adder ([[Media:VLSI.Arith.1.A.FPGA-CCA.20210421.pdf |pdf]]) * FPGA Carry Select Adder ([[Media:VLSI.Arith.1.B.FPGA-CarrySelect.20210522.pdf |pdf]]) * FPGA Variable Block Adder ([[Media:VLSI.Arith.1.C.FPGA-VariableBlock.20220125.pdf |pdf]]) * FPGA Carry Lookahead Adder ([[Media:VLSI.Arith.1.D.FPGA-CLookahead.20210304.pdf |pdf]]) * Carry-Skip Adder </br> == Barrel Shifter == * Barrel Shifter Architecture Exploration ([[Media:bshift.20131105.pdf |bshfit.vhdl]], [[Media:bshift.makefile.20131109.pdf |bshfit.makefile]]) </br> '''Mux Based Barrel Shifter''' * Analysis ([[Media:Arith.BShfiter.20151207.pdf |pdf]]) * Implementation </br> == Multiplier == === Array Multipliers === * Analysis ([[Media:VLSI.Arith.1.A.Mult.20151209.pdf |pdf]]) </br> === Tree Mulltipliers === * Lattice Multiplication ([[Media:VLSI.Arith.LatticeMult.20170204.pdf |pdf]]) * Wallace Tree ([[Media:VLSI.Arith.WallaceTree.20170204.pdf |pdf]]) * Dadda Tree ([[Media:VLSI.Arith.DaddaTree.20170701.pdf |pdf]]) </br> === Booth Multipliers === * [[Media:RNS4.BoothEncode.20161005.pdf |Booth Encoding Note]] * Booth Multiplier Note ([[Media:BoothMult.20160929.pdf |H1.pdf]]) </br> == Divider == * Binary Divider ([[Media:VLSI.Arith.1.A.Divider.20131217.pdf |pdf]])</br> </br> </br> go to [ [[Electrical_%26_Computer_Engineering_Studies]] ] [[Category:Computer architecture]] nndivlbodlvmgzosifupasmmtjrmr0s 0 169944 2408155 2406726 2022-07-20T10:38:59Z ThaniosAkro 2805358 /* Python Floats */ wikitext text/x-wiki =Objective= {{RoundBoxTop|theme=3}} [[file:Books-aj.svg_aj_ashton_01f.png|right|100px]] * Learn about Python integers. * Learn about non-decimal integers. * Learn about Python floats. * Learn about precision of floats. * Learn about Boolean algebra. (Booleans are a subclass of integers.<ref>http://docs.python.org/3.4/library/functions.html#bool</ref>) * Learn about [[Wikipedia:Complex number|complex numbers]] in Python. * Learn how to convert numbers into different basic data types. {{RoundBoxBottom}} =Lesson= {{RoundBoxTop|theme=2}} ==Data Types== This is the first of several lessons on the data types used by Python. Computer programs can process instructions that work with many different kinds of data, and the instructions need to be very precise. If you add a word to this sentence, 'add' means something very different from when you add 2 and 3. A computer language has to have a set of rules defining what operations can be applied to different kinds of data, and for this to work, there also has to be a set of rules defining exactly what data can be used with each operation. For example, if you want to calculate grossProfit = salesIncome - costs, a program has to know that these quantities are variables containing numbers rather than just strings of letters. They must have a numerical data type rather than string data type. If you are not clear about the meaning in computer science of variables and of data types, it may help to brush up on the lesson [[Introduction_to_Programming/Variables]]. ===Two useful Built-in Functions=== ====class type(object)==== With one argument, return the type of an object. <syntaxhighlight lang=Python> >>> type(6) <class 'int'> >>> >>> type(6.4) <class 'float'> >>> >>> type('6.4') <class 'str'> >>> >>> type(b'6.4') <class 'bytes'> >>> >>> type(['6.4']) <class 'list'> >>> </syntaxhighlight> ====isinstance(object, classinfo)==== Return true if the object argument is an instance of the classinfo argument. classinfo can be a tuple. isinstance() arg 2 must be a type or tuple of types. <syntaxhighlight lang=Python> >>> isinstance(6,int) True >>> >>> isinstance(6,str) False >>> >>> isinstance('6',str) True >>> >>> isinstance('6',(int,float,bytes)) False >>> >>> isinstance('6',(int,float,bytes,str)) True >>> >>> isinstance({},dict) True >>> >>> isinstance({3,4,5},set) True >>> >>> isinstance(b'',str) False >>> >>> isinstance(b'',bytes) True >>> </syntaxhighlight> {{RoundBoxBottom}} =Python Integers= {{RoundBoxTop|theme=2}} ==Introduction to integers== Python has several data types to represent numbers. This lesson introduces two: integers, and floating point numbers, or 'floats'. We'll discuss floats later in the lesson. An integer, commonly abbreviated to ''int'', is a whole number (positive, negative, or zero). So <code>7</code>, <code>0</code>, <code>-11</code>, <code>2</code>, and <code>5</code> are integers. <code>3.14159</code>, <code>0.0001</code>, <code>11.11111</code>, and even <code>2.0</code> are not integers, they are floats in Python. To test if this is true, we can use the <code>isinstance</code> built-in function to test if a number is or isn't an integer. <syntaxhighlight lang=python> >>> isinstance(7, int) True >>> isinstance(0, int) True >>> isinstance(-11, int) True >>> isinstance(2, int) True >>> isinstance(5, int) True >>> isinstance(3.14159, int) False >>> isinstance(0.0001, int) False >>> isinstance(11.11111, int) False >>> isinstance(2.0, int) False </syntaxhighlight> A decimal integer contains one or more digits "0" ... "9". Underscores may be used to improve readability. With one exception described in floats below, leading zeros in a non-zero decimal number are not allowed. We can perform simple mathematical operations with integers, like addition (<code>+</code>), subtraction (<code>-</code>), multiplication (<code>*</code>), and division (<code>/</code>). Here are some examples using simple math. <syntaxhighlight lang=Python> >>> 2+2 4 >>> 4-2 2 >>> 6+1 7 >>> 6+7-3 10 >>> 2*2 4 >>> 2*2*2 8 >>> -2 -2 >>> 8/2 4.0 >>> 4*4/2 8.0 >>> 4-4*2 -4 >>> 2-4 -2 >>> 10+10/2 15.0 </syntaxhighlight> You should have noticed three things in the above example. First, all mathematical operations follow an [[Wikipedia:Order of operations|order of operations]], called precedence; multiplication and division are done first, then addition and subtraction are performed, hence why <code>10+10/2</code> didn't result in <code>10.0</code>. Secondly, when you divide, a float is always the result. Lastly, by putting a minus sign (<code>-</code>) in front of a number, it will become a negative number. You can do more mathematical operations than the previously demonstrated ones. We can perform a ''floor division'' by using two forward slashes (<code>//</code>) to divide and have the result as an integer. <syntaxhighlight lang=python> >>> 4 // 2 2 >>> 1 // 8 0 >>> 5 // 5 1 >>> 100 // 5 20 >>> 4 // 3 1 </syntaxhighlight> Now, that may save us trouble, but what if we want to get '''just''' the [[Wikipedia:Remainder|''remainder'']] of a division? We can perform a [[Wikipedia:Modulo operation|modulo operation]] to get the remainder. To perform a modulo, use a percent sign (<code>%</code>). <syntaxhighlight lang=python> >>> 5 % 4 1 >>> 1 % 4 1 >>> 4 % 4 0 >>> 2 % 4 2 >>> 2 % 1 0 >>> 20 % 2 0 >>> 20 % 3 2 >>> -20 % 3 1 </syntaxhighlight> The <code>divmod()</code> built-in function returns both quotient and remainder: <syntaxhighlight lang=python> >>> divmod(7,3) (2, 1) >>> (q,r) = divmod(7,3) >>> q; r 2 1 </syntaxhighlight> You can also find the power of a number by using two asterisk symbols (<code>**</code>). <syntaxhighlight lang=python> >>> 4 ** 2 16 >>> 4 ** 4 256 >>> 1 ** 11278923689 1 >>> 2 ** 4 16 >>> 10 ** 2 100 >>> 1024 ** 2 1048576 >>> 10 ** 6 1000000 >>> 25 ** (-1/2) 0.2 >>> 4 * - 3 ** 2 -36 >>> 4 * (- 3) ** 2 36 >>> 8 / 4 ** 2 0.5 </syntaxhighlight> The operator of exponentiation <code>(**)</code> has higher precedence than <code>*</code> or <code>/</code> or unary <code>-.</code> If unsure of precedence, you can always use parentheses to force the desired result: <syntaxhighlight lang=python> >>> (4 * (- 3)) ** 2 ; 4 * ((- 3) ** 2) 144 36 >>> </syntaxhighlight> There is no limit for the length of integer literals apart from what can be stored in available memory. ==Non-decimal Integers== Almost everyone is familiar with ten based numbers. While base 10 is useful for everyday tasks, it isn't ideal for use in the computer world. Three other numeral systems are commonly used in computer science; binary, octal, and hexadecimal. We'll lightly cover Python's use of these in this section. The binary system is essential as all information is represented in binary form in computer hardware. Octal and hexadecimal are convenient for condensing binary numbers to a form that is more easily read by humans, while (unlike decimal) being simple to translate to or from binary. If you have difficulty with this part of the lesson, it may help to brush up on the lesson [[Numeral_systems]] in the course [[Introduction_to_Computers]]. Most people have heard of binary and it is often associated with computers. Actually, modern binary made its way into the world far before electricity was widely in use. The binary system is 2 based, which means that only two numbers are used. Of course, these numbers are 0 and 1. So <math>1+1=10_2,</math> unlike the decimal's <math>1+1=2_{10}.</math> To use binary numbers in python, prepend <code>0B</code> or <code>0b</code> to the number.<ref>https://docs.python.org/3/reference/lexical_analysis.html#integer-literals</ref> <syntaxhighlight lang=python> >>> 0B11 3 >>> 0B1 + 0B1 2 >>> 0B11 + 0B1 4 >>> 0B10001 + 0B1 18 >>> 0B10001 - 0B1 16 >>> bin(2345) '0b100100101001' >>> 0b_111_0101_0011 1875 </syntaxhighlight> The value returned by <code>bin()</code> is a string. The underscore <code>(_)</code> may be used to make numbers more readable. {{Note|'''Note:''' In computers, a binary digit of information is called a [[Wikipedia:Bit|bit]].}} The octal numeral system is something that really isn't used anymore, since it was superseded by hexadecimal. The octal system made sense decades ago when hardware was expensive, because the 8 based system can fit into three [[Wikipedia:Bit|bits]] perfectly. Though this scheme fits into bits, it does not fit into a [[Wikipedia:Byte|standard byte]], which is 8 ''bits''. Since the octal numeral system is 8 based, you can only use numbers "0"..."7". To use octal numbers in python, prepend <code>0o</code> or <code>0O</code> to the beginning of the number.<ref>https://docs.python.org/3/reference/lexical_analysis.html#integer-literals</ref> You may find it easier to use a lowercase o instead of an uppercase O, since it could be confused as a zero. <syntaxhighlight lang=python> >>> 0o3 3 >>> 0o12 10 >>> 0o12 + 0o10 18 >>> 0o12 - 0o03 7 >>> 0o100 64 >>> 0o777 511 >>> 0o777 - 0o111 438 >>> oct(1_234_987) '0o4554053' >>> 0o_1234_9876 File "<stdin>", line 1 0o_1234_9876 ^ SyntaxError: invalid token >>> 0o_1234_0765 2736629 </syntaxhighlight> The hexadecimal numeral system is widely used when working with computers, because one hexadecimal digit can fit into a [[Wikipedia:Nibble|nibble]] (4 bits). Since a standard ''byte'' is 8 bits, two nibbles could perfectly fit into a byte, hence why the ''octal'' system is rather obsolete. Hexadecimal has 16 digits, which consist of "0"..."9" and "A"..."F" or "a"..."f". "Letters as numbers?", you may say. Indeed, it may be tricky working with letters as numbers, but once you get comfortable with them, it will be easy to use. To use hexadecimal numbers in python, prepend <code>0x</code> or <code>0X</code> to the beginning of the number.<ref>https://docs.python.org/3/reference/lexical_analysis.html#integer-literals</ref> I suggest using a lowercase x, since it is easier to distinguish from the numbers and uppercase letters. <syntaxhighlight lang=python> >>> 0xF 15 >>> 0xF0 240 >>> 0xFF - 0xF 240 >>> 0xF + 0xA 25 >>> 0x2 + 0x2 4 >>> 0x12 - 0xA 8 >>> 0xFF / 0xF 17.0 >>> 0xF * 0xF 225 >>> hex(1_234_987) '0x12d82b' >>> 0x_12_D82B 1234987 </syntaxhighlight> {{Note|'''Note:''' You '''do not''' have to use just uppercase letters when working with hexadecimal, you can also use lowercase letters if you find it easier.}} This topic has been lightly brushed up on and will probably not be used until later in advanced lessons. If you feel a need to learn this, or you want to be proficient at it, the course [[Introduction to Computers]] has a lesson called [[Numeral systems]] that deals with these numeral systems with a little more in depth teaching. ===Bitwise Operators=== All integers may be tested or modified by the [https://docs.python.org/3/library/stdtypes.html#bitwise-operations-on-integer-types Bitwise Operators]: <code>&</code> (and), <code>|</code> (or), <code>^</code> (exclusive or), <code><<</code> (shift left), <code>>></code> (shift right) and <code>~</code> (invert). However it makes good sense to confine our description of these operators to non-decimal integers, particularly binary and hexadecimal. These operators are called 'bitwise' because they operate on individual bits within the integer. 1. The <code>&</code> operator produces a true output when both corresponding bits are true: <syntaxhighlight lang=python> >>> bin (0b1010101 & 0b1111) '0b101' >>> bin (0b1010101 & 0b111000) '0b10000' >>> hex (0xFF00FF & 0xFF00) '0x0' </syntaxhighlight> In the first example both input operands <syntaxhighlight lang=python> 0b1010101 0b 1111 ^ ^ </syntaxhighlight> have the marked bits set and the result is <code>'0b101'.</code> 2. The <code>|</code> operator produces a true output when at least one of both corresponding bits is true: <syntaxhighlight lang=python> >>> bin (0b1010101 | 0b1110) '0b1011111' >>> bin (0b1010101 | 0b1100) '0b1011101' >>> hex (0xFF00FF | 0x3F0) '0xff03ff' </syntaxhighlight> In the first example both input operands <syntaxhighlight lang=python> 0b1010101 0b 1110 ^ ^^^^^ </syntaxhighlight> have the marked bits set in at least one of the operands and the result is <code>'0b1011111'.</code> 3. The <code>^</code> operator produces a true output when exactly one of both corresponding bits is true: <syntaxhighlight lang=python >>> bin (0b1010101 ^ 0b1110) '0b1011011' >>> bin (0b1010101 ^ 0b1100) '0b1011001' >>> hex (0xFF00FF ^ 0x3F0) '0xff030f' </syntaxhighlight> In the first example both input operands <syntaxhighlight lang=python> 0b1010101 0b 1110 ^ ^^ ^^ </syntaxhighlight> have the marked bits set in exactly one of the operands and the result is <code>'0b1011011'.</code> 4. The <code> << </code> operator shifts the operand left by the number of bits specified: <syntaxhighlight lang=python >>> bin(0b10101 << 2) '0b1010100' >>> bin(0b10101 << 5) '0b1010100000' >>> hex(0xFF00FF << 8) '0xff00ff00' >>> (0xFF00FF << 8) == (0xFF00FF * 2**8) True </syntaxhighlight> In the first example the output is the input shifted left 2 bits: <syntaxhighlight lang=python> 0b 10101 0b1010100 ^^ </syntaxhighlight> The ouput is the input with two 0's at the right hand end. 5. The <code> >> </code> operator shifts the operand right by the number of bits specified: <syntaxhighlight lang=python >>> bin(0b10101 >> 2) '0b101' >>> bin(0b10101 >> 5) '0b0' >>> hex(0xFF00FF >> 8) '0xff00' >>> (0xFF00FF >> 8) == (0xFF00FF // 2**8) True </syntaxhighlight> In the first example the output is the input shifted right 2 bits: <syntaxhighlight lang=python> 0b10101 0b 101 </syntaxhighlight> The rightmost two bits of the input are lost forever. If you wish to preserve the 2 rightmost bits of the input, before shifting execute: <syntaxhighlight lang=python> twoBits = operand & 0x3 </syntaxhighlight> The bitwise operators above perform as expected on all integers of (almost) unlimited length: <syntaxhighlight lang=python> >>> hex( ( 0x1234_FEDC << 120 ) | ( 0x_CDE_90AB << 60 ) ) '0x1234fedc00000000cde90ab000000000000000' >>> hex( ( 0x1234_FEDC << 200 ) ^ ( 0x_CDE_90AB << 207 ) ) '0x67d7cab5c00000000000000000000000000000000000000000000000000' </syntaxhighlight> 6. The behavior of the invert (~) operator shows that negative numbers are treated as their 2’s complement value: <syntaxhighlight lang=Python> >>> a = 0b1100101100101 ; bin(~a) '-0b1100101100110' </syntaxhighlight> For a true 1's complement bitwise invert here is one way to do it: <syntaxhighlight lang=Python> >>> a = 0b1100101100101 ; b = a ^ ( (1 << a.bit_length()) - 1 ); bin(b) '0b11010011010' >>> c = a + b; bin(c) '0b1111111111111' # to test the operation, all bits of c should be set. >>> (c+1) == ( 1 << (c.bit_length()) ) True # they are. </syntaxhighlight> And another way to do it: <syntaxhighlight lang=python> from decimal import * a = 0b11100100011001110001010111 # a is int b = bin(a) # b is string print ('a =', b) formerPrecision = getcontext().prec getcontext().prec = a.bit_length() d = Decimal.logical_invert( Decimal( b[2:] ) ) # d is Decimal object. getcontext().prec = formerPrecision print ('d =', d) e = int(str(d),2) # e is int print ('e =', bin(e)) ( (a + e) == ( ( 1 << a.bit_length() ) - 1 ) ) and print ('successful inversion') </syntaxhighlight> When you execute the above code, you see the following results: <syntaxhighlight lang=python> a = 0b11100100011001110001010111 d = 11011100110001110101000 e = 0b11011100110001110101000 successful inversion </syntaxhighlight> The Decimal.logical_invert() performs a 1's complement inversion. {{RoundBoxBottom}} =Python Floats= ==Introduction to floats== {{RoundBoxTop|theme=5}} Although integers are great for many situations, they have a serious limitation, integers are [[Wikipedia:Natural number|whole numbers]]. This means that they do not include all [[Wikipedia:Real number|real numbers]]. A ''real number'' is a value that represents a quantity along a continuous line<ref>[[Wikipedia:Real number]]</ref>, which means that it can have fractions in decimal forms. <code>4.5</code>, <code>1.25</code>, and <code>0.75</code> are all real numbers. In computer science, real numbers are represented as floats. To test if a number is float, we can use the <code>isinstance</code> built-in function. <syntaxhighlight lang=python> >>> isinstance(4.5, float) True >>> isinstance(1.25, float) True >>> isinstance(0.75, float) True >>> isinstance(3.14159, float) True >>> isinstance(2.71828, float) True >>> isinstance(1.0, float) True >>> isinstance(271828, float) False >>> isinstance(0, float) False >>> isinstance(0.0, float) True </syntaxhighlight> As a general rule of thumb, floats have a ''[[Wikipedia:Decimal mark|decimal point]]'' and integers do not have a ''decimal point''. So even though <code>4</code> and <code>4.0</code> are the same number, <code>4</code> is an integer while <code>4.0</code> is a float. The basic arithmetic operations used for integers will also work for floats. (Bitwise operators will not work with floats.) <syntaxhighlight lang=python> >>> 4.0 + 2.0 6.0 >>> -1.0 + 4.5 3.5 >>> 1.75 - 1.5 0.25 >>> 4.13 - 1.1 3.03 >>> 4.5 // 1.0 4.0 >>> 4.5 / 1.0 4.5 >>> 4.5 % 1.0 0.5 >>> 7.75 * 0.25 1.9375 >>> 0.5 * 0.5 0.25 >>> 1.5 ** 2.0 2.25 </syntaxhighlight> {{RoundBoxBottom}} ==Some technical information about 'floats.'== A floating point literal can be either pointfloat or exponentfloat. A pointfloat contains a decimal point <code>(".")</code> and at least one digit <code>("0"..."9"),</code> for example: <code>34.45 ; 34. ; .45 ; 0. ; -.00 ; -33. ;</code> An exponentfloat contains an exponent which <code>::= ("e" | "E")["+" | "-"]decinteger.</code> <code>("e" | "E")</code> means that <code>"e"</code> or <code>"E"</code> is required. <code>["+" | "-"]</code> means that <code>"+"</code> or <code>"-"</code> is optional. <code>decinteger</code> means decimal integer. <code></code><code></code> These are examples of exponents: <code>e9 ; e-0 ; e+1 ; E2 ; E-3 ; E+4 ;</code> The exponent is interpreted as follows: <math>.5e2 = .5(10^2) = 50.0;</math> <math>-3E1 = -3.0(10^1) = -30.0;</math> <math>.003e-5 = .003(10^{-5}) = 3e-08;</math> <math>3e0 = 3.0(10^{0}) = 3.0;</math> <math>0090.5e-02 = 90.5(10^{-2}) = 0.905;</math> <math>0E0 = 0.0(10^0) = 0.0;</math> An exponent float can be either: decinteger exponent, for example: <code>0e0 ; -3e1 ; 15E-6 ;</code> or pointfloat exponent, for example: <code>.5E+2 ; -3.00e-5 ; 123_456.75E-5 ;</code> The separate parts of a floating point number are: <code>1.2345 = 12345e-4 = </code> <math>\underbrace{12345}_\text{significand} \times \underbrace{10}_\text{base}\!\!\!\!\!\!^{\overbrace{-4}^\text{exponent}}.</math> <ref>https://en.wikipedia.org/wiki/Floating-point_arithmetic#Floating-point_numbers</ref> The <code>significand</code> may be called <code>mantissa</code> or <code>coefficient.</code> The <code>base</code> may be called <code>radix.</code> The <code>exponent</code> may be called <code>characteristic</code> or <code>scale.</code> Within the floating point literal white space is not permitted. An underscore <code>("_")</code> may be used to improve readability. Integer and exponent parts are always interpreted using radix <code>10.</code> Within the context of floating point literals, a "decinteger" may begin with a <code>"0".</code> Numeric literals do not include a sign; a phrase like <code>-1</code> is actually an expression composed of the unary operator <code>-</code> and the literal <code>1.</code> ===sys.float_info=== Object <code>sys.float_info</code> contains information about floats: <syntaxhighlight lang=python> >>> import sys >>> print ( '\n'.join(str(sys.float_info).split(', ')) ) sys.float_info(max=1.7976931348623157e+308 # maximum representable finite float max_exp=1024 max_10_exp=308 min=2.2250738585072014e-308 # minimum positive normalized float min_exp=-1021 min_10_exp=-307 dig=15 # maximum number of decimal digits that can be faithfully represented in a float mant_dig=53 # float precision: the number of base-radix digits in the significand of a float epsilon=2.220446049250313e-16 radix=2 # radix of exponent representation rounds=1) >>> </syntaxhighlight> Information about some of the above values follows: ====sys.float_info.mant_dig==== <syntaxhighlight lang=python> >>> sys.float_info.mant_dig 53 >>> >>> sys.float_info[7] 53 >>> >>> I1 = (1<<53) - 1 ; I1 ; hex(I1) ; I1.bit_length() 9007199254740991 '0x1fffffffffffff' 53 >>> float(I1-1) ; float(I1-1) == I1-1 9007199254740990.0 True >>> float(I1) ; float(I1) == I1 9007199254740991.0 True >>> float(I1+1) ; float(I1+1) == I1+1 9007199254740992.0 True >>> float(I1+2) ; float(I1+2) == I1+2 9007199254740992.0 # Loss of precision occurs here. False >>> >>> I2 = I1 - 10**11 ; I2 ; hex(I2) ; I2.bit_length() ; float(I2) == I2 ; len(str(I2)) 9007099254740991 '0x1fffe8b78917ff' 53 True # I2 can be accurately represented as a float. 16 >>> I3 = I1 + 10**11 ; I3 ; hex(I3) ; I3.bit_length() ; float(I3) == I3 ; len(str(I3)) 9007299254740991 '0x2000174876e7ff' 54 # Too many bits. False # I3 can not be accurately represented as a float. 16 >>> </syntaxhighlight> ====sys.float_info.dig==== <syntaxhighlight lang=python> >>> len(str(I1)) 16 >>> >>> sys.float_info.dig 15 >>> sys.float_info[6] 15 >>> </syntaxhighlight> As shown above some (but not all) decimal numbers of 16 digits can be accurately represented as a float. Hence 15 as the limit in <code>sys.float_info.dig</code>. ====sys.float_info.max==== <syntaxhighlight lang=python> >>> sys.float_info.max 1.7976931348623157e+308 >>> >>> sys.float_info[0] 1.7976931348623157e+308 >>> >>> 1.7976931348623157e+305 1.7976931348623156e+305 >>> 1.7976931348623157e+306 1.7976931348623156e+306 >>> 1.7976931348623157e+307 1.7976931348623158e+307 >>> 1.7976931348623157e+308 1.7976931348623157e+308 >>> 1.7976931348623157e+309 inf >>> </syntaxhighlight> ====sys.float_info.min==== <syntaxhighlight lang=python> >>> sys.float_info.min 2.2250738585072014e-308 >>> sys.float_info[3] 2.2250738585072014e-308 >>> >>> 2.2250738585072014e-306 2.2250738585072014e-306 >>> 2.2250738585072014e-307 2.2250738585072014e-307 >>> 2.2250738585072014e-308 2.2250738585072014e-308 >>> 2.2250738585072014e-309 2.225073858507203e-309 # Loss of precision. >>> 2.2250738585072014e-310 2.2250738585072e-310 >>> 2.2250738585072014e-311 2.225073858507e-311 >>> </syntaxhighlight> ==The Precision of Floats== Before you start calculating with floats you should understand that the precision of floats has limits, due to Python and the architecture of a computer. Some examples of errors due to finite precision are displayed below. <syntaxhighlight lang=Python> >>> 1.13 - 1.1 0.029999999999999805 >>> 0.001 / 11.11 9.000900090009002e-05 >>> 1 + .0000000000000001 1.0 >>> -5.5 % 3.2 0.9000000000000004 >>> float(1_234_567_890_123_456) 1234567890123456.0 >>> float(12_345_678_901_234_567) 1.2345678901234568e+16 </syntaxhighlight> In the first example, <code>1.13 - 1.1 = 0.03</code>, although Python comes to the conclusion that the real answer is <code>0.029999999999999805</code>. The fact behind this reasoning is based on how the computer stores memory, so the ''[[Wikipedia:Subtraction|difference]]'' lost a little of its precision. As the ''minuend'' increases in size, so does its precision. <code> 2.13 - 1.1 = 1.0299999999999998 </code> and <code>3.13 - 1.1 = 2.03</code>. In the second example, <code>0.001 / 11.11 = 9.000900090009002e-05</code> where <code>e-05</code> means ten to the power of negative five. The answer could also be <code>9.000900090009001e-05</code> depending on how the ''[[Wikipedia:Quotient|quotient]]'' is rounded, how long the quotient can be stored on the computer, and the most significant number on the right hand side. In the third example, the ''[[Wikipedia:Addition|sum]]'' of the ''addends'' <code>1 + .0000000000000001 = 1.0</code> although we know that it really is <code>1 + .0000000000000001 = 1.0000000000000001</code>. The reason the second addend is left out is because of its insignificance. Although this might not matter for every day situations, it may be important for such uses as rocket science and possibly calculus. The fourth example gives the correct result if rewritten: <syntaxhighlight lang=Python> >>> ((-5.5*10 ) % (3.2*10)) / 10.0 0.9 </syntaxhighlight> When working with Python floats, we need to be aware that there will probably be a margin of error. ==Decimal fixed point and floating point arithmetic for extreme precision== The Python [https://docs.python.org/3/library/decimal.html#module-decimal "Decimal"] module provides support for fast correctly-rounded decimal floating point arithmetic. The module offers several advantages over the float datatype, including: * Decimal numbers can be represented exactly. * The decimal module has a user alterable precision (defaulting to 28 places) which can be as large as needed for a given problem. The usual start to using decimals is importing the module, viewing the current context with getcontext() and, if necessary, setting new values for precision, rounding, or enabled traps: <syntaxhighlight lang=Python> >>> from decimal import * >>> getcontext() Context(prec=28, rounding=ROUND_HALF_EVEN, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[Inexact, FloatOperation, Rounded], traps=[InvalidOperation, DivisionByZero, Overflow]) >>> setcontext(ExtendedContext) >>> getcontext() Context(prec=9, rounding=ROUND_HALF_EVEN, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[], traps=[]) >>> setcontext(BasicContext) >>> getcontext() Context(prec=9, rounding=ROUND_HALF_UP, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[], traps=[Clamped, InvalidOperation, DivisionByZero, Overflow, Underflow]) >>> c = getcontext() >>> c.flags[Inexact] = True >>> c.flags[FloatOperation] = True >>> c.flags[Rounded] = True >>> getcontext() Context(prec=9, rounding=ROUND_HALF_UP, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[Inexact, FloatOperation, Rounded], traps=[Clamped, InvalidOperation, DivisionByZero, Overflow, Underflow]) >>> getcontext().prec = 75 # set desired precision >>> getcontext() Context(prec=75, rounding=ROUND_HALF_UP, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[Inexact, FloatOperation, Rounded], traps=[Clamped, InvalidOperation, DivisionByZero, Overflow, Underflow]) </syntaxhighlight> We are now ready to use the decimal module. <syntaxhighlight lang=Python> >>> Decimal(3.14) # Input to decimal() is float. Decimal('3.140000000000000124344978758017532527446746826171875') # Exact value of float 3.14. >>> Decimal('3.14') # Input to decimal() is string. Decimal('3.14') # Exact value of 3.14 in decimal floating point arithmetic. </syntaxhighlight> <math>(\sqrt{2})^2</math> <syntaxhighlight lang=Python> >>> (2 ** 0.5)**2 2.0000000000000004 # Result of binary floating point operation. We expect 2. >>> (Decimal('2') ** Decimal('0.5')) ** Decimal('2') Decimal('1.99999999999999999999999999999999999999999999999999999999999999999999999999') # Result of decimal floating point operation with string input. We expect 2. </syntaxhighlight> <math>(2.12345678^{(\frac{1}{2.345})})^{2.345}</math> <syntaxhighlight lang=Python> >>> (2.12345678 ** (1/2.345)) ** 2.345 2.1234567800000006 # Result of floating point operation. We expect 2.12345678. >>> (Decimal('2.12345678') ** (Decimal('1')/Decimal('2.345'))) ** Decimal('2.345') Decimal('2.12345677999999999999999999999999999999999999999999999999999999999999999999') # Result of decimal floating point operation with string input . We expect 2.12345678. >>> getcontext().rounding=ROUND_UP >>> (Decimal('2.12345678') ** (Decimal('1')/Decimal('2.345'))) ** Decimal('2.345') Decimal('2.12345678000000000000000000000000000000000000000000000000000000000000000003') # Result of decimal floating point operation with string input . We expect 2.12345678. </syntaxhighlight> Some mathematical functions are also available to Decimal: <syntaxhighlight lang=Python> >>> getcontext().prec = 30 >>> Decimal(2).sqrt() Decimal('1.41421356237309504880168872421') >>> (Decimal(2).sqrt())**2 Decimal('2.00000000000000000000000000001') # We expect 2. >>> Decimal(1).exp() Decimal('2.71828182845904523536028747135') # Value of 'e', base of natural logs. >>> Decimal( Decimal(1).exp() ).ln() Decimal('0.999999999999999999999999999999') # We expect 1. </syntaxhighlight> ==Lack of precision in the real world== (included for philosophical interest) <syntaxhighlight lang=Python> >>> a = 899_999_999_999_999.1 ; a - (a - .1) 0.125 >>> 1.13 - 1.1 0.029999999999999805 </syntaxhighlight> Simple tests indicate that the error inherent in floating point operations is about <math>\frac{1}{10^{16}}.</math> This raises the question "How much precision do we need?" For decades high school students calculated sines and cosines to 4 decimal places by referring to printed look-up tables. Before computers engineers used slide rules to make calculations accurate to about <math>\frac{1}{1000}</math> for most calculations, and the Brooklyn Bridge is still in regular use. With accuracy of <math>\frac{1}{10^{16}}</math> engineers can send a rocket to Pluto and miss by 1cm. If your calculations produce a result of <math>1.0(10^{-14})</math> and you were expecting <math>0,</math> will you be satisfied with your work? If your calculations were in meters, probably yes. If your calculations were in nanometers (<math>10^{-9}</math> of a meter), probably no. Knowing that lack of precision is inherent in floating point operations, you may have to include possibly substantial amounts of code to make allowances for it. ==Extreme Precision== (included for historical interest) If you must have a result correct to 50 places of decimals, Python's integer math comes to the rescue. Suppose your calculation is: <math>123456.789 / 4567.87654 </math> <math>= \frac{123456.789 }{4567.87654 } </math> <math>= \frac{123456.78900 }{4567.87654 }</math> <math>= \frac{12345678900 }{456787654 }.</math> For 50 significant digits after the decimal point your calculation becomes: <math>123456.789 / 4567.87654 </math> <math>= \frac{12345678900(10^{51}) }{456787654(10^{51}) }</math> <math>= \frac{12345678900(10^{51}) }{456787654 }/10^{51}.</math> <syntaxhighlight lang=python> >>> dividend = 12345678900 >>> divisor = 456787654 >>> >>> (quotient, remainder) = divmod(dividend*(10**51), divisor) ; quotient;remainder 27027172892899596625262555804540198890751981663672547 231665262 >>> if remainder >= ((divisor + (divisor & 1)) >> 1) : quotient += 1 ... >>> quotient 27027172892899596625262555804540198890751981663672548 >>> </syntaxhighlight> The correct result <math>= 27027172892899596625262555804540198890751981663672548(10^{-51}),</math> but note: <syntaxhighlight lang=python> >>> quotient*(10**(-51)) 27.027172892899596 # Lack of precision. >>> </syntaxhighlight> Put the decimal point in the correct position within a string to preserve precision: <syntaxhighlight lang=python> >>> str(quotient)[0:-51] + '.' + str(quotient)[-51:] '27.027172892899596625262555804540198890751981663672548' >>> </syntaxhighlight> Format the result: <syntaxhighlight lang=python> >>> s1 = str(quotient)[-51:] ; s1 '027172892899596625262555804540198890751981663672548' >>> L2 = [ s1[p:p+5] for p in range(0,51,5) ] ; L2 ['02717', '28928', '99596', '62526', '25558', '04540', '19889', '07519', '81663', '67254', '8'] >>> decimal = '_'.join(L2) ; decimal '02717_28928_99596_62526_25558_04540_19889_07519_81663_67254_8' >>> str(quotient)[0:-51] + '.' + decimal '27.02717_28928_99596_62526_25558_04540_19889_07519_81663_67254_8' # The result formatted for clarity and accurate to 50 places of decimals. >>> </syntaxhighlight> Both strings <code>'27.027172892899596625262555804540198890751981663672548'</code> and <code>'27.02717_28928_99596_62526_25558_04540_19889_07519_81663_67254_8'</code> are acceptable as input to Python's Decimal module. ==Lack of precision and what to do about it== Lack of precision in floating point operations quickly becomes apparent: <syntaxhighlight lang=python> sum = 0 increment = 0.000_000_000_1 for count in range(1,1000) : sum += increment print ('count= {}, sum = {}'.format(count,sum)) if sum != count/10_000_000_000 : break </syntaxhighlight> <pre> count= 1, sum = 1e-10 count= 2, sum = 2e-10 count= 3, sum = 3e-10 count= 4, sum = 4e-10 count= 5, sum = 5e-10 count= 6, sum = 6e-10 count= 7, sum = 7e-10 count= 8, sum = 7.999999999999999e-10 </pre> The problem seems to be that floating point numbers are contained in 53 bits, limiting the number of significant digits in the decimal number displayed to 15 or 16. But this is not really the problem. If the standard limits the number of significant digits displayed to 15 or 16, so be it. The real problem is that underlying calculations are also performed in 53 bits. <syntaxhighlight lang=python> >>> (0.000_000_000_1).hex() '0x1.b7cdfd9d7bdbbp-34' >>> h1 = '0x1b7cdfd9d7bdbbp-86' # increment with standard precision. >>> float.fromhex(h1) 1e-10 >>> </syntaxhighlight> ===Precision greater than standard=== {{RoundBoxTop|theme=2}} Rewrite the above code so that the value <code>increment</code> has precision greater than standard. <code>increment</code><math> = \frac{1}{10^{10}} = \frac{x}{16^{26}};\ x = \frac{16^{26}}{10^{10}}</math> <syntaxhighlight lang=python> >>> x,r = divmod (16**26,10**10) ;x;r 2028240960365167042394 7251286016 >>> x += (r >= (10**10)/2);x 2028240960365167042395 >>> h1 = hex(x)[2:].upper();h1 '6DF37F675EF6EADF5B' >>> increment = '0x' + h1 + 'p-104' ; increment '0x6DF37F675EF6EADF5Bp-104' # Current value of increment. >>> int(increment[:-5],16).bit_length() 71 # Greater precision than standard by 18 bits. >>> float.fromhex(increment) 1e-10 >>> </syntaxhighlight> Exact value of increment: <syntaxhighlight lang=python> >>> from decimal import * >>> Decimal(x) / Decimal(16**26) Decimal('1.0000_0000_0000_0000_0000_01355220626007433600102690740628157139990861423939350061118602752685546875E-10') >>> # 22 significant digits. </syntaxhighlight> <syntaxhighlight lang=python> sum = '0x0p0' for count in range(1,1000) : hex_val = sum.partition('p')[0] sum = hex( eval(hex_val) + x ) + 'p-104' f1 = float.fromhex(sum) print ( 'count = {}, sum = {}, sum as float = {}'.format(count, sum, f1) ) if f1 != count/10_000_000_000 : exit(99) </syntaxhighlight> <pre> count = 1, sum = 0x6df37f675ef6eadf5bp-104, sum as float = 1e-10 count = 2, sum = 0xdbe6fecebdedd5beb6p-104, sum as float = 2e-10 count = 3, sum = 0x149da7e361ce4c09e11p-104, sum as float = 3e-10 ........................... count = 997, sum = 0x1ac354f2d94d7a0b7dd67p-104, sum as float = 9.97e-08 count = 998, sum = 0x1aca342acfc3697a2bcc2p-104, sum as float = 9.98e-08 count = 999, sum = 0x1ad11362c63958e8d9c1dp-104, sum as float = 9.99e-08 </pre> Consider the last line above: <code>count = 999, sum = 0x1ad11362c63958e8d9c1dp-104, f1 = 9.99e-08</code>. The most accurate hex representation of value <code>9.99e-08</code> with this precision is in fact <code>'0x1ad11362c63958e8d9b0ap-104'</code> different from the above value by <code>'0x113p-104'</code>. If counting continues, drift increases but, as a fraction of sum, it remains fairly constant, apparently enabling accurate counting up to and including the theoretical limit of floats (15 decimal digits.) <pre> drift vvv count = 999, sum = 0x1ad11362c63958e8d9c1dp-104, sum as float = 9.99e-08 0x1AD11362C63958E8D9B0Ap-104 most accurate hex representation of sum as float ^^^^^^^^^^^^^^^^^^ 18 hex digits = 69 bits drift vvvvv count = 99999, sum = 0xa7c53e539be0252c255b85p-104, sum as float = 9.9999e-06 0xA7C53E539BE0252C24F026p-104 most accurate hex representation of sum as float ^^^^^^^^^^^^^^^^^ 17 hex digits = 68 bits drift vvvvvvvv count = 9999999999, sum = 0xffffffff920c8098a1aceb2ca5p-104, sum as float = 0.9999999999 0xFFFFFFFF920C8098A1091520A5p-104 most accurate hex representation of sum as float ^^^^^^^^^^^^^^^^^^ 18 hex digits = 72 bits drift 15 decimal digits vvvvvvvvvvvvv count = 999999999999999, sum = 0x1869fffffffff920c81929f8524a0a5p-104, sum as float = 99999.9999999999 0x1869FFFFFFFFF920C8098A1091520A5p-104 most accurate hex representation of sum as float ^^^^^^^^^^^^^^^^^^ 18 hex digits = 69 bits </pre> {{RoundBoxTop|theme=2}} Exact value of sum: <syntaxhighlight lang=python> >>> from decimal import * >>> getcontext().prec=150 >>> >>> top = Decimal(0x1869fffffffff920c81929f8524a0a5); top Decimal('2028240960365165014154039634832957605') >>> bottom = Decimal(1<<104); bottom Decimal('20282409603651670423947251286016') >>> >>> d1 = top/bottom; d1 # Exact value of sum. Decimal('99999.99999999990000001355220626007432244882064733194557037300120795782210070257178813335485756397247314453125') >>> len(str(d1)) 110 >>> float(d1) 99999.9999999999 </syntaxhighlight> {{RoundBoxBottom}} While floating point operations implemented in software might not depend on conversion to and from hex strings, the above illustrates the accuracy that could be obtained if floating point software of selectable precision were to replace now antiquated floating point hardware. Python's decimal module allows floating point calculations of (almost) infinite precision, but importing a special module to perform a calculation like <math>1.13 - 1.1</math> seems onerous. <syntaxhighlight lang=python> >>> 1.13 - 1.1 0.029999999999999805 >>> </syntaxhighlight> In a programming language as magnificent as Python, the above result is intolerable. {{RoundBoxBottom}} ===Python's Decimal module=== {{RoundBoxTop|theme=2}} With a few simple changes the above counting loop takes full advantage of Python's Decimal module, and possible loss of precision becomes irrelevant. <syntaxhighlight lang=python> from decimal import * def D(v1) : return Decimal(str(v1)) sum = 0 increment = D(0.000_000_000_1) for count in range(1,1000) : sum += increment print ('count = {}, sum = {}'.format(count,sum)) if sum != count * increment : exit (99) exit (0) </syntaxhighlight> <pre> count = 1, sum = 1E-10 count = 2, sum = 2E-10 count = 3, sum = 3E-10 ................. count = 997, sum = 9.97E-8 count = 998, sum = 9.98E-8 count = 999, sum = 9.99E-8 </pre> A float is displayed with 'e', a Decimal object with 'E'. <syntaxhighlight lang=python> >>> 9.99E-8 9.99e-08 >>> Decimal(str(9.99e-8)) Decimal('9.99E-8') >>> </syntaxhighlight> {{RoundBoxBottom}} ===Reset the float=== ====Using formatted string==== {{RoundBoxTop|theme=2}} <syntaxhighlight lang=python> sum = 0 increment = 0.000_000_000_1 for count in range(1,1000) : sum += increment s1 = '{0:.10f}'.format(sum) sum = float(s1) print ('count= {}, sum = {}'.format(count,sum)) if sum != count / 10_000_000_000 : exit (99) exit (0) </syntaxhighlight> <pre> count= 1, sum = 1e-10 count= 2, sum = 2e-10 count= 3, sum = 3e-10 ................. count= 997, sum = 9.97e-08 count= 998, sum = 9.98e-08 count= 999, sum = 9.99e-08 </pre> {{RoundBoxBottom}} ====Using Decimal precision==== {{RoundBoxTop|theme=2}} Python's floating point standard states that the best accuracy to be expected is 15 significant decimal digits. <syntaxhighlight lang=python> from decimal import * getcontext().prec = 15 sum = 0 increment = 0.000_000_000_1 for count in range(1,1000) : print ( 'count =', (' '+str(count))[-3:], end=' ' ) sum += increment d1 = Decimal(str(sum)) print ( 'd1 = sum =', (' ' + str(d1))[-21:], end=' ' ) d1 += 0 # This forces d1 to conform to 15 digits of precision. print ( 'd1 =', (' ' + str(d1))[-20:], end=' ' ) sum = float(d1) print ('sum =', sum) if sum != count / 10_000_000_000 : print (' ', sum, count, increment, count*increment) exit (99) exit (0) </syntaxhighlight> <pre> count = 1 d1 = sum = 1E-10 d1 = 1E-10 sum = 1e-10 count = 2 d1 = sum = 2E-10 d1 = 2E-10 sum = 2e-10 count = 3 d1 = sum = 3E-10 d1 = 3E-10 sum = 3e-10 count = 4 d1 = sum = 4E-10 d1 = 4E-10 sum = 4e-10 count = 5 d1 = sum = 5E-10 d1 = 5E-10 sum = 5e-10 count = 6 d1 = sum = 6E-10 d1 = 6E-10 sum = 6e-10 count = 7 d1 = sum = 7E-10 d1 = 7E-10 sum = 7e-10 count = 8 d1 = sum = 7.999999999999999E-10 d1 = 8.00000000000000E-10 sum = 8e-10 count = 9 d1 = sum = 9E-10 d1 = 9E-10 sum = 9e-10 count = 10 d1 = sum = 1E-9 d1 = 1E-9 sum = 1e-09 count = 11 d1 = sum = 1.1000000000000001E-9 d1 = 1.10000000000000E-9 sum = 1.1e-09 count = 12 d1 = sum = 1.2E-9 d1 = 1.2E-9 sum = 1.2e-09 count = 13 d1 = sum = 1.3E-9 d1 = 1.3E-9 sum = 1.3e-09 count = 14 d1 = sum = 1.4000000000000001E-9 d1 = 1.40000000000000E-9 sum = 1.4e-09 count = 15 d1 = sum = 1.5E-9 d1 = 1.5E-9 sum = 1.5e-09 count = 16 d1 = sum = 1.6E-9 d1 = 1.6E-9 sum = 1.6e-09 .............................. count = 296 d1 = sum = 2.96E-8 d1 = 2.96E-8 sum = 2.96e-08 count = 297 d1 = sum = 2.97E-8 d1 = 2.97E-8 sum = 2.97e-08 count = 298 d1 = sum = 2.9800000000000002E-8 d1 = 2.98000000000000E-8 sum = 2.98e-08 count = 299 d1 = sum = 2.9899999999999996E-8 d1 = 2.99000000000000E-8 sum = 2.99e-08 count = 300 d1 = sum = 3.0000000000000004E-8 d1 = 3.00000000000000E-8 sum = 3e-08 count = 301 d1 = sum = 3.01E-8 d1 = 3.01E-8 sum = 3.01e-08 count = 302 d1 = sum = 3.02E-8 d1 = 3.02E-8 sum = 3.02e-08 .............................. count = 997 d1 = sum = 9.97E-8 d1 = 9.97E-8 sum = 9.97e-08 count = 998 d1 = sum = 9.98E-8 d1 = 9.98E-8 sum = 9.98e-08 count = 999 d1 = sum = 9.989999999999999E-8 d1 = 9.99000000000000E-8 sum = 9.99e-08 </pre> The last line: count = 999<math>\ \ \ \ </math> d1 = sum = <math>\ \ \underbrace{9.9899\_9999\_9999\_999}_\text{16 significant digits}</math>E-8<math>\ \ \ \ </math> d1 = <math>\ \ \underbrace{9.9900\_0000\_0000\_00}_\text{15 significant digits}</math>E-8<math>\ \ \ \ </math> sum = 9.99e-08 The value <code>9.9900_0000_0000_00</code> means that this is the most accurate value for <code>d1</code> that can fit in 15 significant digits. {{RoundBoxBottom}} =The Boolean= {{RoundBoxTop|theme=2}} In Python and most languages, a [[Wikipedia:Boolean data type|Boolean]] can be either <code>True</code> or <code>False</code>. A Boolean is a special data type and is a subclass of int.<ref>http://docs.python.org/3.4/library/functions.html#bool</ref> Since a Boolean has two states and only one at a time, a Boolean creates a special relationship between things. We can think of some Boolean values that we deal with in real life, for example: on or off, hot or cold, light or darkness, etc. Although a Boolean can be <code>True</code> or <code>False</code> a ''Boolean expression'' can take a statement, like <code>1 == 1</code> or <code>1 == 0</code>, and turn it into a Boolean, <code>True</code> for the former and <code>False</code> for the latter. We can use the <code>bool()</code> method to check the Boolean value of an object, which will be <code>False</code> for integer zero and for objects (numerical and other data types) that are empty, and <code>True</code> for anything else. <syntaxhighlight lang=python> >>> 1 == 1 True >>> 1 == 0 False >>> bool(0) False >>> bool(1) True >>> bool(10001219830) True >>> bool(-1908) True >>> bool("Hello!") True >>> bool("") False >>> bool(" ") True >>> bool(None) False >>> bool(0.000000000000000000000000000000000) False >>> bool("0.000000000000000000000000000000000") True >>> bool(0.0) False >>> bool([]) False >>> bool([1, 2, 3]) True >>> bool() False >>> bool(True) True >>> bool(False) False >>> bool(1==1) True >>> bool(1==0) False </syntaxhighlight> {{Note|'''Note:''' <code>True</code> and <code>False</code> are both case-sensitive, which means that you must type them exactly as shown, otherwise you'll get a syntax error.}} You can also use three operators to alter a Boolean statement<ref>https://docs.python.org/3//library/stdtypes.html#boolean-operations-and-or-not</ref>: <code>or</code>, <code>and</code>, <code>not</code>. You can use an <code>or</code> statement to allow one or more Booleans to be False so long as one is True. An <code>and</code> statement requires all of the Booleans to be True for it be True. The <code>not</code> statement reverses a Boolean so <code> not True</code> is <code>False</code> and <code>not False</code> is <code>True</code>. Here are some examples: <syntaxhighlight lang=python> >>> not False True >>> not True False >>> True and True True >>> True and False False >>> True or False True >>> False or False False >>> not(False or False) True >>> not(False and False) True >>> not(False and True) True </syntaxhighlight> All of the possible combinations are: <syntaxhighlight lang=python> True and True: True True and False: False False and True: False False and False: False True or True: True True or False: True False or True: True False or False: False (not(True and True)) == ((not True) or (not True)): True (not(True and False)) == ((not True) or (not False)): True (not(False and True)) == ((not False) or (not True)): True (not(False and False)) == ((not False) or (not False)): True (not(True or True)) == ((not True) and (not True)): True (not(True or False)) == ((not True) and (not False)): True (not(False or True)) == ((not False) and (not True)): True (not(False or False)) == ((not False) and (not False)): True </syntaxhighlight> The above negated statements reflect [https://en.wikipedia.org/wiki/De_Morgan%27s_laws#Engineering "De Morgan's laws."] For example, the statement <syntaxhighlight lang=python> (not(True and True)) == ((not True) or (not True)): True </syntaxhighlight> is equivalent to: {{overline|True and True}} <math>\equiv</math> {{overline|True}} or {{overline|True}}. ==A simple way to choose one of two possible values:== <syntaxhighlight lang=python> >>> L1 = [1,2,0,3,0,5] </syntaxhighlight> Produce list L2, a copy of L1, except that each value 0 in L1 has been replaced by 0xFF: <syntaxhighlight lang=python> >>> L2 = [] >>> >>> for p in L1 : ... L2 += ([p], [0xFF])[p == 0] ... >>> L2 [1, 2, 255, 3, 255, 5] >>> </syntaxhighlight> ==Expressions containing multiple booleans== Consider the expression: <syntaxhighlight lang=python> A and B or C </syntaxhighlight> Does this mean <syntaxhighlight lang=python> (A and B) or C </syntaxhighlight> Does it mean <syntaxhighlight lang=python> A and (B or C) </syntaxhighlight> It might be tempting to say that there is no difference, but look closely: <syntaxhighlight lang=python> for A in True, False : for B in True, False : for C in True, False : b1 = (A and B) or C b2 = A and (B or C) if b1 != b2 : print ( ''' for A = {}, B = {}, C = {} (A and B) or C = {} A and (B or C) = {} '''.format(A, B, C, b1, b2) ) </syntaxhighlight> <pre> for A = False, B = True, C = True (A and B) or C = True A and (B or C) = False for A = False, B = False, C = True (A and B) or C = True A and (B or C) = False </pre> Add another boolean to the expression: <syntaxhighlight lang=python> A and B or C and D </syntaxhighlight> and the number of different possibilities is at least 96. You can see that the complexity of these expressions quickly becomes unmanageable. The essence of this section: Keep your expressions simple and use parentheses as necessary to ensure that your code is interpreted exactly as you expect. {{RoundBoxBottom}} =Complex Numbers= {{RoundBoxTop|theme=2}} A [[Wikipedia:Complex number|complex number]] is represented as <code>a+bi</code> where <code>a</code> and b are real numbers, like 7 or 12, and <code>i</code> is an [[Wikipedia:Imaginary number|imaginary number]], where <code>i² = -1</code>. In the computer field, and in the world of Python, <code>i</code> is denoted as <code>j</code> for technical reasons, so we use <code>a+bj</code>. It should also be noted that <code>a</code> and <code>b</code> are '''both''' treated as floats. This subject will be briefly covered until later lessons. <syntaxhighlight lang=python> >>> 1+2j (1+2j) >>> -1+5.5j (-1+5.5j) >>> 0+5.5j 5.5j >>> 2j 2j >>> 1+0j (1+0j) >>> complex(3,-2) (3-2j) </syntaxhighlight> Note also that j cannot be used on its own without b. If you try to use j on its own, Python will look for a variable <code>j</code> and use the value of that variable, or report an error if the variable is not known or a wrong type. So the imaginary number i or j must always be written as 1j. <syntaxhighlight lang=python> >>> a = 5 + 3j >>> a - j Traceback (most recent call last): File "<stdin>", line 1, in <module> NameError: name 'j' is not defined >>> a - 1j (5+2j) >>> j = -3j >>> a - j (5+6j) >>> a - 1j (5+2j) </syntaxhighlight> The last result illustrates that even when the variable j has a numerical value, 1j (where, as above, can be any number) is always interpreted as the imaginary number j, not the variable j. The usual mathematical operations can be performed on complex numbers: <syntaxhighlight lang=python> >>> (1+3j)+(2-5j) (3-2j) >>> (1+3j)-(2-5j) (-1+8j) >>> (1+3j)*(2-5j) (17+1j) >>> a = complex(3,-5) ; b = 1 ; b += 2j ; a ; b (3-5j) (1+2j) >>> a + b ; a - b (4-3j) (2-7j) >>> a * b ; a / b (13+1j) (-1.4-2.2j) >>> a + 4 ; b - 2j ; a * 3.1 ; b / 2 (7-5j) (1+0j) (9.3-15.5j) (0.5+1j) >>> b ; b /= 5 ; b (1+2j) (0.2+0.4j) >>> a = complex(3,-5j) ; a (8-0j) </syntaxhighlight> Look closely at the last example. It does not produce an error, but is it what you want? {{Note|'''Note:''' the imaginary number, <code>j</code>, isn't case-sensitive, so you can use <code>j</code> or <code>J</code>.}} You can extract the real number and the imaginary number by using <code>.real</code> and <code>.imag</code> respectively. <syntaxhighlight lang=python> >>> (1+2j).real 1.0 >>> (1+2j).imag 2.0 >>> var = 5+3j >>> var.real 5.0 >>> var.imag 3.0 </syntaxhighlight> {{Note|'''Note:'''You'll get '''weird''' results if you '''don't''' use parentheses on a real number that '''isn't''' stored in a variable.}} ==[https://docs.python.org/3/library/cmath.html?highlight=complex#module-cmath cmath] — Mathematical functions for complex numbers== </br> ===Introduction=== {{RoundBoxTop|theme=2}} [[File:20180311Complex.png|thumb|400px|''' Figure 1: Components of complex number Z.''' </br></br> Origin at point <math>(0,0)</math>.</br> <math>Z.real</math> parallel to <math>X</math> axis.</br> <math>Z.imag</math> parallel to <math>Y</math> axis.</br> <math>r = abs(Z)</math></br> <math>Z = r(\cos\phi + 1j*\sin \phi) = Z.real + 1j*Z.imag</math> ]] A Python complex number <code>Z</code> is stored internally using rectangular or Cartesian coordinates. It is completely determined by its real part <code>Z.real</code> and its imaginary part <code>Z.imag</code>. See Figure 1. In Cartesian Geometry of 2 dimensions the real part of complex number <code>Z</code> is parallel to the <math>X</math> axis and the imaginary part is parallel to the <math>Y</math> axis. The <code>modulus</code> of <code>Z</code> is the line from origin to <code>Z</code> with length <code>r</code>. In scientific notation the number <code>Z</code> is written as <math>a + bi</math> where <math>i = \sqrt{-1}.</math> Within Python <code>Z</code> is written as <code>(a + bj).</code> '''Note:''' Because the expression 'bj' could be the name of a variable, and to avoid confusion, it might be better to express a complex number within Python as <code>(a + b*1j)</code>. The values <code>a,b</code> are the rectangular coordinates of complex number <code>(a + bj)</code>. <syntaxhighlight lang=python> >>> Z = complex(3.6, 2.7) ; Z (3.6+2.7j) >>> Z = 3.6 + 2.7j ; Z (3.6+2.7j) >>> Z = 3.6 + 2.7J ; Z # 'J' upper case. (3.6+2.7j) >>> Z.real ; Z.imag 3.6 2.7 >>> >>> Z.real + 1j*Z.imag (3.6+2.7j) >>> Z.real + 1j*Z.imag == Z True >>> </syntaxhighlight> The absolute value of a complex number is the length of the modulus: <math>r = \sqrt{Z.real^2 + Z.imag^2}</math> <syntaxhighlight lang=python> >>> abs(Z) 4.5 >>> (Z.real**2 + Z.imag**2)**(1/2) 4.5 >>> </syntaxhighlight> Some useful [https://docs.python.org/3/library/cmath.html?highlight=complex#constants constants]: <syntaxhighlight lang=python> >>> import cmath >>> ε = cmath.e ; ε # Greek epsilon, base of natural logarithms. 2.718281828459045 >>> π = cmath.pi ; π # Greek pi. 3.141592653589793 >>> τ = cmath.tau ; τ # Greek tau. 6.283185307179586 >>> τ == 2*π >>> True </syntaxhighlight> ====Addition of complex numbers==== {{RoundBoxTop|theme=2}} To add two complex numbers in rectangular format, simply add the real parts, then the imaginary parts: <syntaxhighlight lang=python> >>> import cmath >>> >>> cn1 = 1+3j ; cn1 (1+3j) >>> cn2 = 2-5j ; cn2 (2-5j) >>> cn1 + cn2 == cn1.real + cn2.real + 1j*(cn1.imag + cn2.imag) True >>> </syntaxhighlight> {{RoundBoxBottom}} {{RoundBoxBottom}} ===Polar coordinates=== Polar coordinates provide an alternative way to represent a complex number. In polar coordinates, a complex number <code>Z</code> is defined by the <code>modulus r</code> and the <code>phase angle φ (phi)</code>. The modulus <code>r</code> is <code>abs(Z)</code> as above, while the phase <code>φ</code> is the counterclockwise angle, measured in radians, from the positive x-axis to the line segment that joins the origin to <code>Z</code>. <math>\tan \phi = \frac{Z.imag}{Z.real}.</math> <syntaxhighlight lang=python> >>> tan_phi = Z.imag/Z.real ; tan_phi 0.75 >>> φ = cmath.atan(tan_phi).real ; φ 0.6435011087932844 # φ in radians >>> φ * (180/π) 36.86989764584402 # φ in degrees. >>> </syntaxhighlight> Class method [https://docs.python.org/3/library/cmath.html?highlight=complex#cmath.phase <code>cmath.phase(Z)</code>] returns the phase: <syntaxhighlight lang=python> >>> φ1 = cmath.phase(Z) ; φ1 0.6435011087932844 >>> φ1 == φ True >>> </syntaxhighlight> From figure 1: <math>\cos \phi = \frac{Z.real}{r};\ Z.real = r \cos \phi.</math> <math>\sin \phi = \frac{Z.imag}{r};\ Z.imag = r \sin \phi.</math> If polar coordinates are known: <math>Z = r \cos \phi + 1j * r \sin \phi = r (\cos \phi + 1j * \sin \phi).</math> <syntaxhighlight lang=python> >>> Z ; r ; φ (3.6+2.7j) 4.5 0.6435011087932844 >>> >>> cosφ = Z.real / r ; cosφ 0.8 >>> sinφ = Z.imag / r ; sinφ 0.6 >>> >>> Z1 = r*( cosφ + 1j*sinφ ) ; Z1 (3.6+2.7j) >>> </syntaxhighlight> ====De Moivre's formula==== The format containing polar coordinates is useful [https://en.wikipedia.org/wiki/De_Moivre%27s_formula because]: <math>Z^n = r^n(\cos(n\phi) + i\sin(n\phi))</math> =====Z^2===== {{RoundBoxTop|theme=2}} <math>Z^2 = r^2(\cos(2\phi) + i\sin(2\phi))</math> ======Proof====== {{RoundBoxTop|theme=2}} <math>Z = r(\cos\phi + i\sin\phi)</math> <math>Z^2 = (r(\cos\phi + i\sin\phi))^2</math> <math>Z^2 = r^2(\cos\phi + i\sin\phi)^2</math> <math>Z^2 = r^2(\cos^2\phi + 2i\sin\phi\cos\phi - \sin^2\phi)</math> <math>Z^2 = r^2(\cos^2\phi - \sin^2\phi + 2i\sin\phi\cos\phi)</math> <math>Z^2 = r^2(\cos(2\phi) + i\sin(2\phi))</math> {{RoundBoxBottom}} ======An example====== {{RoundBoxTop|theme=2}} <syntaxhighlight lang=python> >>> sin2φ = cmath.sin(2*φ).real ; sin2φ 0.96 >>> cos2φ = cmath.cos(2*φ).real ; cos2φ 0.28 >>> Z (3.6+2.7j) >>> Z**2 (5.67+19.44j) >>> r*r*(cos2φ + 1J*sin2φ) (5.67+19.44j) >>> </syntaxhighlight> {{RoundBoxBottom}} ======Z and Z^2 on polar diagram====== {{RoundBoxTop|theme=2}} [[File:ZandZ^2onPolarDiagram1.png|thumb|400px|''' Figure 2: Z and Z^2.''' </br></br> <math>abs(Z_1) = abs(Z_2) = r_1 = r_2</math>.</br> Phase of <math>Z_1 = \phi</math>. Phase of <math>Z_2 = 180 + \phi</math>.</br> <math>Z_2 = -Z_1</math>.</br> <math>abs(Z) = r = r_1^2</math>. Phase of <math>Z = 2\phi</math>.</br> <math>Z = Z_1^2 = Z_2^2</math>.</br> ]] In Figure 2 <math>Z_1 = 3 + 1j*\frac{5}{4}</math>. <math>Z_2 = -3 + 1j*(-\frac{5}{4})</math> <math>= -3 - 1j*\frac{5}{4}</math> <math>= -(3 + 1j*\frac{5}{4}) = -Z_1.</math> <math>r_1</math> = length <math>OZ_1</math> = abs<math>(Z_1) = r_2</math> = length <math>OZ_2</math> = abs<math>(Z_2) = \frac{13}{4}.</math> <math></math><math></math><math></math><math></math> Angle <math>\phi</math> is the phase of <math>Z_1.\ \cos \phi = \frac{12}{13}.\ \sin \phi = \frac{5}{13}</math>. <math>Z_1 = r_1*(\cos \phi + 1j* \sin \phi) = \frac{13}{4}*(\frac{12}{13} + 1j*\frac{5}{13}) = 3 + 1j*\frac{5}{4}.</math><math></math> <math>r</math> = length <math>OZ</math> = abs<math>(Z) = r_1^2 = \frac{169}{16}.</math> Phase of <math>Z = 2\phi.</math> Therefore: <math>Z = Z_1^2 = Z_2^2.</math> <math>\sin 2\phi = 2\sin\phi\cos\phi = 2(\frac{5}{13})(\frac{12}{13}) = \frac{120}{169}.</math> <math>\cos 2\phi = \cos^2\phi - \sin^2\phi = (\frac{12}{13})(\frac{12}{13}) - (\frac{5}{13})(\frac{5}{13}) = \frac{144-25}{169} = \frac{119}{169}.</math> <math>Z = r*(\cos 2\phi + 1j*\sin 2\phi) = \frac{169}{16}(\frac{119}{169} + 1j*\frac{120}{169}) = \frac{119}{16} + 1j*\frac{120}{16} = 7\frac{7}{16} + 1j*7\frac{1}{2}.</math> <syntaxhighlight lang=python> >>> Z1 = 3+1j*(5/4) ; Z1 ; abs(Z1) ; abs(Z1) == 13/4 (3+1.25j) 3.25 True >>> Z = Z1*Z1 ; Z ; Z.real == 7+(7/16) (7.4375+7.5j) True >>> </syntaxhighlight> {{RoundBoxBottom}} {{RoundBoxBottom}} =====\sqrt{Z}===== ------------------------------- <math>\sqrt{Z} = \sqrt{r}(\cos(\phi/2) + i\sin(\phi/2))</math> <syntaxhighlight lang=python> >>> sinφ_2 = cmath.sin(φ/2).real ; sinφ_2 0.31622776601683794 >>> cosφ_2 = cmath.cos(φ/2).real ; cosφ_2 0.9486832980505138 >>> Z (3.6+2.7j) >>> cmath.sqrt(Z) (2.0124611797498106+0.670820393249937j) >>> (r**0.5)*(cosφ_2 + 1J*sinφ_2) (2.0124611797498106+0.6708203932499369j) >>> </syntaxhighlight> ======\sqrt{1}====== {{RoundBoxTop|theme=2}} <math>\cos(0) + 1j*\sin(0) = 1 + 1j*0 = 1</math> <math>\sqrt{1} = \sqrt{\cos(0) + 1j*\sin(0)}</math> <math>= \cos(0/2) + 1j*\sin(0/2)</math> <math>= \cos(0) + 1j*\sin(0) = 1</math> Trigonometric functions are cyclical: <math>\cos(360) + 1j*\sin(360) = 1 + 1j*0 = 1</math> <math>\sqrt{1} = \sqrt{\cos(360) + 1j*\sin(360)}</math> <math>= \cos(360/2) + 1j*\sin(360/2)</math> <math>= \cos(180) + 1j*\sin(180) = -1 + 1j*0 = -1</math> The two square roots of <code>1</code> are <code>1</code> and <code>-1.</code> <syntaxhighlight lang=python> >>> 1**2 ; (-1)**2 1 1 >>> </syntaxhighlight> {{RoundBoxBottom}} ======\sqrt{-1}====== {{RoundBoxTop|theme=2}} <math>\cos(180) + 1j*\sin(180) = -1 + 1j*0 = -1</math> <math>\sqrt{-1} = \sqrt{\cos(180) + 1j*\sin(180)}</math> <math>= \cos(180/2) + 1j*\sin(180/2)</math> <math>= \cos(90) + 1j*\sin(90) = 0 + 1j*1 = 1j</math> Trigonometric functions are cyclical: <math>\cos(180+360) + 1j*\sin(180+360) = -1 + 1j*0 = -1</math> <math>\sqrt{-1} = \sqrt{\cos(180+360) + 1j*\sin(180+360)}</math> <math>= \cos(90+180) + 1j*\sin(90+180)</math> <math>= \cos(270) + 1j*\sin(270) = 0 + 1j*(-1) = -1j</math> The two square roots of <code>-1</code> are <code>1j</code> and <code>-1j.</code> <syntaxhighlight lang=python> >>> (1j)**2 ; (-1j)**2 (-1+0j) (-1+0j) >>> </syntaxhighlight> {{RoundBoxBottom}} =====Cube roots of 1 simplified===== {{RoundBoxTop|theme=2}} <math>\cos(0) + 1j*\sin(0) = 1 + 1j*0 = 1</math> <math>\sqrt[3]{1} = (\cos(0) + 1j*\sin(0))^{(1/3)}</math> <math>= \cos(0/3) + 1j*\sin(0/3)</math> <math>= \cos(0) + 1j*\sin(0) = 1</math> Trigonometric functions are cyclical: <math>\cos(360) + 1j*\sin(360) = 1 + 1j*0 = 1</math> <math>\sqrt[3]{1} = (\cos(360) + 1j*\sin(360))^{(1/3)}</math> <math>= \cos(360/3) + 1j*\sin(360/3)</math> <math>= \cos(120) + 1j*\sin(120) = -\cos(60) + 1j*\sin(60) </math> <math>= -\frac{1}{2} + 1j\frac{\sqrt{3}}{2} = \frac{-1 + 1j*\sqrt{3}}{2}</math> Proof: <math>r_2 = -1(\cos(60) - 1J*\sin(60)) = -1(\cos(-60) + 1J*\sin(-60)).</math> <math>r_2^3 = (-1)^3(\cos(-180) + 1J*\sin(-180)) = -1(-1 + 1J*0) = 1.</math> <math>\cos(720) + 1j*\sin(720) = 1 + 1j*0 = 1</math> <math>\sqrt[3]{1} = (\cos(720) + 1j*\sin(720))^{(1/3)}</math> <math>= \cos(720/3) + 1j*\sin(720/3)</math> <math>= \cos(240) + 1j*\sin(240) = -\cos(60) - 1j*\sin(60) </math> <math>= -\frac{1}{2} - 1j\frac{\sqrt{3}}{2} = \frac{-1 - 1j*\sqrt{3}}{2}</math> Proof: <math>r_3 = -1(\cos(60) + 1J*\sin(60))</math>. <math>r_3^3 = (-1)^3(\cos(180) + 1J*\sin(180)) = -1(-1 + 1J*0) = 1.</math> The three cube roots of 1 are : <math>1, -\cos 60^\circ \pm 1j*\sin 60^\circ</math> or <math>1,\ \frac{-1 + 1j*\sqrt{3}}{2},\ \frac{-1 - 1j*\sqrt{3}}{2}.</math> <syntaxhighlight lang=python> >>> r1 = 1 ; v1 = r1**3 ; v1 1 >>> r2 = ( -1 + 1j * (3**0.5)) / 2 ; v2 = r2**3 ; v2 (0.9999999999999998+1.1102230246251565e-16j) >>> r3 = ( -1 - 1j * (3**0.5)) / 2 ; v3 = r3**3 ; v3 (0.9999999999999998-1.1102230246251565e-16j) >>> >>> [ cmath.isclose(v,1,abs_tol=1e-15) for v in (v1,v2,v3) ] [True, True, True] >>> </syntaxhighlight> {{RoundBoxBottom}} ====Multiplication of complex numbers==== {{RoundBoxTop|theme=2}} To multiply two complex numbers in polar format, multiply the moduli and add the phases. <syntaxhighlight lang=python> >>> cn1 = 3+4j ; cn1 (3+4j) >>> r1,φ1 = cmath.polar(cn1) ; r1 ; φ1 5.0 0.9272952180016122 # radians >>> >>> cn2 = -4+3j ; cn2 (-4+3j) >>> r2,φ2 = cmath.polar(cn2) ; r2 ; φ2 5.0 2.498091544796509 # radians >>> >>> v1 = cn1*cn2 ; v1 (-24-7j) >>> v2 = 25*( cmath.cos(φ1 + φ2) + 1j*cmath.sin(φ1 + φ2) ) ; v2 # r1 * r2 = 25 (-24-7.000000000000002j) >>> >>> cmath.isclose(v1, v2, abs_tol=1e-15) True >>> </syntaxhighlight> =====Proof===== <math>(\cos A + 1j*\sin A)*(\cos B + 1j*\sin B)</math> <math>= \cos A \cos B + 1j*\cos A \sin B + 1j*\sin A \cos B + j^2\sin A\sin B</math> <math>= \cos A \cos B - \sin A\sin B + 1j*(\cos A \sin B + \sin A \cos B) </math> <math>= \cos(A + B) + 1j*\sin(A + B)</math> {{RoundBoxBottom}} ===Classification functions=== ====[https://docs.python.org/3/library/cmath.html?highlight=complex#cmath.isclose cmath.isclose(a, b, *, rel_tol=1e-09, abs_tol=0.0)]==== Return True if the values a and b are close to each other and False otherwise. Whether or not two values are considered close is determined according to given absolute and relative tolerances. <syntaxhighlight lang=python> >>> v1; cmath.polar(v1) (87283949+87283949j) (123438144.45328155, 0.7853981633974483) >>> v2; cmath.polar(v2) (87283949+87283950j) (123438145.16038834, 0.7853981691258783) >>> cmath.isclose(v1,v2) False >>> >>> cmath.isclose(v1,v2, rel_tol=8e-9) False >>> cmath.isclose(v1,v2, rel_tol=9e-9) True >>> >>> cmath.isclose(v1,v2, abs_tol=1) True >>> cmath.isclose(v1,v2, abs_tol=.5) False >>> </syntaxhighlight> The following python code implements this functionality with a list or tuple of numbers as input. {{RoundBoxTop|theme=4}} <syntaxhighlight lang=python> # python code import decimal D = decimal.Decimal allEqualDebug = 0 def allEqual(values, tolerance=1e-15) : ''' status = allEqual(values[, tolerance]) status may be: True, False or None. To check for "close to zero", include 0 in values: status = allEqual(list(values)+[0] [, tolerance]) ''' if type(values) not in (tuple,list) : print ('allEqual()1:', type(values), 'not in (tuple,list)') return None if len(values) < 2 : print ('allEqual()2: Must have >= 2 values to compare.') return None if type(tolerance) not in (float,D,complex) : print ('allEqual()3:', type(tolerance), 'not in (float,Decimal,complex)') return None tolerance = abs (tolerance) zeroInValues = (0 in values) for v in values : if type (v) not in (int,float,complex,D) : print ('allEqual()4:', type(v), 'not in (int,float,complex,Decimal)') return None set1 = set(values) - {0} if zeroInValues : for v in set1 : if abs(v) > tolerance : if allEqualDebug: print ('allEqual()5: value not close to 0.', v ) return False return True values = [] for v in set1 : if type(v) in (int,D) : values += [float(v)] else : values += [v] # All values are float or complex and non-zero without duplicates. for p in range (0, len(values)) : for q in range (p+1, len(values)) : a = values[p] ; b = values[q] v1,v2 = abs(a-b) , tolerance*abs((a+b)/2) # tolerance is relative value. if v1 > v2 : if allEqualDebug: print ('allEqual()6: 2 values not close.', a,',',b ) print (' abs(a-b) =', v1) print (' comparison =', v2) return False return True </syntaxhighlight> The above test for "approximately equal" is: <code>abs(a-b) <= tolerance*abs((a+b)/2).</code> This test works for floating point numbers, complex numbers or a mixture of both. It also ensures that 2 not-equal complex numbers of same absolute value (<code>3+4j, 4+3j</code> for example) fail the test. With this algorithm, 2 small numbers (<code>1.23456e-17, -1.23456e-17</code> for example) both pass the test for "close to 0," but fail the test for "approximately equal." {{RoundBoxBottom}} ===Power and logarithmic functions=== ====[https://docs.python.org/3/library/cmath.html?highlight=complex#cmath.sqrt cmath.sqrt(x)]==== {{RoundBoxTop|theme=2}} Return the square root of <code>x.</code> <syntaxhighlight lang=python> >>> cmath.sqrt(-1) 1j >>> >>> cmath.sqrt(7+24j) (4+3j) >>> -cmath.sqrt(7+24j) (-4-3j) # sqrt has both positive and negative values. >>> (-cmath.sqrt(7+24j))**2 (7+24j) >>> >>> cmath.sqrt(7+(7/16) + 1j*7.5) (3+1.25j) >>> </syntaxhighlight> {{RoundBoxBottom}} ====[https://docs.python.org/3/library/cmath.html?highlight=complex#cmath.exp cmath.exp(x)]==== {{RoundBoxTop|theme=2}} Return the exponential value <code>e**x</code>. <syntaxhighlight lang=python> >>> cmath.exp(1) (2.718281828459045+0j) # Value of e, base of natural logarithms. >>> </syntaxhighlight> [https://en.wikipedia.org/wiki/Euler%27s_formula Euler's formula:] <math>e^{i \theta} = \cos\theta + 1j*\sin\theta</math> When <math>\theta</math> has the value <math>\frac{\pi}{3}</math> or <math>60</math> degrees: <syntaxhighlight lang=python> >>> π = cmath.pi ; π 3.141592653589793 >>> >>> cmath.exp(1j*π/3) # π/3 = 60 degrees. (0.5+0.8660254037844386j) >>> >>> cmath.cos(π/3) (0.5-0j) >>> cmath.sin(π/3) (0.8660254037844386+0j) >>> >>> cmath.exp(1j*π/3) == cmath.cos(π/3) + 1j*cmath.sin(π/3) True >>> </syntaxhighlight> The case when <math>\theta = \pi</math>: <syntaxhighlight lang=python> >>> cmath.exp(1j*π) (-1+0j) >>> </syntaxhighlight> The combination of value <code>-1</code> and expression <code>cmath.exp(1j*π)</code> is equivalent to [https://en.wikipedia.org/wiki/Euler%27s_identity Euler's famous Identity]: <math>e^{i \pi} = -1</math> =====When <code>x</code> is complex:===== {{RoundBoxTop|theme=2}} According to the [https://en.wikipedia.org/wiki/Exponentiation#Imaginary_exponents_with_base_e rules of exponents], the expression <code>cmath.exp(a+bj)</code> is equivalent to: <math>e^{(a+bj)} = e^ae^{bj} = e^a(\cos b + 1j*\sin b)</math> <math>e^{(1+1j*\pi)} = e^1e^{1j*\pi} = e(-1)</math> <syntaxhighlight lang=python> >>> e = cmath.exp(1) ; e (2.718281828459045+0j) >>> >>> b = cmath.exp(1j*π) ; b (-1+1.2246467991473532e-16j) >>> cmath.isclose(b.imag,0,abs_tol=1e-15) True >>> b=complex(b.real,0);b (-1+0j) >>> >>> c = cmath.exp(1+1j*π) ; c (-2.718281828459045+3.328935140402784e-16j) >>> cmath.isclose(c.imag,0,abs_tol=1e-15) True >>> c=complex(c.real,0);c (-2.718281828459045+0j) >>> >>> c == e*b == e*(-1) True >>> </syntaxhighlight> {{RoundBoxBottom}} {{RoundBoxBottom}} {{RoundBoxBottom}} =Number Conversions= {{RoundBoxTop|theme=3}} ==Introduction== {{RoundBoxTop|theme=2}} Since integers and floats can't be mixed together in some situations, you'll need to be able to convert them from one type to another. Luckily, it's very easy to perform a conversion. To convert a data type to an integer, use the <code>int()</code> function. <syntaxhighlight lang=python> >>> int(1.5) 1 >>> int(10.0) 10 >>> int(True) 1 >>> int(False) 0 >>> int('0xFF', base=16) ; int('0xF1F0', 16) ; int('0b110100111', 0) ; int('11100100011',2) 255 61936 423 1827 </syntaxhighlight> You can even convert strings, which you'll learn about later. <syntaxhighlight lang=python> >>> int("100") 100 </syntaxhighlight> To convert a data type to a float, use the <code>float()</code> function. Like the integer, you can convert strings to floats. <syntaxhighlight lang=python> >>> float(102) 102.0 >>> float(932) 932.0 >>> float(True) 1.0 >>> float(False) 0.0 >>> float("101.42") 101.42 >>> float("4") 4.0 </syntaxhighlight> {{Note|'''Note''': You cannot use any of the above conversions on a complex number, as it will raise an error. You can work around this by using <code>.real</code> and <code>.imag</code>}} You can also use the <code>bool()</code> function to convert a data type to a Boolean. <syntaxhighlight lang=python> >>> bool(1) True >>> bool(0) False >>> bool(0.0) False >>> bool(0.01) True >>> bool(14) True >>> bool(14+3j) True >>> bool(3j) True >>> bool(0j) False >>> bool("") False >>> bool("Hello") True >>> bool("True") True >>> bool("False") True </syntaxhighlight> {{Note|'''Note:''' Notice that <code>bool("False")</code> is <code>True</code>. Unlike <code>int()</code> and <code>float()</code>, when <code>bool()</code> converts a string, it checks to see if the string is empty or not.}} Converting a data type to a complex is a little more tricky, but still easy. All you need to do is use the function <code>complex()</code> which takes two parameters, one of which is optional. The first parameter is the real number, which is required, and the second parameter is the imaginary number, which is optional. <syntaxhighlight lang=python> >>> complex(True) (1+0j) >>> complex(False) 0j >>> complex(3, 1) (3+1j) >>> complex(1, 22/7) (1+3.142857142857143j) >>> complex(0, 1.5) 1.5j >>> complex(7, 8) (7+8j) >>> complex("1") (1+0j) >>> complex("1+4j") (1+4j) >>> complex("9.75j") 9.75j </syntaxhighlight> {{RoundBoxBottom}} ==Converting integers, decimal to non-decimal== {{RoundBoxTop|theme=2}} This conversion is from int to str representing int: <syntaxhighlight lang=python> >>> a = 12345678901234567890 >>> b = bin(a) ; b '0b1010101101010100101010011000110011101011000111110000101011010010' >>> h = hex(a) ; h '0xab54a98ceb1f0ad2' >>> o = oct(a) ; o '0o1255245230635307605322' >>> </syntaxhighlight> {{RoundBoxBottom}} ==Converting integers, non-decimal to decimal== {{RoundBoxTop|theme=2}} This conversion is from str representing int to int: <syntaxhighlight lang=python> >>> a;b;h;o 12345678901234567890 '0b1010101101010100101010011000110011101011000111110000101011010010' '0xab54a98ceb1f0ad2' '0o1255245230635307605322' >>> >>> int(b,base=0) == int(b,base=2) == int(b,0) == int(b,2) == a # Base 0 or correct base is required. True >>> int(h,16) == a True >>> int(o,8) == a True >>> >>> int ('ab54a98ceb1f0ad2', 16) == a # When base 16 is supplied, the prefix '0x' is not necessary. True >>> >>> eval(b) == a # Function eval(...) provides simple conversion from str to base type. True >>> eval(h) == a True >>> eval(o) == a True >>> >>> int('12345678901234567890',0) == int('12345678901234567890',base=0) == a True >>> int('12345678901234567890',10) == int('12345678901234567890',base=10) == a True >>> eval('12345678901234567890') == int('12345678901234567890') == a True >>> </syntaxhighlight> {{RoundBoxBottom}} ==Interfacing with Python's Decimal module== {{RoundBoxTop|theme=2}} <syntaxhighlight lang=python> >>> from decimal import * >>> float1 = 3.14159 >>> dec1 = Decimal(float1) ; dec1 Decimal('3.14158999999999988261834005243144929409027099609375') >>> str(dec1) '3.14158999999999988261834005243144929409027099609375' >>> >>> float2 = eval(str(dec1)) ; float2 3.14159 >>> isinstance(float2, float) True >>> float2 == float1 True >>> >>> float2 = float(dec1) ; float2 3.14159 >>> isinstance(float2, float) True >>> float2 == float1 True >>> </syntaxhighlight> {{RoundBoxBottom}} ==Converting <code>int</code> to <code>bytes</code>== {{RoundBoxTop|theme=2}} Method <code>int.'''to_bytes'''(length, byteorder, *, signed=False)</code> returns a bytes object representing an integer where: <pre> length (in bytes) must be sufficient to contain int, at least (int.bit_length() + 7) // 8 byteorder can be 'big', 'little' or sys.byteorder, signed must be True if int is negative. </pre> For example: <syntaxhighlight lang=python> >>> int1 = 0x1205 >>> bytes1 = int1.to_bytes(2, byteorder='big') ; bytes1 b'\x12\x05' # A bytes object containing int1. >>> isinstance(bytes1, bytes) True >>> >>> int2 = 0xe205 >>> bytes2 = int2.to_bytes(2, byteorder='big', signed=True) ; bytes2 Traceback (most recent call last): File "<stdin>", line 1, in <module> OverflowError: int too big to convert >>> >>> bytes2 = int2.to_bytes(3, byteorder='big', signed=True) ; bytes2 b'\x00\xe2\x05' >>> >>> bytes2 = int2.to_bytes(2, byteorder='big') ; bytes2 b'\xe2\x05' >>> >>> int3 = -7675 >>> bytes3 = int3.to_bytes(2, byteorder='big') ; bytes3 Traceback (most recent call last): File "<stdin>", line 1, in <module> OverflowError: can't convert negative int to unsigned >>> >>> bytes3 = int3.to_bytes(2, byteorder='big', signed=True) ; bytes3 b'\xe2\x05' >>> >>> bytes2 == bytes3 True >>> </syntaxhighlight> The bytes object <code>b'\xe2\x05'</code> can represent 0xe205 or -7675 depending on whether it's interpreted as signed or unsigned. To preserve the original int, let <code>length = ((int.bit_length() + 7) // 8) + 1</code> if necessary and use signed=True. <syntaxhighlight lang=python> >>> hex(int2); hex(int3) '0xe205' '-0x1dfb' >>> bytes2 = int2.to_bytes(3, byteorder='big', signed=True) ; bytes2 b'\x00\xe2\x05' # Most significant bit (value=0) preserves sign (+). >>> bytes3 = int3.to_bytes(2, byteorder='big', signed=True) ; bytes3 b'\xe2\x05' # Most significant bit (value=1) preserves sign (-). >>> </syntaxhighlight> {{RoundBoxBottom}} ==Converting <code>bytes</code> to <code>int</code>== {{RoundBoxTop|theme=2}} A bytes object is an immutable sequence with every member <math>x</math> an int satisfying 0xFF <math>>= x >= 0.</math> The classmethod <code>int.from_bytes(bytes, byteorder, *, signed=False)</code> may be used to convert from bytes object to int. The value returned is an int represented by the given bytes object or any sequence convertible to bytes object: <syntaxhighlight lang=python> >>> hex(int.from_bytes(b'\xcd\x34', byteorder='little')) '0x34cd' >>> hex(int.from_bytes(b'\xcd\x34', byteorder='big')) '0xcd34' >>> hex(int.from_bytes(b'\xcd\x34', byteorder='little', signed=True)) '0x34cd' >>> hex(int.from_bytes(b'\xcd\x34', byteorder='big', signed=True)) '-0x32cc' >>> hex(int.from_bytes([0xCD,0x34], byteorder='big')) # Input is list convertible to bytes. '0xcd34' >>> hex(int.from_bytes((0xCD,0x34), byteorder='big')) # Input is tuple convertible to bytes. '0xcd34' >>> hex(int.from_bytes({0xCD,0x34}, byteorder='big')) '0x34cd' # Ordering of set is unpredictable. >>> hex(int.from_bytes(bytes([0xCD,0x34]), byteorder='big')) # Input is bytes object. '0xcd34' >>> hex(int.from_bytes(bytearray([0xCD,0x34]), byteorder='big')) # Input is bytearray. '0xcd34' >>> </syntaxhighlight> ===Complete conversion=== Complete conversion means conversion from int to bytes to int, or from bytes to int to bytes. When converting int/bytes/int, it is reasonable to expect that the final int should equal the original int. If you keep byteorder consistent and signed=True, you will produce consistent results: Positive number with msb (most significant bit) clear: <syntaxhighlight lang=python> >>> int1 = 0x1205 >>> bytes1 = int1.to_bytes(2, byteorder='big', signed=True) ; bytes1 b'\x12\x05' >>> int1a = int.from_bytes(bytes1, byteorder='big', signed=True) ; hex(int1a) '0x1205' >>> int1==int1a True </syntaxhighlight> Negative number with msb clear: <syntaxhighlight lang=python> >>> int1 = -0x1205 >>> bytes1 = int1.to_bytes(2, byteorder='big', signed=True) ; bytes1 b'\xed\xfb' >>> int1a = int.from_bytes(bytes1, byteorder='big', signed=True) ; hex(int1a) '-0x1205' >>> int1==int1a True </syntaxhighlight> Positive number with msb set: <syntaxhighlight lang=python> >>> int1 = 0xF205 >>> bytes1 = int1.to_bytes(2, byteorder='big', signed=True) ; bytes1 Traceback (most recent call last): File "<stdin>", line 1, in <module> OverflowError: int too big to convert >>> bytes1 = int1.to_bytes(3, byteorder='big', signed=True) ; bytes1 b'\x00\xf2\x05' >>> int1a = int.from_bytes(bytes1, byteorder='big', signed=True) ; hex(int1a) '0xf205' >>> int1==int1a True </syntaxhighlight> Negative number with msb set: <syntaxhighlight lang=python> >>> int1 = -0xF305 >>> bytes1 = int1.to_bytes(2, byteorder='big', signed=True) ; bytes1 Traceback (most recent call last): File "<stdin>", line 1, in <module> OverflowError: int too big to convert >>> bytes1 = int1.to_bytes(3, byteorder='big', signed=True) ; bytes1 b'\xff\x0c\xfb' >>> int1a = int.from_bytes(bytes1, byteorder='big', signed=True) ; hex(int1a) '-0xf305' >>> int1==int1a True </syntaxhighlight> {{RoundBoxBottom}} ==floats== {{RoundBoxTop|theme=2}} Two methods support conversion to and from hexadecimal strings. Because Python’s floats are stored internally as binary numbers, converting a float to or from a decimal string usually involves a small rounding error. In contrast, hexadecimal strings allow exact representation and specification of floating-point numbers. ===from hex=== {{RoundBoxTop|theme=3}} A hexadecimal float as represented by a hexadecimal string and similar to decimal floats can be int, point float or exponent float. A point float contains a decimal point and at least one hex digit. It may contain an exponent represented by <code>p</code> and a power of 2. An exponent float contains at least one hex digit and exponent. Class method <code>float.fromhex(s)</code> returns the float represented by hexadecimal string <code>s</code>. The string <code>s</code> may have leading and trailing whitespace. <syntaxhighlight lang=python> >>> float.fromhex(' ABC ') ; 0xABC 2748.0 2748 >>> float.fromhex(' 0xABCp6 ') ; 0xABC *(2**6) # Within the string ' 0xABCp6 ' the prefix '0x' is optional. 175872.0 175872 >>> float.fromhex(' ABCp-5 ') ; 0xABC *(2**(-5)) 85.875 85.875 >>> </syntaxhighlight> ====point float==== Consider <code>f1 = float.fromhex('0x3.a7d4')</code>. f1 = <math>(3 + \frac{0xA}{16} + \frac{0x7}{16^2} + \frac{0xD}{16^3} + \frac{0x4}{16^4})</math> To simplify the conversion put the hex string in the format of exponent float without decimal point: f1 = <math>(3 + \frac{0xA}{16} + \frac{0x7}{16^2} + \frac{0xD}{16^3} + \frac{0x4}{16^4})(16^4)(16^{-4})</math> f1 = <math>(3(16^4) + \frac{0xA(16^4)}{16} + \frac{0x7(16^4)}{16^2} + \frac{0xD(16^4)}{16^3} + \frac{0x4(16^4)}{16^4})(16^{-4})</math> f1 = <math>(0x30000 + 0xA000 + 0x700 + 0xD0 + 0x4)(16^{-4})</math> f1 = <math>(0x3A7D4)(16^{-4}) = 0x3A7D4(2^{-16})</math> <syntaxhighlight lang=python> >>> float.fromhex('0x3.a7d4') ; float.fromhex('0x3a7d4p-16') ; 0x3A7D4 * (16**(-4)) 3.65557861328125 3.65557861328125 3.65557861328125 >>> </syntaxhighlight> ====point float with exponent==== Consider <code>f1 = float.fromhex('0x3.a7p10')</code>. f1 = <math>(3 + \frac{0xA}{16} + \frac{0x7}{16^2} ) * (2^{10})</math> To simplify the conversion put the hex string in the format of exponent float without decimal point: <syntaxhighlight lang=python> >>> float.fromhex('0x3.a7p10') ; float.fromhex('0x3a7p2') ; 0x3A7 * (2 ** 2) 3740.0 3740.0 3740 >>> </syntaxhighlight> ====1/3==== Consider <code>f1 = float.fromhex('0x0.55555555555555555555')</code> f1 = <math>(0 + \frac{5}{16} + \frac{5}{16^2} + \frac{5}{16^3} + ... + \frac{5}{16^{20}})</math> To simplify calculation of f1: f1 = <math>0x \underbrace{55555555555555555555}_\text{20 hex digits} (16^{-20}) = 0x55555555555555555555(2^{-80})</math> <syntaxhighlight lang=python> >>> fives = '0x' + '5'*20 ; fives '0x55555555555555555555' >>> >>> v1 = '0x0.'+fives[2:] ; v1 '0x0.55555555555555555555' # Point float. >>> >>> v2 = fives + 'p-80' ; v2 '0x55555555555555555555p-80' # Exponent float without point. >>> >>> v3 = fives[:-18] + '.' + fives[-18:] + 'p-8' ; v3 '0x55.555555555555555555p-8' # Point float with exponent. >>> >>> float.fromhex(v1) ; float.fromhex(v2) ; float.fromhex(v3) ; eval(fives)*(2**(-80)) 0.3333333333333333 0.3333333333333333 0.3333333333333333 0.3333333333333333 >>> >>> v4 = '0x' + hex( eval(fives) << 3 )[2:].upper() + 'p-83' ; v4 '0x2AAAAAAAAAAAAAAAAAAA8p-83' # Exponent float with significand shifted left 3 bits. >>> float.fromhex(v4) 0.3333333333333333 >>> </syntaxhighlight> Exact value of hex string representing <math>\frac{1}{3}</math> <code>= '0x55555555555555555555p-80' =</code> <math>\frac{0x55555555555555555555}{2^{80}}.</math> <syntaxhighlight lang=python> >>> from decimal import * >>> getcontext().prec = 100 >>> >>> d1 = Decimal( eval(fives) ) / Decimal(2**80) ; d1 Decimal('0.33333333333333333333333305760646248232410837619710264334571547806262969970703125') >>> float(d1) 0.3333333333333333 >>> len(str(d1)) 82 # Well within precision of 100. >>> </syntaxhighlight> ====More room for error with greater precision==== Consider the hex representation of float <code>0.03</code>. <syntaxhighlight lang=python> >>> (0.03).hex() '0x1.eb851eb851eb8p-6' >>> </syntaxhighlight> See what happens when there is an error of only 1 in the rightmost hex digit: <syntaxhighlight lang=python> >>> float.fromhex('0x1.eb851eb851eb8p-6') 0.03 >>> float.fromhex('0x1.eb851eb851eb7p-6') 0.029999999999999995 >>> float.fromhex('0x1.eb851eb851eb9p-6') 0.030000000000000002 >>> </syntaxhighlight> With limited precision calculations have to be perfect because there is no room for error. See what happens when there is greater precision: <syntaxhighlight lang=python> >>> float.fromhex('0x1eb851eb851eb77fffffp-82') 0.029999999999999995 >>> float.fromhex('0x1eb851eb851eb7800000p-82') 0.03 >>> float.fromhex('0x1eb851eb851eb8800000p-82') 0.03 >>> float.fromhex('0x1eb851eb851eb8800001p-82') 0.030000000000000002 >>> >>> eval('0x1eb851eb851eb8800000') - eval('0x1eb851eb851eb77fffff') 16,777,217 # A range of more than 16,000,000 values that all convert to 0.03. >>> </syntaxhighlight> Less than perfect floating point calculations can be tolerated when there is greater precision in the underlying calculations. If floating point software with greater precision were to be used, reset the underlying hex value when it's obvious that it should reflect the correct value of the displayed float. <syntaxhighlight lang=python> >>> h1 >>> '0x1eb851eb851eb7812345p-82' >>> float.fromhex(h1) 0.03 >>> h1 = '0x1eb851eb851eb851eb85p-82' # Most accurate hex representation of float 0.03 with this precision. >>> float.fromhex(h1) 0.03 >>> </syntaxhighlight> {{RoundBoxBottom}} ===to hex=== {{RoundBoxTop|theme=3}} Instance method <code>float.hex()</code> returns a representation of a floating-point number as a hexadecimal string. <syntaxhighlight lang=python> >>> (24.567).hex() '0x1.89126e978d4fep+4' # 13 places of hex decimals. >>> >>> float.fromhex('0x189126e978d4fep-48') 24.567 >>> </syntaxhighlight> The significand in standard form: <math>0x1 \underbrace{89126e978d4fe}_\text{13 hex digits}</math> Number of bits in significand = <code>1 + 13*4 = 53.</code> Recall that <code>sys.float_info.mant_dig = 53.</code> ====In standard form==== Conversion to hex string with 13 places of decimals as above: <math>\frac{24567}{1000} = \frac{x}{16^{13}};</math> <math>x = \frac{24567(16^{13})}{1000}</math> <syntaxhighlight lang=python> >>> x,r = divmod( 24567*(16**13), 1000 ) ; x; r 110639932045610975 232 >>> h1 = '0x' + hex(x)[2:].upper() ; h1 '0x189126E978D4FDF' >>> v1 = h1 + 'p-52' ; v1 '0x189126E978D4FDFp-52' >>> float.fromhex(v1) 24.567 >>> x.bit_length() 57 >>> </syntaxhighlight> Truncate and round <code>x</code> so that the result fits in 53 bits: <syntaxhighlight lang=python> >>> x1 = (x >> 4) + ((x & 0xF) >= 8) ; x1 ; hex(x1) 6914995752850686 '0x189126e978d4fe' >>> x1.bit_length() 53 >>> h1a = '0x' + hex(x1)[2:].upper() ; h1a '0x189126E978D4FE' >>> >>> v1a = h1a + 'p-48' ; v1a '0x189126E978D4FEp-48' # Exponent float. >>> v1b = h1a[:-12] + '.' + h1a[-12:] ; v1b '0x18.9126E978D4FE' # Point float >>> v1c = h1a[:-13] + '.' + h1a[-13:] + 'p+4' ; v1c '0x1.89126E978D4FEp+4' # Standard format, point float with exponent. >>> >>> float.fromhex(v1a) ; float.fromhex(v1b) ; float.fromhex(v1c) 24.567 24.567 24.567 >>> v1c.lower() == (24.567).hex() True >>> </syntaxhighlight> ====float.as_integer_ratio()==== Instance method <code>float.as_integer_ratio()</code> returns a pair of integers whose ratio is exactly equal to the hex representation of the original float and with a positive denominator. <syntaxhighlight lang=python> >>> a,b = (1.13 - 1.1).as_integer_ratio(); a; b; a/b 67553994410557 2251799813685248 0.029999999999999805 >>> </syntaxhighlight> <math>\frac{a}{b} = \frac{67553994410557}{2251799813685248} = \frac{0x3d70a3d70a3d}{2^{51}}</math> = <code>'0x3d70a3d70a3dp-51'.</code> <syntaxhighlight lang=python> >>> float.fromhex('0x3d70a3d70a3dp-51') 0.029999999999999805 >>> </syntaxhighlight> ====Conversion with more precision than standard form==== To convert <code>24.567</code> to hex with greater precision than standard form: Get the power of 2 in standard form: <syntaxhighlight lang=python> >>> a,b = (24.567).as_integer_ratio() >>> power_of_2 = len(bin(b))-3 >>> b == 2**power_of_2 True >>> </syntaxhighlight> Decide what precision you want. For example, with 4 more hex digits. <syntaxhighlight lang=python> >>> power_of_2 += 16 >>> power_of_2 63 >>> </syntaxhighlight> Get the value of float <code>24.567</code> as the exact ratio of two integers: <syntaxhighlight lang=python> >>> a1,b1 = Decimal(str(24.567)).as_integer_ratio();a1;b1 24567 1000 >>> </syntaxhighlight> <math>\frac{24567}{1000} = \frac{x}{2^{63}};\ x = \frac{24567(2^{63})}{1000}</math> <syntaxhighlight lang=python> >>> x,r = divmod( 24567*(2**63),1000 );x;r 226590580829411277275 136 >>> h1 = hex(x).upper().replace('X','x') + 'p-63' ; h1 '0xC489374BC6A7EF9DBp-63' >>> float.fromhex(h1) 24.567 >>> </syntaxhighlight> Exact value of <code>24.567:</code> <syntaxhighlight lang=python> >>> d1 = Decimal(24.567);d1;float(d1) Decimal('24.5670_0000_0000_0001_7053025658242404460906982421875') # 17 significant digits. 24.567 >>> </syntaxhighlight> Exact value of <code>24.567</code> with greater precision (h1): <syntaxhighlight lang=python> >>> d2 = Decimal( eval(h1[:-4]) ) / Decimal(2**63);d2;float(d2) Decimal('24.5669_9999_9999_9999_9998_5254850454197139697498641908168792724609375') # 21 significant digits. 24.567 >>> </syntaxhighlight> Compare the differences: <syntaxhighlight lang=python> >>> diff1 = Decimal('24.567') - d1 >>> diff2 = Decimal('24.567') - d2 >>> diff1;diff2 Decimal('-1.7053025658242404460906982421875E-16') Decimal('1.4745149545802860302501358091831207275390625E-20') >>> </syntaxhighlight> ====Exact conversion==== The only floating point numbers that can be converted exactly to hex are those that, when expressed as a fraction, have a divisor that is an integer power of 2. <syntaxhighlight lang=python> >>> (1+71/(2**67)).hex() '0x1.0000000000000p+0' >>> </syntaxhighlight> To convert <code>1+71/(2**67)</code> to hex exactly: <math>1+\frac{71}{2^{67}}</math> <math> = 1+\frac{142}{2^{68}}</math> <math> = 1+\frac{0x8E}{16^{17}}</math> <math> = 0x1\_\underbrace{0000\_0000\_0000\_0008\_E}_\text{17 hex digits} (16^{-17})</math> <math> = 0x1.0000000000000008E</math> <math> = 0x10000000000000008E(2^{-68})</math> <syntaxhighlight lang=python> >>> h1 = '0x1' + '0'*15 + '8E' ; h1 '0x10000000000000008E' >>> v1 = h1+'p-68' ; v1 '0x10000000000000008Ep-68' # exact hex value of 1 + 71/(2**67) >>> float.fromhex(v1) 1.0 # lack of precision. >>> >>> getcontext().prec 150 >>> d1 = Decimal(1) + Decimal(71)/Decimal(2**67) ; d1 Decimal('1.0000000000000000004811147140404425925908071803860366344451904296875') # exact decimal value of 1 + 71/(2**67) >>> >>> len(str(d1)) 69 >>> d2 = Decimal(eval(h1)) / Decimal(2**68) ; d2 Decimal('1.0000000000000000004811147140404425925908071803860366344451904296875') # exact decimal value of '0x10000000000000008Ep-68' >>> d1 == d2 True >>> >>> float(d1) 1.0 >>> </syntaxhighlight> {{RoundBoxBottom}} ===Floating point calculation of <code>1.13 - 1.1</code>=== {{RoundBoxTop|theme=3}} <syntaxhighlight lang=python> >>> (1.1).hex() '0x1.199999999999ap+0' >>> v1 = '0x1199999999999Ap-52' ; float.fromhex(v1) 1.1 >>> >>> (1.13).hex() '0x1.2147ae147ae14p+0' >>> v2 = '0x12147AE147AE14p-52' ; float.fromhex(v2) 1.13 >>> </syntaxhighlight> Difference <code>= 1.13 - 1.1 = v2 - v1 = '0x12147AE147AE14p-52' - '0x1199999999999Ap-52'</code> <code>= (0x12147AE147AE14 - 0x1199999999999A)</code><math>2^{-52}</math> <code>= 0x7AE147AE147A</code><math>(2^{-52})</math> <code>= '0x7AE147AE147Ap-52'</code> <syntaxhighlight lang=python> >>> float.fromhex('0x7AE147AE147Ap-52') 0.029999999999999805 >>> 1.13-1.1 0.029999999999999805 >>> </syntaxhighlight> Exact value of v1: <syntaxhighlight lang=python> >>> d1 = Decimal(eval(v1[:-4])) / Decimal(2**52) ; d1 ; d1 == Decimal(1.1) Decimal('1.100000000000000088817841970012523233890533447265625') # > 1.1 >>> True >>> </syntaxhighlight> Exact value of v2: <syntaxhighlight lang=python> >>> d2 = Decimal(eval(v2[:-4])) / Decimal(2**52) ; d2 ; d2 == Decimal(1.13) Decimal('1.12999999999999989341858963598497211933135986328125') # < 1.13 >>> True >>> </syntaxhighlight> Exact value of difference: <syntaxhighlight lang=python> >>> d1a = d2-d1 ; d1a Decimal('0.029999999999999804600747665972448885440826416015625') >>> >>> d1a == Decimal(1.13 - 1.1) >>> True >>> float(d1a) 0.029999999999999805 >>> </syntaxhighlight> ====Why the error appears to be so great==== <syntaxhighlight lang=python> >>> error2 = d2-Decimal('1.13'); error2 Decimal('-1.0658141036401502788066864013671875E-16') # Negative number. >>> >>> error1 = d1-Decimal('1.1'); error1 Decimal('8.8817841970012523233890533447265625E-17') # Positive number. >>> >>> total_error = error2-error1 ; total_error Decimal('-1.95399252334027551114559173583984375E-16') # Relatively large negative number. >>> >>> total_error + ( Decimal('1.13')-Decimal('1.1') - Decimal(1.13-1.1) ) Decimal('0E-51') >>> </syntaxhighlight> ====An observation==== While the value <code>0.03</code> does not contain a repeating decimal, it seems that there is a repeating "decimal" in the hex representation. Repeat the sequence in hex and see what happens: <syntaxhighlight lang=python> >>> diff1 = '0x7AE14_7AE14_7AE14_7AE14_7AE14p-104' >>> float.fromhex( diff1.replace('_', '') ) 0.03 >>> </syntaxhighlight> Exact decimal value of <code>diff1</code>: <syntaxhighlight lang=python> >>> diff2 = Decimal(eval(diff1[:-5])) / Decimal(2**104) ; diff2 Decimal('0.029999999999999999999999999999976334172843369645837648143041516413109803806946729309856891632080078125') >>> float(diff2) 0.03 >>> </syntaxhighlight> Should the point in the hex representation be called a "heximal" point? ====User-written floating point software for an accurate result==== <syntaxhighlight lang=python> >>> (1.13).hex() '0x1.2_147ae_147ae_14_p+0' # 13 hexadecimal digits after the hexadecimal point. >>> (1.1).hex() '0x1.1_99999_99999_9a_p+0' # 13 hexadecimal digits after the hexadecimal point. >>> </syntaxhighlight> By inspection produce hex values for <code>1.13</code> and <code>1.1</code> accurate to 14 hexadecimal places after the hexadecimal point. <syntaxhighlight lang=python> >>> v1 = '0x12_147ae_147ae_148_p-56' # '0x1.2_147ae_147ae_147ae_147ae_147ae_p+0' accurate to 14 hexadecimal digits after the hexadecimal point. >>> float.fromhex(v1.replace('_','')) 1.13 >>> >>> v2 = '0x1_19999_99999_999a_p-56' # Accurate to 14 hexadecimal digits after the hexadecimal point. >>> float.fromhex(v2.replace('_','')) 1.1 >>> </syntaxhighlight> Slightly more precision in the underlying calculations produces an accurate difference: <syntaxhighlight lang=python> >>> diff = hex(eval(v1[:-5]) - eval(v2[:-5])) + 'p-56' ; diff '0x7ae147ae147aep-56' >>> float.fromhex(diff) 0.03 >>> </syntaxhighlight> Exact value of <code>diff:</code> <syntaxhighlight lang=python> >>> from decimal import * >>> getcontext().prec = 100 >>> >>> d1 = Decimal( eval(diff[:-4]) ) / Decimal(2**56) ; d1 Decimal('0.0299999999999999988897769753748434595763683319091796875') >>> float(d1) 0.03 >>> >>> getcontext().prec = 15 # Maximum precision of floats. >>> d1 += 0 ; d1 Decimal('0.0300000000000000') # Accurate to 15 digits of precision. >>> float(d1) 0.03 >>> </syntaxhighlight> Summary: <syntaxhighlight lang=python> >>> import sys >>> sys.float_info.mant_dig 53 >>> sys.float_info.mant_dig = 57 Traceback (most recent call last): File "<stdin>", line 1, in <module> AttributeError: readonly attribute >>> </syntaxhighlight> This section simulates the floating-point calculation of <math>1.13 - 1.1</math> if the value of attribute <code>sys.float_info.mant_dig</code> could be set to <math>57</math> by user. For examples of professionally written code that temporarily increases precision for underlying calculations and then restores precision to display result, see [https://docs.python.org/3/library/decimal.html?highlight=recipes#recipes recipes.] {{RoundBoxBottom}} {{RoundBoxBottom}} {{RoundBoxBottom}} =Miscellaneous Topics= {{RoundBoxTop|theme=3}} ==Plus zero and minus zero== {{RoundBoxTop|theme=2}} The concept of plus and minus zero does not apply to the integers: <syntaxhighlight lang="Python"> >>> +0 ; -0 0 0 >>> </syntaxhighlight> Floats retain the distinction: <syntaxhighlight lang="Python"> >>> +0. ; -0. ; +0. == -0. == 0 0.0 -0.0 True >>> </syntaxhighlight> As do complex numbers: <syntaxhighlight lang="Python"> >>> complex(-0., -0.) (-0-0j) >>> complex(-0., -0.).real -0.0 >>> complex(-0., -0.).imag -0.0 >>> </syntaxhighlight> ===Examples of plus and minus zero=== <syntaxhighlight lang="Python"> >>> '{0:0.2f}'.format(.0000) '0.00' >>> '{0:0.2f}'.format(.0003) '0.00' >>> '{0:0.2f}'.format(-.0000) '-0.00' >>> '{0:0.2f}'.format(-.0003) '-0.00' >>> </syntaxhighlight> A small non-zero positive number was displayed as <code>'0.00'</code>; a small non-zero negative number was displayed as <code>'-0.00'</code>. According to values under [https://en.wikiversity.org/wiki/Python_Concepts/Numbers#Cube_roots_of_1_simplified "Cube roots of 1 simplified,"] one of the cube roots of unity is <math>r_3 = \frac{-1 - 1j*\sqrt{3}}{2}.</math> We expect that <math>r_3^3</math> should equal <math>1.</math> However: <syntaxhighlight lang="Python"> >>> r3 = ( -1 - 1j * (3**0.5)) / 2 ; v3 = r3**3 ; v3 (0.9999999999999998-1.1102230246251565e-16j) >>> </syntaxhighlight> The best accuracy which we can expect from floats is 15 significant digits: <syntaxhighlight lang="Python"> >>> '{0:0.15f}'.format( v3.real ) '1.000000000000000' >>> '{0:0.15f}'.format( v3.imag ) '-0.000000000000000' >>> </syntaxhighlight> The respective values <code>'1.000000000000000', '-0.000000000000000'</code> are the most accurate that can be displayed with 15 places of decimals. <code>v3.imag,</code> a small non-zero negative number was displayed as <code>'-0.000000000000000'</code>. <syntaxhighlight lang="Python"> >>> float( '-0.000000000000000' ) -0.0 >>> </syntaxhighlight> The conversion from string to float preserves the distinction of minus zero, indicating that the original value was, probably, a small, non-zero, negative number. {{RoundBoxBottom}} ==Precision and formatted decimals== {{RoundBoxTop|theme=2}} Within this section the expression "decimal precision" means precision as implemented by Python's decimal module. Precision means the number of digits used to display a value beginning with and containing the first non-zero digit. Some examples using decimal precision: <syntaxhighlight lang="Python"> >>> from decimal import * >>> getcontext().prec = 4 >>> >>> Decimal('0.0034567') Decimal('0.0034567') # Precision not enforced here. >>> Decimal('0.0034567') + 0 Decimal('0.003457') # '+ 0' forces result to conform to precision of 4. >>> Decimal('0.003456432') + 0 Decimal('0.003456') >>> Decimal('3456432') + 0 Decimal('3.456E+6') >>> Decimal('3456789') + 0 Decimal('3.457E+6') >>> >>> Decimal('0.00300055') + 0 Decimal('0.003001') >>> Decimal('0.00300033') + 0 Decimal('0.003000') # Trailing Zeroes are retained to conform to precision of 4. >>> </syntaxhighlight> Note how the following values are rounded. More about rounding in the next section. <syntaxhighlight lang="Python"> >>> from decimal import * >>> getcontext().prec = 4 >>> >>> Decimal('3456500') + 0 Decimal('3.456E+6') # Rounded down. >>> Decimal('3457500') + 0 Decimal('3.458E+6') # Rounded up. >>> </syntaxhighlight> Python's string method <code>.format</code> can be used to display a value accurate to a given number of decimal positions. <syntaxhighlight lang="Python"> >>> '{0:.4f}'.format(0.003456) '0.0035' # Accurate to four places of decimals. >>> '{0:.4f}'.format(0.003446) '0.0034' # Accurate to four places of decimals. >>> </syntaxhighlight> Default rounding provided by python's string method <code>.format</code> is same as that for decimal precision: <syntaxhighlight lang="Python"> >>> >>> '{0:.4f}'.format(0.00345) '0.0034' # Rounded down. >>> '{0:.4f}'.format(0.00355) '0.0036' # Rounded up. >>> </syntaxhighlight> {{RoundBoxBottom}} ==Rounding of close but inexact values== {{RoundBoxTop|theme=2}} Even elementary calculations lead to increasing complexity in the practical execution of a task involving numbers. It is fairly easy to imagine one fifth of one inch shown mathematically as <math>\frac{1}{5}</math> inch. What if you had to cut from a piece of steel rod a smaller piece with an exact length of <math>\frac{1}{5}</math> inch? Most [https://en.wikipedia.org/wiki/Tape_measure#Types common measuring instruments] have lengths expressed in inches and sixteenths of an inch. Then <math>\frac{1}{5}</math> inch becomes <math>\frac{3.2}{16}</math> inch. You use a [https://en.wikipedia.org/wiki/Micrometer#Customary/Imperial_system micrometer measuring instrument] accurate to <math>\frac{1}{1000}</math> inch and <math>\frac{200}{1000}</math> inch is <math>\frac{1}{5}</math> inch exactly. What if you had to produce a piece of steel rod with length <math>\frac{1}{7}</math> feet exactly? <math>\frac{1}{7}</math> feet = <math>\frac{12}{7}</math> inches = <math>1.714285714285</math> inches = <math>1\frac{11.428571428571}{16}</math> inches. Both the measuring tape and micrometer seem inadequate for the task. You devise a system dependent on similar triangles and parallel lines. Success. The value <math>\frac{1}{7}</math> can be produced geometrically. What if you had to produce a square with an exact area of <math>2</math> square inches? The side of the square would be <math>\sqrt{2}</math> inches exactly, but how do you measure <math>\sqrt{2}</math> inches exactly? In practical terms your task becomes feasible if some tolerance in the area of the finished product is allowed, for example <math>2 \pm 0.0002</math> square inches. Then a "square" with adjacent sides of 1.4142 and 1.4143 inches has an area within the specified tolerance. ===DRIP for example=== Even simple calculations based on exact decimals quickly lead to impractical numbers. Suppose you have a DRIP ([https://en.wikipedia.org/wiki/Dividend_reinvestment_plan Dividend ReInvestment Plan]) with any of the big well-known corporations. Most DRIPs permit you to purchase fractions of a share of stock. Shares of an attractive stock are currently trading for <math>\$38</math> and you invest <math>\$100</math>, buying <math>\frac{100}{38}</math> shares of stock. On your statement you don't see a credit of <math>2\frac{24}{38}</math> shares of stock. The custodian of the plan may show your holding accurate to four places of decimals: <math>2.6315</math> shares. The fraction <math>\frac{24}{38}</math> is actually <math>0.63157894736........</math> but your credit is <math>2.6315</math> called 'rounding down.' The corporation then issues a dividend of <math>\$0.37</math> per share when the stock is trading for <math>\$37.26</math> per share and you reinvest the dividend. If the custodian reinvests the dividend for you at a <math>5\%</math> discount to market price, your credit is <math>\frac{0.37 * 2.6315}{37.26 * 0.95} = 0.02750670960.....</math> shares, shown on your statement as <math>0.0275</math> shares giving you a total holding of <math>2.6315 + 0.0275 = 2.659</math> shares probably shown on your statement as <math>2.6590</math> with a current market value of <math>\$2.659 * 37.26 = \$99.07434</math> shown on your statement as <math>\$99.07</math>. The result of your mathematical calculations will probably be a close approximation of the exact value after allowing for tolerable errors based on precision and rounding of intermediate results. ===Default rounding=== When you import python's decimal module, values are initialized as the 'default' values. <syntaxhighlight lang=python> >>> from decimal import * >>> getcontext() Context(prec=28, rounding=ROUND_HALF_EVEN, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[], traps=[InvalidOperation, DivisionByZero, Overflow]) >>> setcontext(DefaultContext) >>> getcontext() Context(prec=28, rounding=ROUND_HALF_EVEN, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[], traps=[InvalidOperation, DivisionByZero, Overflow]) # Same as above. >>> </syntaxhighlight> The default rounding method is called [https://docs.python.org/3/library/decimal.html#decimal.ROUND_HALF_EVEN <code>ROUND_HALF_EVEN</code>]. This means that, if your result is exactly half-way between two limits, the result is rounded to the nearest even number. For simplicity set precision to 4: <syntaxhighlight lang=python> >>> getcontext().prec = 4 >>> getcontext() Context(prec=4, rounding=ROUND_HALF_EVEN, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[], traps=[InvalidOperation, DivisionByZero, Overflow]) >>> >>> Decimal('0.012344') + 0 Decimal('0.01234') >>> Decimal('0.012345') + 0 Decimal('0.01234') # Rounded down to nearest even number. >>> Decimal('0.045674') + 0 Decimal('0.04567') >>> Decimal('0.045675') + 0 Decimal('0.04568') # Rounded up to nearest even number. >>> </syntaxhighlight> Default rounding provided by python's string method .format is same as that for decimal precision: <syntaxhighlight lang=python> >>> >>> '{0:.4f}'.format(0.00345) '0.0034' # Rounded down. >>> '{0:.4f}'.format(0.00355) '0.0036' # Rounded up. >>> </syntaxhighlight> A disadvantage of this method of rounding is that an examination of the result does not indicate what the original value was: <syntaxhighlight lang=python> >>> Decimal('0.045675') + 0 == Decimal('0.045685') + 0 True >>> </syntaxhighlight> ===Other rounding modes=== ====ROUND_HALF_UP==== Rounding mode [https://docs.python.org/3/library/decimal.html#decimal.ROUND_HALF_UP ROUND_HALF_UP] is illustrated as follows: <syntaxhighlight lang=python> >>> getcontext().rounding=ROUND_HALF_UP >>> getcontext() Context(prec=4, rounding=ROUND_HALF_UP, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[], traps=[InvalidOperation, DivisionByZero, Overflow]) >>> >>> Decimal('0.012345') + 0 Decimal('0.01235') >>> Decimal('0.012355') + 0 Decimal('0.01236') >>> Decimal('0.012365') + 0 Decimal('0.01237') >>> Decimal('0.012375') + 0 Decimal('0.01238') </syntaxhighlight> Same logic for negative numbers: <syntaxhighlight lang=python> >>> Decimal('-0.012345') + 0 Decimal('-0.01235') >>> Decimal('-0.012355') + 0 Decimal('-0.01236') >>> Decimal('-0.012365') + 0 Decimal('-0.01237') >>> Decimal('-0.012375') + 0 Decimal('-0.01238') </syntaxhighlight> ====ROUND_DOWN==== The numbers in the example under DRIP above are derived using python's [https://docs.python.org/3/library/decimal.html#decimal.Decimal.quantize <code>.quantize()</code>] method and rounding set to [https://docs.python.org/3/library/decimal.html#decimal.ROUND_DOWN ROUND_DOWN]. <syntaxhighlight lang=python> setcontext(DefaultContext) number_of_initial_shares = 100/38 print ('number_of_initial_shares =', number_of_initial_shares) number_of_initial_shares = Decimal(number_of_initial_shares).quantize(Decimal('.0001'), rounding=ROUND_DOWN) print ( '''After rounding down number_of_initial_shares =''', number_of_initial_shares ) shares_added = 0.37*float(number_of_initial_shares) / (37.26*0.95) print (''' shares_added =''', shares_added) shares_added = Decimal(shares_added).quantize(Decimal('.0001'), rounding=ROUND_DOWN) print ( '''After rounding down shares_added =''', shares_added ) total_shares = shares_added + number_of_initial_shares value = total_shares * Decimal('37.26') print (''' value =''', value) value = value.quantize(Decimal('.01'), rounding=ROUND_DOWN) print ( '''After rounding down value =''', '$'+str(value) ) </syntaxhighlight> <syntaxhighlight lang="Python"> number_of_initial_shares = 2.6315789473684212 After rounding down number_of_initial_shares = 2.6315 shares_added = 0.02750670960815888 After rounding down shares_added = 0.0275 value = 99.074340 After rounding down value = $99.07 </syntaxhighlight> When using method <code>.quantize(....)</code>, ensure that <code>getcontext().prec</code> is adequate: <syntaxhighlight lang=python> >>> getcontext().prec = 6 >>> Decimal('0.0000123456').quantize(Decimal('1e-6')) Decimal('0.000012') >>> Decimal('123.0000123456').quantize(Decimal('1e-6')) Traceback (most recent call last): File "<stdin>", line 1, in <module> decimal.InvalidOperation: [<class 'decimal.InvalidOperation'>] >>> getcontext().prec = 9 >>> Decimal('123.0000123456').quantize(Decimal('1e-6')) Decimal('123.000012') # Desired result has precision of 9. >>> </syntaxhighlight> {{RoundBoxBottom}} {{RoundBoxBottom}} =Assignments= {{RoundBoxTop|theme=4}} [[File:Crystal_Clear_app_kedit.svg|right|100px]] * Experiment with the python interpreter using integers, floats, Booleans, and complex numbers, noting errors, for example: <syntaxhighlight lang=python> >>> + 44 ; eval(' - 33 ') ; eval(' - 0003.e-002 ') ; eval(' + 0003.00000E-002 ') ; eval(' + 0003.12E0073 ') >>> + 4 + 1j*3 ; complex(2,-3) ; complex("2+3j") ; eval("2+3J") ; complex('-3',7j) >>> bool(6) ; bool(0) ; bool('0') ; '123'+0 ; bool('123') + 1 ; 1+3 == 4 ; 2**2 == -3 </syntaxhighlight> * Think critically about integers and floats. When should you use integers? When should you use floats? * A [[Wikipedia:Loss of significance|loss of significance]] for a float value should be expected when working with long or insignificant numbers. When would this become a problem? * Under [https://en.wikiversity.org/wiki/Python_Concepts/Numbers#Using_formatted_string "Using formatted string"] above the test for correct summation is: <syntaxhighlight lang=python> if sum != count / 10_000_000_000 : </syntaxhighlight> This could be written as: <syntaxhighlight lang=python> if sum != count * increment : </syntaxhighlight> However: <syntaxhighlight lang=python> >>> 5*(1e-10) ; 6*(1e-10) ; 7*(1e-10) 5e-10 6e-10 7.000000000000001e-10 >>> >>> 7 / (1e10) 7e-10 >>> </syntaxhighlight> How would you write the line <code>if sum != count * increment :</code> to ensure an accurate test? * Using techniques similar to those contained in section [https://en.wikiversity.org/wiki/Python_Concepts/Numbers#Cube_roots_of_1_simplified "Cube roots of 1 simplified"] calculate [https://en.wikiversity.org/w/index.php?title=Python_Concepts/Numbers&oldid=1977300#Fifth_roots_of_unity all five] of the fifth roots of unity. * Using the [https://en.wikiversity.org/wiki/Python_Concepts/Numbers#Proof_2 "Proof"] under "Multiplication of complex numbers" [https://en.wikiversity.org/w/index.php?title=Python_Concepts/Numbers&oldid=1977300#Division_of_complex_numbers_in_polar_format show that]: <math>\frac{\cos A + 1j*\sin A}{\cos B + 1j*\sin B} = \cos(A-B) + 1j* \sin (A-B)</math> * One of the cube roots of unity, <math>r_2 = \frac{-1+1j*\sqrt{3}}{2}.</math> For greater precision than is available with floating point arithmetic, [https://en.wikiversity.org/w/index.php?title=Python_Concepts/Numbers&oldid=1979009#Python's_decimal_module_for_greater_precision use Python's decimal module] to calculate <math>r_2^3.</math> {{RoundBoxBottom}} =Further Reading or Review= {{RoundBoxTop|theme=2}} {{testing}} * [[../To Get You Started/ | Previous Lesson: To Get You Started]] * [https://en.wikiversity.org/wiki/Python_Concepts/Numbers This Lesson:Numbers] * [[../Strings/ | Next Lesson: Strings]] * [[../ | Course Home Page]] {{RoundBoxBottom}} =References= {{reflist}} Python's built-in functions: [https://docs.python.org/3/library/functions.html#abs "abs()"], [https://docs.python.org/3/library/functions.html#bin "bin()"], [https://docs.python.org/3/library/functions.html#bool "bool()"], [https://docs.python.org/3/library/functions.html#complex "complex()"], [https://docs.python.org/3/library/functions.html#divmod "divmod()"], [https://docs.python.org/3.4/library/functions.html?highlight=eval#eval "eval(expression, ....)"], [https://docs.python.org/3/library/functions.html#float "float()"], [https://docs.python.org/3/library/functions.html#hex "hex()"], [https://docs.python.org/3/library/functions.html#int "int()"], [https://docs.python.org/3/library/functions.html#oct "oct()"], [https://docs.python.org/3/library/functions.html#pow "pow()"], [https://docs.python.org/3/library/functions.html#round "round()"], [https://docs.python.org/3.4/library/sys.html?highlight=sys.exc#sys.float_info "sys.float_info"], [https://docs.python.org/3.4/library/sys.html?highlight=sys.exc#sys.int_info "sys.int_info"] Python's documentation: [https://docs.python.org/3/tutorial/introduction.html#numbers "3.1.1. Numbers"], [https://docs.python.org/3/library/stdtypes.html#typesnumeric "Numeric Types"], [https://docs.python.org/3/reference/lexical_analysis.html#integer-literals "Integer literals"], [https://docs.python.org/3/reference/lexical_analysis.html#floating-point-literals "Floating point literals"], [https://docs.python.org/3/reference/lexical_analysis.html#imaginary-literals "Imaginary literals"], [https://docs.python.org/3/reference/expressions.html#operator-precedence "Operator precedence"], [https://docs.python.org/3/faq/design.html?highlight=goto#why-are-floating-point-calculations-so-inaccurate "Why are floating-point calculations so inaccurate?"], [https://docs.python.org/3.4/tutorial/floatingpoint.html#floating-point-arithmetic-issues-and-limitations "15. Floating Point Arithmetic: Issues and Limitations"], [https://docs.python.org/3.4/library/decimal.html?highlight=decimal#module-decimal "9.4. decimal — Decimal fixed point and floating point arithmetic"], [https://docs.python.org/3/library/stdtypes.html#additional-methods-on-integer-types "4.4.2. Additional Methods on Integer Types"], [https://docs.python.org/3/library/stdtypes.html#additional-methods-on-float "4.4.3. Additional Methods on Float"] [https://docs.python.org/3/library/cmath.html?highlight=isclose#cmath.isclose "cmath.isclose(a, b, ....)"] [[Category:Python|{{SUBPAGENAME}}]] fv0ftirkxy6fdfd5ist2vqie08urb7m 0 171005 2408002 2407056 2022-07-19T14:36:36Z Young1lim 21186 /* Geometric Series Examples */ wikitext text/x-wiki Many of the functions that arise naturally in mathematics and real world applications can be extended to and regarded as complex functions, meaning the input, as well as the output, can be complex numbers <math>x+iy</math>, where <math>i=\sqrt{-1}</math>, in such a way that it is a more natural object to study. '''Complex analysis''', which used to be known as '''function theory''' or '''theory of functions of a single complex variable''', is a sub-field of analysis that studies such functions (more specifically, '''holomorphic''' functions) on the complex plane, or part (domain) or extension (Riemann surface) thereof. It notably has great importance in number theory, e.g. the [[Riemann zeta function]] (for the distribution of primes) and other <math>L</math>-functions, modular forms, elliptic functions, etc. <blockquote>The shortest path between two truths in the real domain passes through the complex domain. — [[wikipedia:Jacques_Hadamard|Jacques Hadamard]]</blockquote>In a certain sense, the essence of complex functions is captured by the principle of [[analytic continuation]].{{mathematics}} ==''' Complex Functions '''== * Complex Functions ([[Media:CAnal.1.A.CFunction.20140222.Basic.pdf|1.A.pdf]], [[Media:CAnal.1.B.CFunction.20140111.Octave.pdf|1.B.pdf]], [[Media:CAnal.1.C.CFunction.20140111.Extend.pdf|1.C.pdf]]) * Complex Exponential and Logarithm ([[Media:CAnal.5.A.CLog.20131017.pdf|5.A.pdf]], [[Media:CAnal.5.A.Octave.pdf|5.B.pdf]]) * Complex Trigonometric and Hyperbolic ([[Media:CAnal.7.A.CTrigHyper..pdf|7.A.pdf]], [[Media:CAnal.7.A.Octave..pdf|7.B.pdf]]) '''Complex Function Note''' : 1. Exp and Log Function Note ([[Media:ComplexExp.29160721.pdf|H1.pdf]]) : 2. Trig and TrigH Function Note ([[Media:CAnal.Trig-H.29160901.pdf|H1.pdf]]) : 3. Inverse Trig and TrigH Functions Note ([[Media:CAnal.Hyper.29160829.pdf|H1.pdf]]) ==''' Complex Integrals '''== * Complex Integrals ([[Media:CAnal.2.A.CIntegral.20140224.Basic.pdf|2.A.pdf]], [[Media:CAnal.2.B.CIntegral.20140117.Octave.pdf|2.B.pdf]], [[Media:CAnal.2.C.CIntegral.20140117.Extend.pdf|2.C.pdf]]) ==''' Complex Series '''== * Complex Series ([[Media:CPX.Series.20150226.2.Basic.pdf|3.A.pdf]], [[Media:CAnal.3.B.CSeries.20140121.Octave.pdf|3.B.pdf]], [[Media:CAnal.3.C.CSeries.20140303.Extend.pdf|3.C.pdf]]) ==''' Residue Integrals '''== * Residue Integrals ([[Media:CAnal.4.A.Residue.20140227.Basic.pdf|4.A.pdf]], [[Media:CAnal.4.B.pdf|4.B.pdf]], [[Media:CAnal.4.C.Residue.20140423.Extend.pdf|4.C.pdf]]) ==='''Residue Integrals Note'''=== * Laurent Series with the Residue Theorem Note ([[Media:Laurent.1.Residue.20170713.pdf|H1.pdf]]) * Laurent Series with Applications Note ([[Media:Laurent.2.Applications.20170327.pdf|H1.pdf]]) * Laurent Series and the z-Transform Note ([[Media:Laurent.3.z-Trans.20170831.pdf|H1.pdf]]) * Laurent Series as a Geometric Series Note ([[Media:Laurent.4.GSeries.20170802.pdf|H1.pdf]]) === Laurent Series and the z-Transform Example Note === * Overview ([[Media:Laurent.4.z-Example.20170926.pdf|H1.pdf]]) ====Geometric Series Examples==== * Causality ([[Media:Laurent.5.Causality.1.A.20191026n.pdf|A.pdf]], [[Media:Laurent.5.Causality.1.B.20191026.pdf|B.pdf]]) * Time Shift ([[Media:Laurent.5.TimeShift.2.A.20191028.pdf|A.pdf]], [[Media:Laurent.5.TimeShift.2.B.20191029.pdf|B.pdf]]) * Reciprocity ([[Media:Laurent.5.Reciprocity.3A.20191030.pdf|A.pdf]], [[Media:Laurent.5.Reciprocity.3B.20191031.pdf|B.pdf]]) * Combinations ([[Media:Laurent.5.Combination.4A.20200702.pdf|A.pdf]], [[Media:Laurent.5.Combination.4B.20201002.pdf|B.pdf]]) * Properties ([[Media:Laurent.5.Property.5A.20220105.pdf|A.pdf]], [[Media:Laurent.5.Property.5B.20220126.pdf|B.pdf]]) * Applications ([[Media:Laurent.6.Application.6A.20210719.pdf|A.pdf]], [[Media:Laurent.5.Application.6B.20210928.pdf|B.pdf]]) * Double Pole Case :- Examples ([[Media:Laurent.5.DPoleEx.7A.20220718.pdf|A.pdf]], [[Media:Laurent.5.DPoleEx.7B.20220718.pdf|B.pdf]]) :- Properties ([[Media:Laurent.5.DPoleProp.5A.20190226.pdf|A.pdf]], [[Media:Laurent.5.DPoleProp.5B.20190228.pdf|B.pdf]]) ====The Case Examples==== * Example Overview : ([[Media:Laurent.4.Example.0.A.20171208.pdf|0A.pdf]], [[Media:Laurent.6.CaseExample.0.B.20180205.pdf|0B.pdf]]) * Example Case 1 : ([[Media:Laurent.4.Example.1.A.20171107.pdf|1A.pdf]], [[Media:Laurent.4.Example.1.B.20171227.pdf|1B.pdf]]) * Example Case 2 : ([[Media:Laurent.4.Example.2.A.20171107.pdf|2A.pdf]], [[Media:Laurent.4.Example.2.B.20171227.pdf|2B.pdf]]) * Example Case 3 : ([[Media:Laurent.4.Example.3.A.20171017.pdf|3A.pdf]], [[Media:Laurent.4.Example.3.B.20171226.pdf|3B.pdf]]) * Example Case 4 : ([[Media:Laurent.4.Example.4.A.20171017.pdf|4A.pdf]], [[Media:Laurent.4.Example.4.B.20171228.pdf|4B.pdf]]) * Example Summary : ([[Media:Laurent.4.Example.5.A.20171212.pdf|5A.pdf]], [[Media:Laurent.4.Example.5.B.20171230.pdf|5B.pdf]]) ==''' Conformal Mapping '''== * Conformal Mapping ([[Media:CAnal.6.A.Conformal.20131224.pdf|6.A.pdf]], [[Media:CAnal.6.A.Octave..pdf|6.B.pdf]]) go to [ [[Electrical_%26_Computer_Engineering_Studies]] ] [[Category:Complex analysis]] trxj88q16ln7zgnxw18oqta0gntb32g 2408010 2408002 2022-07-19T14:41:49Z Young1lim 21186 /* Geometric Series Examples */ wikitext text/x-wiki Many of the functions that arise naturally in mathematics and real world applications can be extended to and regarded as complex functions, meaning the input, as well as the output, can be complex numbers <math>x+iy</math>, where <math>i=\sqrt{-1}</math>, in such a way that it is a more natural object to study. '''Complex analysis''', which used to be known as '''function theory''' or '''theory of functions of a single complex variable''', is a sub-field of analysis that studies such functions (more specifically, '''holomorphic''' functions) on the complex plane, or part (domain) or extension (Riemann surface) thereof. It notably has great importance in number theory, e.g. the [[Riemann zeta function]] (for the distribution of primes) and other <math>L</math>-functions, modular forms, elliptic functions, etc. <blockquote>The shortest path between two truths in the real domain passes through the complex domain. — [[wikipedia:Jacques_Hadamard|Jacques Hadamard]]</blockquote>In a certain sense, the essence of complex functions is captured by the principle of [[analytic continuation]].{{mathematics}} ==''' Complex Functions '''== * Complex Functions ([[Media:CAnal.1.A.CFunction.20140222.Basic.pdf|1.A.pdf]], [[Media:CAnal.1.B.CFunction.20140111.Octave.pdf|1.B.pdf]], [[Media:CAnal.1.C.CFunction.20140111.Extend.pdf|1.C.pdf]]) * Complex Exponential and Logarithm ([[Media:CAnal.5.A.CLog.20131017.pdf|5.A.pdf]], [[Media:CAnal.5.A.Octave.pdf|5.B.pdf]]) * Complex Trigonometric and Hyperbolic ([[Media:CAnal.7.A.CTrigHyper..pdf|7.A.pdf]], [[Media:CAnal.7.A.Octave..pdf|7.B.pdf]]) '''Complex Function Note''' : 1. Exp and Log Function Note ([[Media:ComplexExp.29160721.pdf|H1.pdf]]) : 2. Trig and TrigH Function Note ([[Media:CAnal.Trig-H.29160901.pdf|H1.pdf]]) : 3. Inverse Trig and TrigH Functions Note ([[Media:CAnal.Hyper.29160829.pdf|H1.pdf]]) ==''' Complex Integrals '''== * Complex Integrals ([[Media:CAnal.2.A.CIntegral.20140224.Basic.pdf|2.A.pdf]], [[Media:CAnal.2.B.CIntegral.20140117.Octave.pdf|2.B.pdf]], [[Media:CAnal.2.C.CIntegral.20140117.Extend.pdf|2.C.pdf]]) ==''' Complex Series '''== * Complex Series ([[Media:CPX.Series.20150226.2.Basic.pdf|3.A.pdf]], [[Media:CAnal.3.B.CSeries.20140121.Octave.pdf|3.B.pdf]], [[Media:CAnal.3.C.CSeries.20140303.Extend.pdf|3.C.pdf]]) ==''' Residue Integrals '''== * Residue Integrals ([[Media:CAnal.4.A.Residue.20140227.Basic.pdf|4.A.pdf]], [[Media:CAnal.4.B.pdf|4.B.pdf]], [[Media:CAnal.4.C.Residue.20140423.Extend.pdf|4.C.pdf]]) ==='''Residue Integrals Note'''=== * Laurent Series with the Residue Theorem Note ([[Media:Laurent.1.Residue.20170713.pdf|H1.pdf]]) * Laurent Series with Applications Note ([[Media:Laurent.2.Applications.20170327.pdf|H1.pdf]]) * Laurent Series and the z-Transform Note ([[Media:Laurent.3.z-Trans.20170831.pdf|H1.pdf]]) * Laurent Series as a Geometric Series Note ([[Media:Laurent.4.GSeries.20170802.pdf|H1.pdf]]) === Laurent Series and the z-Transform Example Note === * Overview ([[Media:Laurent.4.z-Example.20170926.pdf|H1.pdf]]) ====Geometric Series Examples==== * Causality ([[Media:Laurent.5.Causality.1.A.20191026n.pdf|A.pdf]], [[Media:Laurent.5.Causality.1.B.20191026.pdf|B.pdf]]) * Time Shift ([[Media:Laurent.5.TimeShift.2.A.20191028.pdf|A.pdf]], [[Media:Laurent.5.TimeShift.2.B.20191029.pdf|B.pdf]]) * Reciprocity ([[Media:Laurent.5.Reciprocity.3A.20191030.pdf|A.pdf]], [[Media:Laurent.5.Reciprocity.3B.20191031.pdf|B.pdf]]) * Combinations ([[Media:Laurent.5.Combination.4A.20200702.pdf|A.pdf]], [[Media:Laurent.5.Combination.4B.20201002.pdf|B.pdf]]) * Properties ([[Media:Laurent.5.Property.5A.20220105.pdf|A.pdf]], [[Media:Laurent.5.Property.5B.20220126.pdf|B.pdf]]) * Applications ([[Media:Laurent.6.Application.6A.20210719.pdf|A.pdf]], [[Media:Laurent.5.Application.6B.20210928.pdf|B.pdf]]) * Double Pole Case :- Examples ([[Media:Laurent.5.DPoleEx.7A.20220719.pdf|A.pdf]], [[Media:Laurent.5.DPoleEx.7B.20220719.pdf|B.pdf]]) :- Properties ([[Media:Laurent.5.DPoleProp.5A.20190226.pdf|A.pdf]], [[Media:Laurent.5.DPoleProp.5B.20190228.pdf|B.pdf]]) ====The Case Examples==== * Example Overview : ([[Media:Laurent.4.Example.0.A.20171208.pdf|0A.pdf]], [[Media:Laurent.6.CaseExample.0.B.20180205.pdf|0B.pdf]]) * Example Case 1 : ([[Media:Laurent.4.Example.1.A.20171107.pdf|1A.pdf]], [[Media:Laurent.4.Example.1.B.20171227.pdf|1B.pdf]]) * Example Case 2 : ([[Media:Laurent.4.Example.2.A.20171107.pdf|2A.pdf]], [[Media:Laurent.4.Example.2.B.20171227.pdf|2B.pdf]]) * Example Case 3 : ([[Media:Laurent.4.Example.3.A.20171017.pdf|3A.pdf]], [[Media:Laurent.4.Example.3.B.20171226.pdf|3B.pdf]]) * Example Case 4 : ([[Media:Laurent.4.Example.4.A.20171017.pdf|4A.pdf]], [[Media:Laurent.4.Example.4.B.20171228.pdf|4B.pdf]]) * Example Summary : ([[Media:Laurent.4.Example.5.A.20171212.pdf|5A.pdf]], [[Media:Laurent.4.Example.5.B.20171230.pdf|5B.pdf]]) ==''' Conformal Mapping '''== * Conformal Mapping ([[Media:CAnal.6.A.Conformal.20131224.pdf|6.A.pdf]], [[Media:CAnal.6.A.Octave..pdf|6.B.pdf]]) go to [ [[Electrical_%26_Computer_Engineering_Studies]] ] [[Category:Complex analysis]] 286b26mcfkwp4ghmy6m7ku7vbllhtqa 0 203942 2408032 2407530 2022-07-19T16:47:34Z Young1lim 21186 /* Monads III : Mutable State Monads */ wikitext text/x-wiki ==Introduction== * Overview I ([[Media:HSKL.Overview.1.A.20160806.pdf |pdf]]) * Overview II ([[Media:HSKL.Overview.2.A.20160926.pdf |pdf]]) * Overview III ([[Media:HSKL.Overview.3.A.20161011.pdf |pdf]]) * Overview IV ([[Media:HSKL.Overview.4.A.20161104.pdf |pdf]]) * Overview V ([[Media:HSKL.Overview.5.A.20161108.pdf |pdf]]) </br> ==Applications== * Sudoku Background ([[Media:Sudoku.Background.0.A.20161108.pdf |pdf]]) * Bird's Implementation :- Specification ([[Media:Sudoku.1Bird.1.A.Spec.20170425.pdf |pdf]]) :- Rules ([[Media:Sudoku.1Bird.2.A.Rule.20170201.pdf |pdf]]) :- Pruning ([[Media:Sudoku.1Bird.3.A.Pruning.20170211.pdf |pdf]]) :- Expanding ([[Media:Sudoku.1Bird.4.A.Expand.20170506.pdf |pdf]]) </br> ==Using GHCi== * Getting started ([[Media:GHCi.Start.1.A.20170605.pdf |pdf]]) </br> ==Using Libraries== * Library ([[Media:Library.1.A.20170605.pdf |pdf]]) </br> </br> ==Function Oriented Typeclasses== === Background === * Constructors ([[Media:Background.1.A.Constructor.20180904.pdf |pdf]]) * TypeClasses ([[Media:Background.1.B.TypeClass.20180904.pdf |pdf]]) * Functions ([[Media:Background.1.C.Function.20180712.pdf |pdf]]) * Expressions ([[Media:Background.1.D.Expression.20180707.pdf |pdf]]) * Operators ([[Media:Background.1.E.Operator.20180707.pdf |pdf]]) === Functors === * Functor Overview ([[Media:Functor.1.A.Overview.20180802.pdf |pdf]]) * Function Functor ([[Media:Functor.2.A.Function.20180804.pdf |pdf]]) * Functor Lifting ([[Media:Functor.2.B.Lifting.20180721.pdf |pdf]]) === Applicatives === * Applicatives Overview ([[Media:Applicative.3.A.Overview.20180606.pdf |pdf]]) * Applicatives Methods ([[Media:Applicative.3.B.Method.20180519.pdf |pdf]]) * Function Applicative ([[Media:Applicative.3.A.Function.20180804.pdf |pdf]]) * Applicatives Sequencing ([[Media:Applicative.3.C.Sequencing.20180606.pdf |pdf]]) === Monads I : Background === * Side Effects ([[Media:Monad.P1.1A.SideEffect.20190316.pdf |pdf]]) * Monad Overview ([[Media:Monad.P1.2A.Overview.20190308.pdf |pdf]]) * Monadic Operations ([[Media:Monad.P1.3A.Operations.20190308.pdf |pdf]]) * Maybe Monad ([[Media:Monad.P1.4A.Maybe.201900606.pdf |pdf]]) * IO Actions ([[Media:Monad.P1.5A.IOAction.20190606.pdf |pdf]]) * Several Monad Types ([[Media:Monad.P1.6A.Types.20191016.pdf |pdf]]) === Monads II : State Transformer Monads === * State Transformer : - State Transformer Basics ([[Media:MP2.1A.STrans.Basic.20191002.pdf |pdf]]) : - State Transformer Generic Monad ([[Media:MP2.1B.STrans.Generic.20191002.pdf |pdf]]) : - State Transformer Monads ([[Media:MP2.1C.STrans.Monad.20191022.pdf |pdf]]) * State Monad : - State Monad Basics ([[Media:MP2.2A.State.Basic.20190706.pdf |pdf]]) : - State Monad Methods ([[Media:MP2.2B.State.Method.20190706.pdf |pdf]]) : - State Monad Examples ([[Media:MP2.2C.State.Example.20190706.pdf |pdf]]) === Monads III : Mutable State Monads === * Mutability Background : - Types ([[Media:MP3.1A.Mut.Type.20200721.pdf |pdf]]) : - Primitive Types ([[Media:MP3.1B.Mut.PrimType.20200611.pdf |pdf]]) : - Polymorphic Types ([[Media:MP3.1C.Mut.Polymorphic.20201212.pdf |pdf]]) : - Continuation Passing Style ([[Media:MP3.1D.Mut.Continuation.20220110.pdf |pdf]]) : - Expressions ([[Media:MP3.1E.Mut.Expression.20220628.pdf |pdf]]) : - Lambda Calculus ([[Media:MP3.1F.Mut.LambdaCal.20220718.pdf |pdf]]) : - Non-terminating Expressions ([[Media:MP3.1F.Mut.Non-terminating.20220616.pdf |pdf]]) : - Inhabitedness ([[Media:MP3.1F.Mut.Inhabited.20220319.pdf |pdf]]) : - Existential Types ([[Media:MP3.1E.Mut.Existential.20220128.pdf |pdf]]) : - forall Keyword ([[Media:MP3.1E.Mut.forall.20210316.pdf |pdf]]) : - Mutability and Strictness ([[Media:MP3.1C.Mut.Strictness.20200613.pdf |pdf]]) : - Strict and Lazy Packages ([[Media:MP3.1D.Mut.Package.20200620.pdf |pdf]]) * Mutable Objects : - Mutable Variables ([[Media:MP3.1B.Mut.Variable.20200224.pdf |pdf]]) : - Mutable Data Structures ([[Media:MP3.1D.Mut.DataStruct.20191226.pdf |pdf]]) * IO Monad : - IO Monad Basics ([[Media:MP3.2A.IO.Basic.20191019.pdf |pdf]]) : - IO Monad Methods ([[Media:MP3.2B.IO.Method.20191022.pdf |pdf]]) : - IORef Mutable Variable ([[Media:MP3.2C.IO.IORef.20191019.pdf |pdf]]) * ST Monad : - ST Monad Basics ([[Media:MP3.3A.ST.Basic.20191031.pdf |pdf]]) : - ST Monad Methods ([[Media:MP3.3B.ST.Method.20191023.pdf |pdf]]) : - STRef Mutable Variable ([[Media:MP3.3C.ST.STRef.20191023.pdf |pdf]]) === Monads IV : Reader and Writer Monads === * Function Monad ([[Media:Monad.10.A.Function.20180806.pdf |pdf]]) * Monad Transformer ([[Media:Monad.3.I.Transformer.20180727.pdf |pdf]]) * MonadState Class :: - State & StateT Monads ([[Media:Monad.9.A.MonadState.Monad.20180920.pdf |pdf]]) :: - MonadReader Class ([[Media:Monad.9.B.MonadState.Class.20180920.pdf |pdf]]) * MonadReader Class :: - Reader & ReaderT Monads ([[Media:Monad.11.A.Reader.20180821.pdf |pdf]]) :: - MonadReader Class ([[Media:Monad.12.A.MonadReader.20180821.pdf |pdf]]) * Control Monad ([[Media:Monad.9.A.Control.20180908.pdf |pdf]]) === Monoid === * Monoids ([[Media:Monoid.4.A.20180508.pdf |pdf]]) === Arrow === * Arrows ([[Media:Arrow.1.A.20190504.pdf |pdf]]) </br> ==Polymorphism== * Polymorphism Overview ([[Media:Poly.1.A.20180220.pdf |pdf]]) </br> ==Concurrent Haskell == </br> go to [ [[Electrical_%26_Computer_Engineering_Studies]] ] ==External links== * [http://learnyouahaskell.com/introduction Learn you Haskell] * [http://book.realworldhaskell.org/read/ Real World Haskell] * [http://www.scs.stanford.edu/14sp-cs240h/slides/ Standford Class Material] [[Category:Computer programming]] 922mtbb7zfzqtabmuhfuq3gv33p3vuj 2408034 2408032 2022-07-19T16:49:11Z Young1lim 21186 /* Monads III : Mutable State Monads */ wikitext text/x-wiki ==Introduction== * Overview I ([[Media:HSKL.Overview.1.A.20160806.pdf |pdf]]) * Overview II ([[Media:HSKL.Overview.2.A.20160926.pdf |pdf]]) * Overview III ([[Media:HSKL.Overview.3.A.20161011.pdf |pdf]]) * Overview IV ([[Media:HSKL.Overview.4.A.20161104.pdf |pdf]]) * Overview V ([[Media:HSKL.Overview.5.A.20161108.pdf |pdf]]) </br> ==Applications== * Sudoku Background ([[Media:Sudoku.Background.0.A.20161108.pdf |pdf]]) * Bird's Implementation :- Specification ([[Media:Sudoku.1Bird.1.A.Spec.20170425.pdf |pdf]]) :- Rules ([[Media:Sudoku.1Bird.2.A.Rule.20170201.pdf |pdf]]) :- Pruning ([[Media:Sudoku.1Bird.3.A.Pruning.20170211.pdf |pdf]]) :- Expanding ([[Media:Sudoku.1Bird.4.A.Expand.20170506.pdf |pdf]]) </br> ==Using GHCi== * Getting started ([[Media:GHCi.Start.1.A.20170605.pdf |pdf]]) </br> ==Using Libraries== * Library ([[Media:Library.1.A.20170605.pdf |pdf]]) </br> </br> ==Function Oriented Typeclasses== === Background === * Constructors ([[Media:Background.1.A.Constructor.20180904.pdf |pdf]]) * TypeClasses ([[Media:Background.1.B.TypeClass.20180904.pdf |pdf]]) * Functions ([[Media:Background.1.C.Function.20180712.pdf |pdf]]) * Expressions ([[Media:Background.1.D.Expression.20180707.pdf |pdf]]) * Operators ([[Media:Background.1.E.Operator.20180707.pdf |pdf]]) === Functors === * Functor Overview ([[Media:Functor.1.A.Overview.20180802.pdf |pdf]]) * Function Functor ([[Media:Functor.2.A.Function.20180804.pdf |pdf]]) * Functor Lifting ([[Media:Functor.2.B.Lifting.20180721.pdf |pdf]]) === Applicatives === * Applicatives Overview ([[Media:Applicative.3.A.Overview.20180606.pdf |pdf]]) * Applicatives Methods ([[Media:Applicative.3.B.Method.20180519.pdf |pdf]]) * Function Applicative ([[Media:Applicative.3.A.Function.20180804.pdf |pdf]]) * Applicatives Sequencing ([[Media:Applicative.3.C.Sequencing.20180606.pdf |pdf]]) === Monads I : Background === * Side Effects ([[Media:Monad.P1.1A.SideEffect.20190316.pdf |pdf]]) * Monad Overview ([[Media:Monad.P1.2A.Overview.20190308.pdf |pdf]]) * Monadic Operations ([[Media:Monad.P1.3A.Operations.20190308.pdf |pdf]]) * Maybe Monad ([[Media:Monad.P1.4A.Maybe.201900606.pdf |pdf]]) * IO Actions ([[Media:Monad.P1.5A.IOAction.20190606.pdf |pdf]]) * Several Monad Types ([[Media:Monad.P1.6A.Types.20191016.pdf |pdf]]) === Monads II : State Transformer Monads === * State Transformer : - State Transformer Basics ([[Media:MP2.1A.STrans.Basic.20191002.pdf |pdf]]) : - State Transformer Generic Monad ([[Media:MP2.1B.STrans.Generic.20191002.pdf |pdf]]) : - State Transformer Monads ([[Media:MP2.1C.STrans.Monad.20191022.pdf |pdf]]) * State Monad : - State Monad Basics ([[Media:MP2.2A.State.Basic.20190706.pdf |pdf]]) : - State Monad Methods ([[Media:MP2.2B.State.Method.20190706.pdf |pdf]]) : - State Monad Examples ([[Media:MP2.2C.State.Example.20190706.pdf |pdf]]) === Monads III : Mutable State Monads === * Mutability Background : - Types ([[Media:MP3.1A.Mut.Type.20200721.pdf |pdf]]) : - Primitive Types ([[Media:MP3.1B.Mut.PrimType.20200611.pdf |pdf]]) : - Polymorphic Types ([[Media:MP3.1C.Mut.Polymorphic.20201212.pdf |pdf]]) : - Continuation Passing Style ([[Media:MP3.1D.Mut.Continuation.20220110.pdf |pdf]]) : - Expressions ([[Media:MP3.1E.Mut.Expression.20220628.pdf |pdf]]) : - Lambda Calculus ([[Media:MP3.1F.Mut.LambdaCal.20220719.pdf |pdf]]) : - Non-terminating Expressions ([[Media:MP3.1F.Mut.Non-terminating.20220616.pdf |pdf]]) : - Inhabitedness ([[Media:MP3.1F.Mut.Inhabited.20220319.pdf |pdf]]) : - Existential Types ([[Media:MP3.1E.Mut.Existential.20220128.pdf |pdf]]) : - forall Keyword ([[Media:MP3.1E.Mut.forall.20210316.pdf |pdf]]) : - Mutability and Strictness ([[Media:MP3.1C.Mut.Strictness.20200613.pdf |pdf]]) : - Strict and Lazy Packages ([[Media:MP3.1D.Mut.Package.20200620.pdf |pdf]]) * Mutable Objects : - Mutable Variables ([[Media:MP3.1B.Mut.Variable.20200224.pdf |pdf]]) : - Mutable Data Structures ([[Media:MP3.1D.Mut.DataStruct.20191226.pdf |pdf]]) * IO Monad : - IO Monad Basics ([[Media:MP3.2A.IO.Basic.20191019.pdf |pdf]]) : - IO Monad Methods ([[Media:MP3.2B.IO.Method.20191022.pdf |pdf]]) : - IORef Mutable Variable ([[Media:MP3.2C.IO.IORef.20191019.pdf |pdf]]) * ST Monad : - ST Monad Basics ([[Media:MP3.3A.ST.Basic.20191031.pdf |pdf]]) : - ST Monad Methods ([[Media:MP3.3B.ST.Method.20191023.pdf |pdf]]) : - STRef Mutable Variable ([[Media:MP3.3C.ST.STRef.20191023.pdf |pdf]]) === Monads IV : Reader and Writer Monads === * Function Monad ([[Media:Monad.10.A.Function.20180806.pdf |pdf]]) * Monad Transformer ([[Media:Monad.3.I.Transformer.20180727.pdf |pdf]]) * MonadState Class :: - State & StateT Monads ([[Media:Monad.9.A.MonadState.Monad.20180920.pdf |pdf]]) :: - MonadReader Class ([[Media:Monad.9.B.MonadState.Class.20180920.pdf |pdf]]) * MonadReader Class :: - Reader & ReaderT Monads ([[Media:Monad.11.A.Reader.20180821.pdf |pdf]]) :: - MonadReader Class ([[Media:Monad.12.A.MonadReader.20180821.pdf |pdf]]) * Control Monad ([[Media:Monad.9.A.Control.20180908.pdf |pdf]]) === Monoid === * Monoids ([[Media:Monoid.4.A.20180508.pdf |pdf]]) === Arrow === * Arrows ([[Media:Arrow.1.A.20190504.pdf |pdf]]) </br> ==Polymorphism== * Polymorphism Overview ([[Media:Poly.1.A.20180220.pdf |pdf]]) </br> ==Concurrent Haskell == </br> go to [ [[Electrical_%26_Computer_Engineering_Studies]] ] ==External links== * [http://learnyouahaskell.com/introduction Learn you Haskell] * [http://book.realworldhaskell.org/read/ Real World Haskell] * [http://www.scs.stanford.edu/14sp-cs240h/slides/ Standford Class Material] [[Category:Computer programming]] b9mqhk2ywsg32kg502k7hu577dzn9di 102 206220 2408137 1500217 2022-07-20T07:19:30Z 41.105.178.176 wikitext text/x-wiki [[File:Nuvola apps korganizer.png|right|64px]] [[Wikiversity:Be bold|Be bold!]] Help us improve Wikiversity by participating and contributing your expertise. Post any questions you have in the [[Wikiversity:Colloquium]]. {{clear}}تاتن 59rn9f4mxob71wml6v75g1cu58nj8ki 0 207103 2408036 2404973 2022-07-19T17:41:49Z Aherman012 2943941 wikitext text/x-wiki <noinclude>{{Helping Give Away Psychological Science Banner}}</noinclude> {{medical disclaimer}} {{:{{BASEPAGENAME}}/Sidebar}} ==[[Evidence based assessment/Portfolio template/What is a "portfolio"|'''What is a "portfolio"?''']]== * For background information on what assessment portfolios are, click the link in the heading above. Want even 'more' information about this topic? There's an extended version of this page [[Evidence-based assessment/Generalized anxiety disorder (assessment portfolio)/extended version|here]]. ==[[Evidence based assessment/Preparation phase|'''Preparation phase''']]== === Diagnostic criteria for generalized anxiety disorder === {{blockquotetop}} <big>'''ICD-11 Diagnostic Criteria<ref>https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/1712535455</ref>'''</big> *Generalised anxiety disorder is characterized by marked symptoms of anxiety that persist for at least several months, for more days than not, manifested by either general apprehension (i.e. ‘free-floating anxiety’) or excessive worry focused on multiple everyday events, most often concerning family, health, finances, and school or work, together with additional symptoms such as muscular tension or motor restlessness, sympathetic autonomic over-activity, subjective experience of nervousness, difficulty maintaining concentration, irritability, or sleep disturbance. The symptoms result in significant distress or significant impairment in personal, family, social, educational, occupational, or other important areas of functioning. The symptoms are not a manifestation of another health condition and are not due to the effects of a substance or medication on the central nervous system. '''Changes in DSM-5''' * The diagnostic criteria for generalized anxiety disorder changed slightly from DSM-IV-TR to DSM-5. Summaries are available [https://www.ncbi.nlm.nih.gov/books/NBK519712/table/ch3.t9/?report=objectonly here]. {{blockquotebottom}} === Base rates of GAD in different clinical settings === This section describes the demographic setting of the population(s) sampled, base rates of diagnosis, country/region sampled and the diagnostic method that was used. Using this information, clinicians will be able to anchor the rate of GAD that they are likely to see in their clinical practice. * '''''To see prevalence rates across multiple disorders,''''' [[Evidence based assessment/Preparation phase#Base rates for transdiagnostic comparison|'''''click here.''''']] {| class="wikitable sortable" border="1" |- ! Demography ! Setting ! Base Rate ! Diagnostic Method |- | Adults and adolescences in all of U.S.A. | US National Comorbidity Survey Replication (NCS-R; age > = 13) [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005415/pdf/nihms-571992.pdf (2012)]<ref name="KesslerEtAl2012" /> |0.9% (age 13-17) 2.9% (age 18-64) 1.2% (age &gt;= 65) 2.0% (age &gt;=13) | Fully-structured Composite International Diagnostic Interview (CIDI Version 3.0) |- | Psychiatric outpatients | Individuals seeking treatment in a Psychiatric Outpatient Clinic (age range not reported) ([https://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.162.10.1911 2014])<ref name="ZimmermanEtAl2005" /> |21% | Structured Clinical Interview for DSM-IV (SCID) |- | Caucasian youth | Children seeking treatment in a Child &amp; Adolescent Anxiety Diagnostic Clinic (age 7 – 18 years old) ([http://journals.sagepub.com/doi/pdf/10.1177/1073191110375792 2011])<ref name="BrownJacobsenEtAl2011" /> |0.39% (parent report) 0.38% (child report) | Anxiety Disorders Interview Schedule for Children for DSM-IV Spence Children's Anxiety Scale (SCAS) |- | Caucasian, African American, Asian American, and Hispanic population | Collaborative Psychiatric Epidemiology Studies (CPES; age &gt;= 18, data merged from three representative national database) ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135672/pdf/nihms281333.pdf 2011])<ref>{{Cite journal|last=McLean|first=Carmen P.|last2=Asnaani|first2=Anu|last3=Litz|first3=Brett T.|last4=Hofmann|first4=Stefan G.|date=2011-08-01|title=Gender differences in anxiety disorders: Prevalence, course of illness, comorbidity and burden of illness|url=https://www.sciencedirect.com/science/article/pii/S0022395611000458|journal=Journal of Psychiatric Research|language=en|volume=45|issue=8|pages=1027–1035|doi=10.1016/j.jpsychires.2011.03.006|issn=0022-3956|pmc=PMC3135672|pmid=21439576}}</ref> |4.1% (female) 2.1% (male) | World Mental Health Survey Initiative Version of the World Health Organization Composite International Interview (WMH-CIDI) |- | Pennsylvania | Metropolitan Community Sample, all individuals with eating disorders (ages 13 – 65) ([https://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.161.12.2215 2014])<ref name="KayeEtAl2004" /> |10% | Structured Clinical Interview for DSM-IV (SCID) |- | Adolescents in all of U.S.A. | National Comorbidity Survey Replication Adolescent Supplement (NCS-A; ages 3–18 in the continental U.S) ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946114/pdf/nihms214371.pdf 2011])<ref name="MerikangasEtAl2010" /> |2.2% | World Health Organization Composite International Diagnostic Interview (WHO-CIDI) |- |Adolescents in all of U.S.A |National Comorbidity Survey Replication Adolescent Supplement (NCS-A; ages 3–18 in the continental U.S)<ref name=":3">Kessler, R. C., Avenevoli, S., Costello, E. J., Georgiades, K., Green, J. G., Gruber, M. J., . . . Merikangas, K. R. (2012). Prevalence, persistence, and sociodemographic correlates of DSM-IV disorders in the National Comorbidity Survey Replication Adolescent Supplement. Archives of General Psychiatry, 69(4), 372-380. doi:10.1001/archgenpsychiatry.2011.160</ref> |5.4% |Composite International Diagnostic Interview (CIDI) |- | North Carolina | Rural community sample African American and White youth (ages 13-16) [https://www.ncbi.nlm.nih.gov/pubmed/12365876 (2002)]<ref>{{Cite journal|last=Angold|first=Adrian|last2=Erkanli|first2=Alaattin|last3=Farmer|first3=Elizabeth M. Z.|last4=Fairbank|first4=John A.|last5=Burns|first5=Barbara J.|last6=Keeler|first6=Gordon|last7=Costello|first7=E. Jane|date=October 2002|title=Psychiatric disorder, impairment, and service use in rural African American and white youth|url=https://www.ncbi.nlm.nih.gov/pubmed/12365876|journal=Archives of General Psychiatry|volume=59|issue=10|pages=893–901|issn=0003-990X|pmid=12365876}}</ref> |1.4% | The Child and Adolescent Psychiatric Assessment (CAPA) |- | Texas | Metropolitan Community Sample (ages 11-17) ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2736593/pdf/nihms30019.pdf 2007])<ref name="RobertsEtAl2007" /> |0.4% | Diagnostic Interview Schedule for Children, Version IV (DISC-IV) |- | Midwestern Urban | Incarcerated adolescents (ages 10-18)<ref>{{Cite journal|last=ABRAM|first=KAREN M.|last2=CHOE|first2=JEANNE Y.|last3=WASHBURN|first3=JASON J.|last4=TEPLIN|first4=LINDA A.|last5=KING|first5=DEVON C.|last6=DULCAN|first6=MINA K.|title=Suicidal Ideation and Behaviors Among Youths in Juvenile Detention|url=http://linkinghub.elsevier.com/retrieve/pii/S0890856709623121|journal=Journal of the American Academy of Child & Adolescent Psychiatry|volume=47|issue=3|pages=291–300|doi=10.1097/chi.0b013e318160b3ce}}</ref> [http://vb3lk7eb4t.search.serialssolutions.com/?ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Suicidal+Ideation+and+Behaviors+Among+Youths+in+Juvenile+Detention&rft.jtitle=Journal+of+the+American+Academy+of+Child+%26+Adolescent+Psychiatry&rft.au=ABRAM%2C+KAREN+M.%2C+Ph.D&rft.au=CHOE%2C+JEANNE+Y.%2C+B.A&rft.au=WASHBURN%2C+JASON+J.%2C+Ph.D.%2C+A.B.P.P&rft.au=TEPLIN%2C+LINDA+A.%2C+Ph.D&rft.date=2008&rft.issn=0890-8567&rft.eissn=1527-5418&rft.volume=47&rft.issue=3&rft.spage=291&rft.epage=300&rft_id=info:doi/10.1097%2FCHI.0b013e318160b3ce&rft.externalDocID=1_s2_0_S0890856709623121 (2002)] |1% | Diagnostic Interview Schedule for Children, Version IV (DISC-IV) |- |Non-institutionalized general US population |LGBTQ sample (ages 20-65)<ref>{{Cite journal|last=Bostwick|first=Wendy B.|last2=Boyd|first2=Carol J.|last3=Hughes|first3=Tonda L.|last4=McCabe|first4=Sean Esteban|date=2010-3|title=Dimensions of Sexual Orientation and the Prevalence of Mood and Anxiety Disorders in the United States|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820045/|journal=American Journal of Public Health|volume=100|issue=3|pages=468–475|doi=10.2105/AJPH.2008.152942|issn=0090-0036|pmc=PMC2820045|pmid=19696380}}</ref> [http://ajph.aphapublications.org/doi/10.2105/AJPH.2008.152942 (2013)] |Women: 14.8% same-sex 22.5% bisexual Men: 16.9% same-sex 11.5% bisexual |The Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV) |- |Non-institutionalized general US population |Cross-ethnic American population (ages 18+)<ref>{{Cite journal|last=Asnaani|first=Anu|last2=Richey|first2=J. Anthony|last3=Dimaite|first3=Ruta|last4=Hinton|first4=Devon E.|last5=Hofmann|first5=Stefan G.|date=2010-8|title=A Cross-Ethnic Comparison of Lifetime Prevalence Rates of Anxiety Disorders|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931265/|journal=The Journal of nervous and mental disease|volume=198|issue=8|pages=551–555|doi=10.1097/NMD.0b013e3181ea169f|issn=0022-3018|pmc=PMC2931265|pmid=20699719}}</ref> [https://journals.lww.com/jonmd/Abstract/2010/08000/A_Cross_Ethnic_Comparison_of_Lifetime_Prevalence.4.aspx (2018)] |White 8.6% African Americans 4.9% Hispanic Americans 5.8% Asian Americans 2.4% |World Mental Health Survey Initiative Version of the World Health Organization Composite International Interview (WMH-CIDI) |- |Outpatient clinics worldwide |Samples across multiple studies worldwide (all ages)<ref name=":12">{{Cite journal|last=Rettew|first=David C.|last2=Lynch|first2=Alicia Doyle|last3=Achenbach|first3=Thomas M.|last4=Dumenci|first4=Levent|last5=Ivanova|first5=Masha Y.|date=2009-09|title=Meta-analyses of agreement between diagnoses made from clinical evaluations and standardized diagnostic interviews|url=http://dx.doi.org/10.1002/mpr.289|journal=International Journal of Methods in Psychiatric Research|language=en|volume=18|issue=3|pages=169–184|doi=10.1002/mpr.289|issn=1049-8931}}</ref> |5% |Clinical evaluations |- |Outpatient clinic worldwide |Samples across multiple studies worldwide (all ages)<ref name=":12" /> |10% |Standardized Diagnostic Interviews (SDIs) |} '''Search terms:''' [General Anxiety Disorder] AND [youth OR adolescents OR pediatric] AND [prevalence OR incidence] in GoogleScholar and PsycINFO == [[Evidence based assessment/Prediction phase|'''Prediction phase''']] == === Psychometric properties of screening instruments for GAD === The following section contains a list of screening and diagnostic instruments for generalized anxiety disorder. The section includes administration information, psychometric data, and PDFs or links to the screenings. * Screenings are used as part of the [[Evidence based assessment/Prediction phase|prediction phase]] of assessment; for more information on interpretation of this data, or how screenings fit in to the assessment process, click [[Evidence based assessment/Prediction phase|here]]. * '''''For a list of more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Psychometric_properties_of_common_screening_instruments click here.]''''' {| class="wikitable sortable" border="1" ! colspan="5" |Screening measures for GAD |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time ! style="width:12em" | Where to Access |- |Generalized Anxiety Disorder Screener (GAD-7)<ref name=":0" /> |Questionnaire (Self-report) |18+ |5 minutes |[https://www.pfizerpcoa.com/general-anxiety-disorder-7-gad-7-screener GAD-7 homepage] [https://osf.io/szmpu GAD-7] |- | Penn State Worry Questionnaire (PSWQ)<ref name=":0">{{Cite book|url=https://www.worldcat.org/oclc/314222270|title=A guide to assessments that work|date=2008|publisher=Oxford University Press|author=Hunsley, John |author2=Mash, Eric J.|isbn=9780195310641|location=New York|oclc=314222270}}</ref> | Questionnaire (Adult Version, Child Version) | 18+ (Adult Version), 6-18 (Child Version) | 4 minutes |[http://www.midss.org/content/penn-state-worry-questionnaire-pswq PSWQ homepage] [https://mfr.osf.io/render?url=https://osf.io/s7p38/?action=download%26mode=render PSWQ Adult Version] [https://mfr.osf.io/render?url=https://osf.io/6q8y9/?action=download%26mode=render PSWQ Child Version] [https://mfr.osf.io/render?url=https://osf.io/gx5sr/?action=download%26mode=render PSWC-C Korean] [https://mfr.osf.io/render?url=https://osf.io/hc6n2/?action=download%26mode=render PSWQ-C Danish] [https://mfr.osf.io/render?url=https://osf.io/fwbes/?action=download%26mode=render Scoring the PSWQ-C] |- |[[wikipedia:Screen_for_child_anxiety_related_disorders|Screen for Child Anxiety Related Emotional Disorder (SCARED)]]<ref name=":0" /> | Questionnaire (Child, Parent) | 8-19 | 9 or 16 minutes |[http://www.midss.org/content/screen-child-anxiety-related-disorders-scared SCARED] homepage [[wikipedia:Screen_for_child_anxiety_related_disorders#PDFs_and_automated_scoring_for_SCARED|SCARED English + Translations & Automatic Scoring]] |- |Child Behavior Checklist (CBCL)<ref name=":0" /> |Questionnaire (Parent report) |6-18 |10 minutes |[https://aseba.org/ ASEBA homepage][https://store.aseba.org/ Purchase] |} === Likelihood ratios and AUCs of screening instruments for GAD === * '''''For a list of the likelihood ratios for more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Likelihood_ratios_and_AUCs_of_common_screening_instruments click here.]''''' {| class="wikitable sortable" border="1" ! Screening Measure (Primary Reference) ! Area Under Curve (AUC) ! LR+ (Score) ! LR- (Score) ! Clinical Generalizability !Where to Access |- | Penn State Worry Questionnaire (PSWQ)<ref name=":2">{{Cite journal|last=Fresco|first=David M.|last2=Mennin|first2=Douglas S.|last3=Heimberg|first3=Richard G.|last4=Turk|first4=Cynthia L.|title=Using the Penn State Worry Questionnaire to identify individuals with generalized anxiety disorder: a receiver operating characteristic analysis|url=http://linkinghub.elsevier.com/retrieve/pii/S0005791603000569|journal=Journal of Behavior Therapy and Experimental Psychiatry|volume=34|issue=3-4|pages=283–291|doi=10.1016/j.jbtep.2003.09.001}}</ref> | 0.74 (N=164) | 1.8 (65+) | 0.5 (< 65) | Generalized Anxiety Disorder vs. social anxiety disorder, adults presenting to specialty anxiety clinic |[https://mfr.osf.io/render?url=https://osf.io/s7p38/?action=download%26mode=render PSWQ Adult Version] [https://mfr.osf.io/render?url=https://osf.io/6q8y9/?action=download%26mode=render PSWQ Child Version] |- | Generalized Anxiety Disorder Screener (GAD-7)<ref name=":5">{{Cite journal|last=Plummer|first=Faye|last2=Manea|first2=Laura|last3=Trepel|first3=Dominic|last4=McMillan|first4=Dean|date=2016-03-01|title=Screening for anxiety disorders with the GAD-7 and GAD-2: a systematic review and diagnostic metaanalysis|url=https://www.sciencedirect.com/science/article/pii/S0163834315002406|journal=General Hospital Psychiatry|language=en|volume=39|pages=24–31|doi=10.1016/j.genhosppsych.2015.11.005|issn=0163-8343}}</ref> | 0.906<ref>{{Cite journal|last=Spitzer|first=Robert L.|last2=Kroenke|first2=Kurt|last3=Williams|first3=Janet B. W.|last4=Löwe|first4=Bernd|date=2006-05-22|title=A Brief Measure for Assessing Generalized Anxiety Disorder: The GAD-7|url=http://archinte.jamanetwork.com/article.aspx?doi=10.1001/archinte.166.10.1092|journal=Archives of Internal Medicine|language=en|volume=166|issue=10|pages=1092|doi=10.1001/archinte.166.10.1092|issn=0003-9926}}</ref> (N = 2149) | 5.17 (8+)<ref name=":5" /> | .20 (8-)<ref name=":5" /> | Adults aged 16 years and older in any setting (meta-analysis) |[https://osf.io/szmpu GAD-7] |- |[[wikipedia:Screen_for_child_anxiety_related_disorders#PDFs_and_automated_scoring_for_SCARED|Screen for Child Anxiety Related Disorders (SCARED)]]<ref name="BirmaherEtAl1997" /> | .70 (N=243) | 5.0 (+32) | .04 | High: Pure anxiety disorder versus non-anxiety psychiatric disorder, excluding children with disruptive disorder and depression |[http://www.midss.org/content/penn-state-worry-questionnaire-pswq SCARED English + Translations & Automatic Scoring] |- |CBCL Anxious/Depressed Scale T-score<ref>{{Cite journal|last=Eimecke|first=Sylvia D.|last2=Remschmidt|first2=Helmut|last3=Mattejat|first3=Fritz|date=2011-03|title=Utility of the Child Behavior Checklist in screening depressive disorders within clinical samples|url=https://linkinghub.elsevier.com/retrieve/pii/S0165032710005458|journal=Journal of Affective Disorders|language=en|volume=129|issue=1-3|pages=191–197|doi=10.1016/j.jad.2010.08.011}}</ref> |.75 (N = 1445) |1.49 (9+) |.67(9-) |Inpatient and outpatient children and adolescents |[https://store.aseba.org/ Purchase] |} '''Note:''' “LR+” refers to the change in likelihood ratio associated with a positive test score, and “LR-” is the likelihood ratio for a low score. Likelihood ratios of 1 indicate that the test result did not change impressions at all. LRs larger than 10 or smaller than .10 are frequently clinically decisive; 5 or .20 are helpful, and between 2.0 and .5 are small enough that they rarely result in clinically meaningful changes of formulation<ref>Sackett, D. L., Straus, S. E., Richardson, W. S., Rosenberg, W., & Haynes, R. B. (2000). Evidence-based medicine: How to practice and teach EBM. Edinburgh: Churchill Livingstone.</ref>. '''Search terms:''' [General Anxiety Disorder] AND [children OR adolescents OR pediatric] AND [sensitivity OR specificity] in GoogleScholar and PsycINFO === Interpreting depression screening measure scores === * For information on interpreting screening measure scores, click [[Evidence based assessment/Prediction phase#Interpreting screening measure scores|here.]] ==[[Evidence based assessment/Prescription phase|'''Prescription phase''']]== ===Gold standard diagnostic interviews=== * For a list of broad reaching diagnostic interviews sortable by disorder with PDFs (if applicable), [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prescription_phase&wteswitched=1#Common_Diagnostic_Interviews click here.] === Recommended diagnostic instruments for GAD === {| class="wikitable sortable" ! colspan="5" |Diagnostic instruments for GAD |- !Measure !Format (Reporter) !Age Range !Administration/ Completion Time !Where to Access |- |Anxiety Disorders Interview Schedule for Children/Parent<ref name=":1">{{Cite journal|date=2001-08-01|title=Test-Retest Reliability of Anxiety Symptoms and Diagnoses With the Anxiety Disorders Interview Schedule for DSM-IV: Child and Parent Versions|url=https://www.sciencedirect.com/science/article/pii/S0890856709603427|journal=Journal of the American Academy of Child & Adolescent Psychiatry|language=en|volume=40|issue=8|pages=937–944|doi=10.1097/00004583-200108000-00016|issn=0890-8567}}</ref> |Structured Interview (Child (ADIS-C), Parent (ADIS-P)) |6-16<ref>{{Cite journal|last=LYNEHAM|first=HEIDI J.|last2=ABBOTT|first2=MAREE J.|last3=RAPEE|first3=RONALD M.|date=2007-06|title=Interrater Reliability of the Anxiety Disorders Interview Schedule for DSM-IV: Child and Parent Version|url=https://doi.org/10.1097/chi.0b013e3180465a09|journal=Journal of the American Academy of Child &amp; Adolescent Psychiatry|volume=46|issue=6|pages=731–736|doi=10.1097/chi.0b013e3180465a09|issn=0890-8567}}</ref> |Varies |[https://books.google.com/books/about/Anxiety_Disorders_Interview_Schedule_for.html?id=xpR6V3rboxwC Purchase] |- |Anxiety and Related Disorders Interview Schedule for DSM-5 (ADIS-5)<ref name=":0" /> |Structured Interview (Adult) |16+ |Varies |[https://global.oup.com/academic/product/anxiety-and-related-disorders-interview-schedule-for-dsm-5-adis-5---adult-version-9780199325160?cc=us&lang=en& Purchase] |- |Structured Clinical Interview for DSM-5-Clinician Version (SCID-5-CV)<ref>{{Cite journal|last=Shabani|first=Amir|last2=Masoumian|first2=Samira|last3=Zamirinejad|first3=Somayeh|last4=Hejri|first4=Maryam|last5=Pirmorad|first5=Tahereh|last6=Yaghmaeezadeh|first6=Hooman|date=2021-05|title=Psychometric properties of Structured Clinical Interview for DSM‐5 Disorders‐Clinician Version (SCID‐5‐CV)|url=https://onlinelibrary.wiley.com/doi/10.1002/brb3.1894|journal=Brain and Behavior|language=en|volume=11|issue=5|doi=10.1002/brb3.1894|issn=2162-3279|pmc=PMC8119811|pmid=33729681}}</ref> |Structured Interview (Adult ) |16+ |Varies |[https://www.columbiapsychiatry.org/research/research-labs/diagnostic-and-assessment-lab/structured-clinical-interview-dsm-disorders-11 Website and purchase] |} ==[[Evidence based assessment/Process phase|'''Process phase''']]== The following section contains a list of process and outcome measures for generalized anxiety disorder. The section includes benchmarks based on published norms for several outcome and severity measures, as well as information about commonly used process measures. Process and outcome measures are used as part of the [[Evidence based assessment/Process phase|process phase]] of assessment. For more information of differences between process and outcome measures, see the page on the [[Evidence based assessment/Process phase|process phase of assessment]]. === Process measures === === Outcome and severity measures === * This table includes clinically significant benchmarks for '''(insert portfolio name here)''' specific outcome measures * Information on how to interpret this table can be [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase found here]. * Additionally, these [[Evidence based assessment/Vignettes|vignettes]] might be helpful resources for understanding appropriate adaptation of outcome measures in practice. *''<u>For clinically significant change benchmarks for the CBCL, YSR, and TRF total, externalizing, internalizing, and attention benchmarks,</u>'' [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase&wteswitched=1#Clinically_significant_change_benchmarks_for_widely-used_outcome_measures see here.] {| class="wikitable sortable" border="1" | colspan="7" |'''Clinically significant change benchmarks with common instruments for GAD''' |- | rowspan=1" style="text-align:center;font-size:130%;" | <b> Measure</b> | colspan="3" style="text-align:center;font-size:130%" width="300" | <b> Cut-off scores</b> | colspan="3" style="text-align:center;font-size:120%" | <b> Critical Change <br> (unstandardized scores)</b> |- | colspan="7" span style="font-size:110%; text-align:center;" | <b> Benchmarks Based on Published Norms</b> |- | colspan="1" | | style="text-align:center;font-size:110%" | <b> A</b> | style="text-align:center;font-size:110%" | <b> B</b> | style="text-align:center;font-size:110%" | <b> C</b> | style="text-align:center;font-size:110%" | <b> 95%</b> | style="text-align:center;font-size:110%" | <b> 90%</b> | style="text-align:center;font-size:110%" | <b> SE_difference</b> |- | rowspan="1" style="text-align:center;" | <b> GAD-7</b> | style=“text-align:center;”| -1 | style=“text-align:center;”| 1.3 | style=“text-align:center;”| 0.5 | style=“text-align:center;”| 0.6 | style=“text-align:center;”| 0.5 | style=“text-align:center;”| 0.3 |- | rowspan="1" style="text-align:center;" | <b> PSWQ</b> | style=“text-align:center;”| 51 | style=“text-align:center;”| 73 | style=“text-align:center;”| 59 | style=“text-align:center;”| 9 | style=“text-align:center;”| 8 | style=“text-align:center;”| 4.8 |- | rowspan="1" style="text-align:center;" | <b> SCARED </b> | style=“text-align:center;”| 9.9 | style=“text-align:center;”| 18.1 | style=“text-align:center;”| 15.3 | style=“text-align:center;”| 8.9 | style=“text-align:center;”| 7.5 | style=“text-align:center;”| 4.5 |} '''Note:''' “A” = Away from the clinical range, “B” = Back into the nonclinical range, “C” = Closer to the nonclinical than clinical mean. '''Search terms:''' [General Anxiety Disorder] AND [children OR adolescents OR pediatric] AND [clinical significance OR outcomes] in GoogleScholar and PsycINFO === Treatment === {{collapse top| Click here for treatment information}} Individuals suffering from GAD tend to be high users of outpatient medical care. When treating GAD, physicians should first determine whether pharmacotherapy, psychotherapy, or a combination of the two treatments would be most beneficial to the patient. Literature suggests that treatment of GAD frequently consists of a combination of psychotherapy and pharmacotherapy. Although these therapies have the potential to be effective individually, previous work demonstrates that when combined the degree of clinically significant change increases significantly. Recent studies (e.g., Gorman, 2003<ref name="Gorman2003" />; Walkup et al., 2008<ref name="WalkupEtAl2008" />) have provided evidence to support this claim with the most efficacious medication and behavioral interventions listed below. # '''Medication Interventions''' ## ''Sertraline (Zoloft)'' has been shown to reduce experiences and effects of GAD above and beyond that of placebo conditions. ## ''Pregabalin.'' The mean baseline-to-endpoint decreases in total Hamilton anxiety scale score in the patients given 150 mg/day of pregabalin (–9.2) was significantly greater than the decrease in those given placebo (–6.8)<ref name="PandeEtAl2003" />. ## ''Paroxetine.'' Remission was achieved by 30% of patients in the 20-mg paroxetine groups compared with 20% given placebo. For all three domains of the Sheehan Disability Scale, significantly greater improvement was seen with paroxetine than placebo<ref name="RickelsEtAl2003" />. # '''Behavioral interventions''' ## ''Cognitive behavioral therapy.'' Fourteen 60-minute sessions, which include CBT in anxiety-management skills, followed by behavioral exposure to anxiety-provoking situations have been shown to be effective in treating GAD. A review of studies by Fisher and Durham (1999)<ref name="FisherEtAl1999" /> revealed significant recovery rates at a 6 month follow up after CBT. ## ''Exposure therapy and modeling therapy.'' One meta-analysis found that virtual reality exposure therapy for anxiety disorders had a large effect size (Cohen's d=1.11) compared to controls.<ref>{{Cite journal|last=Powers|first=Mark B.|last2=Emmelkamp|first2=Paul M.G.|title=Virtual reality exposure therapy for anxiety disorders: A meta-analysis|url=https://doi.org/10.1016/j.janxdis.2007.04.006|journal=Journal of Anxiety Disorders|volume=22|issue=3|pages=561–569|doi=10.1016/j.janxdis.2007.04.006}}</ref> ## ''Mindfulness meditation.'' New treatment options such as mindfulness meditation-based stress reduction interventions have also shown to reduce symptoms over the long-term.<ref>{{Cite journal|last=Miller|first=J. J.|last2=Fletcher|first2=K.|last3=Kabat-Zinn|first3=J.|date=May 1995|title=Three-year follow-up and clinical implications of a mindfulness meditation-based stress reduction intervention in the treatment of anxiety disorders|url=https://www.ncbi.nlm.nih.gov/pubmed/7649463|journal=General Hospital Psychiatry|volume=17|issue=3|pages=192–200|issn=0163-8343|pmid=7649463}}</ref> # '''Combination treatment''' ## Previous research suggests that combination therapy that includes components of psychotherapy and pharmacotherapy are the most efficacious in treating GAD. In a study comparing the efficacies GAD treatments, Walkup and colleagues demonstrated a 21-25% improvement of combination therapy over cognitive behavioral therapy or sertraline alone during short-term treatment. These findings suggest that among effective treatments, combination therapy has the potential to provide the best chance for a positive outcome. See Gorman, 2003<ref name="Gorman2003" />; Walkup et al., 2008<ref name="WalkupEtAl2008" />. {{collapse bottom}} * Please refer to the page on [[wikipedia:Generalized_anxiety_disorder|generalized anxiety disorder]] for more information on available treatment or go to [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/fear-worry-and-anxiety/ Effective Child Therapy] for a curated resource on effective treatments for GAD. *For information on conducting Exposure Therapy for anxiety disordered youth, see [https://www.bravepracticeforkids.com/ www.BravePracticeForKids.com] =='''External Resources'''== # [http://apps.who.int/classifications/icd10/browse/2010/en#/F41.1 ICD-10 diagnostic criteria] # [https://en.wikiversity.org/w/index.php?title=Helping_Give_Away_Psychological_Science/Resources/Annotated_List_of_Where_and_How_to_Find_a_Therapist&wteswitched=1#Other_low-cost_options Find-a-Therapist] #*This is a curated list of find-a-therapist websites where you can find a provider # [https://www.nimh.nih.gov/health/topics/anxiety-disorders/index.shtml NIMH] entry about anxiety disorders # OMIM (Online Mendelian Inheritance in Man) #*[https://www.omim.org/entry/607834 607834] # [https://emedicine.medscape.com/article/286227-overview#a2 eMedicine entry about anxiety disorders] #[https://sccap53.org Society of Clinical Child and Adolescent Psychology] #[http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/fear-worry-and-anxiety/ Effective Child Therapy information on Fear, Worry, & Anxiety] #*Effective Child Therapy is website sponsored by Division 53 of the American Psychological Association (APA), or The [https://sccap53.org Society of Clinical Child and Adolescent Psychology] (SCCAP), in collaboration with the Association for Behavioral and Cognitive Therapies (ABCT). Use for information on symptoms and available treatments. #[http://pediatricbipolar.pitt.edu/resources/instruments Links to SCARED Child, Parent, and Adult + Translations] =='''References'''== {{collapse top|Click here for references}} {{Reflist|3|refs= <ref name="BirmaherEtAl1997">{{cite journal|last1=Birmaher|first1=B|last2=Khetarpal|first2=S|last3=Brent|first3=D|last4=Cully|first4=M|last5=Balach|first5=L|last6=Kaufman|first6=J|last7=Neer|first7=SM|title=The Screen for Child Anxiety Related Emotional Disorders (SCARED): scale construction and psychometric characteristics.|journal=Journal of the American Academy of Child and Adolescent Psychiatry|date=April 1997|volume=36|issue=4|pages=545-53|pmid=9100430}}</ref> <ref name="BrownJacobsenEtAl2011">{{cite journal|last1=Brown-Jacobsen|first1=AM|last2=Wallace|first2=DP|last3=Whiteside|first3=SP|title=Multimethod, multi-informant agreement, and positive predictive value in the identification of child anxiety disorders using the SCAS and ADIS-C.|journal=Assessment|date=September 2011|volume=18|issue=3|pages=382-92|pmid=20644080}}</ref> <ref name="CostelloEtAl1996">{{cite journal|last1=Costello|first1=EJ|last2=Angold|first2=A|last3=Burns|first3=BJ|last4=Stangl|first4=DK|last5=Tweed|first5=DL|last6=Erkanli|first6=A|last7=Worthman|first7=CM|title=The Great Smoky Mountains Study of Youth. 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journal|last1=Merikangas|first1=KR|last2=He|first2=JP|last3=Burstein|first3=M|last4=Swanson|first4=SA|last5=Avenevoli|first5=S|last6=Cui|first6=L|last7=Benjet|first7=C|last8=Georgiades|first8=K|last9=Swendsen|first9=J|title=Lifetime prevalence of mental disorders in U.S. adolescents: results from the National Comorbidity Survey Replication--Adolescent Supplement (NCS-A).|journal=Journal of the American Academy of Child and Adolescent Psychiatry|date=October 2010|volume=49|issue=10|pages=980-9|pmid=20855043}}</ref> <ref name="PandeEtAl2003">{{cite journal|last1=Pande|first1=AC|last2=Crockatt|first2=JG|last3=Feltner|first3=DE|last4=Janney|first4=CA|last5=Smith|first5=WT|last6=Weisler|first6=R|last7=Londborg|first7=PD|last8=Bielski|first8=RJ|last9=Zimbroff|first9=DL|last10=Davidson|first10=JR|last11=Liu-Dumaw|first11=M|title=Pregabalin in generalized anxiety disorder: a placebo-controlled trial.|journal=The American journal of psychiatry|date=March 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review of the Revised Children's Manifest Anxiety Scale, the State-Trait Anxiety Inventory for Children, and the Child Behavior Checklist.|journal=Journal of clinical child and adolescent psychology : the official journal for the Society of Clinical Child and Adolescent Psychology, American Psychological Association, Division 53|date=September 2004|volume=33|issue=3|pages=557-65|pmid=15271613}}</ref> <ref name="WalkupEtAl2008">{{cite journal|last1=Walkup|first1=JT|last2=Albano|first2=AM|last3=Piacentini|first3=J|last4=Birmaher|first4=B|last5=Compton|first5=SN|last6=Sherrill|first6=JT|last7=Ginsburg|first7=GS|last8=Rynn|first8=MA|last9=McCracken|first9=J|last10=Waslick|first10=B|last11=Iyengar|first11=S|last12=March|first12=JS|last13=Kendall|first13=PC|title=Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety.|journal=The New England journal of medicine|date=25 December 2008|volume=359|issue=26|pages=2753-66|pmid=18974308}}</ref> <ref name="WhitakerEtAl1990">{{cite journal|last1=Whitaker|first1=A|last2=Johnson|first2=J|last3=Shaffer|first3=D|last4=Rapoport|first4=JL|last5=Kalikow|first5=K|last6=Walsh|first6=BT|last7=Davies|first7=M|last8=Braiman|first8=S|last9=Dolinsky|first9=A|title=Uncommon troubles in young people: prevalence estimates of selected psychiatric disorders in a nonreferred adolescent population.|journal=Archives of general psychiatry|date=May 1990|volume=47|issue=5|pages=487-96|pmid=2331210}}</ref> <ref name="SpitzerEtAl2006">{{cite journal|last1=Spitzer|first1=RL|last2=Kroenke|first2=K|last3=Williams|first3=JB|last4=Löwe|first4=B|title=A brief measure for assessing generalized anxiety disorder: the GAD-7.|journal=Archives of internal medicine|date=22 May 2006|volume=166|issue=10|pages=1092-7|pmid=16717171}}</ref> <ref name="vanGastelEtAl2008">{{cite journal|last1=van Gastel|first1=W|last2=Ferdinand|first2=RF|title=Screening capacity of the Multidimensional Anxiety Scale for Children (MASC) for DSM-IV anxiety disorders.|journal=Depression and anxiety|date=2008|volume=25|issue=12|pages=1046-52|pmid=18833579}}</ref> <ref name="WoodEtAl2002">{{cite journal|last1=Wood|first1=JJ|last2=Piacentini|first2=JC|last3=Bergman|first3=RL|last4=McCracken|first4=J|last5=Barrios|first5=V|title=Concurrent validity of the anxiety disorders section of the Anxiety Disorders Interview Schedule for DSM-IV: child and parent versions.|journal=Journal of clinical child and adolescent psychology : the official journal for the Society of Clinical Child and Adolescent Psychology, American Psychological Association, Division 53|date=September 2002|volume=31|issue=3|pages=335-42|pmid=12149971}}</ref> <ref name="ZimmermanEtAl2005">{{cite journal|last1=Zimmerman|first1=M|last2=Rothschild|first2=L|last3=Chelminski|first3=I|title=The prevalence of DSM-IV personality disorders in psychiatric outpatients.|journal=The American journal of psychiatry|date=October 2005|volume=162|issue=10|pages=1911-8|pmid=16199838}}</ref> }} {{collapse bottom|Click here for references}} [[Category:Psychological disorder portfolios|{{SUBPAGENAME}}]] iu6d3ok1k2uieitjxycmyzhs3jez712 0 215948 2408045 2394968 2022-07-19T20:15:38Z KlayLay 2946787 Downplaying innovation wikitext text/x-wiki {{Wikidebate}} {{Economics}} Capitalism is the predominant economic system of our time. But can it remain so? Systems like mercantilism and serfdom lasted for centuries before the establishment of the {{W|Bretton Woods system}}. Have we reached what political theorist {{W|Francis Fukuyama}} has called the "end of history" where liberal democracy matched with free markets are the last viable option for organizing society? If capitalism is to be overthrown, what could replace it and would it be a step forward or back? == Capitalism is sustainable == === Arguments for === * {{Argument for}} There's no viable alternative. ** {{Objection}} This doesn't imply that capitalism is sustainable. ** {{Objection}} An alternative will surface as soon as it becomes necessary. Unenvisioned alternatives have greater plausibility of surfacing with the access to technologies, scientific abilities, tools and processes which didn't exist in former eras. *** {{Objection}} Relying on as-yet unenvisioned alternatives is pure speculation. * {{Argument for}} Although Marx predicted that capitalism is a necessary stage for an eventual worker's revolution, capitalists after Marx have been able to slowly adjust capitalism so that it can sustain itself indefinitely. The shifts from the Industrial Revolution to globalized financial capitalism have made it impossible for workers to ever overthrow the upper class. ** {{Objection}} This argument assumes what must be proven. The fact that capitalism has been slowly adjusting to sustain itself doesn't mean that it will continue to be able to do so. Economists will try, no doubt. *{{Argument for}} Economic growth under capitalism can be separated from unsustainable resource consumption. There is not a fixed supply of resources that is used up, because new resources can be discovered or developed. In other words, advancing technology enables us to access resources which were formerly unreachable. **{{Objection}} While new resources can be used, existing market forces can downplay innovation due to the risk of investing in new products. For example, if an innovation results in reduced demand (although specific to markets), those whose business depends on selling said product have an incentive to control the impacts of such innovation. This could result in the adoption or ''suppression'' of such innovation, as we've seen with the fossil fuels industry. Additionally, those who control much of the market have less of a reason to invest in new technology as it's unlikely they will be outcompeted. === Arguments against === * {{Argument against}} Capitalism requires constant growth,{{Citation needed}} and constant growth is impossible in a limited planet. ** {{Objection}} The planet is not the limit. There's an endless Universe awaiting. *** {{Objection}} Massive space colonization is unfeasible in the near future. We need a solution sooner. *** {{Objection}} If we cannot manage in this planet, how can we even hope to manage others much more hostile? **** {{Objection}} Other planets are relatively benign compared to earth with nothing actually trying to kill humans nor do they have ecosystems to protect, and there are also space habitats. ***** {{Objection}} Like which ones? Naboo? Space habitats disregard resource extraction, they lack rich ecosystems at entropy levels that allow this. Feasible planets to live in, wether hostile or not, are merely fictional, as the ones we may find, will require energy to make habitable for humans, and quite probably, as our knowledge of existing planets suggests, unimaginable amounts of energy, more that we could gather or have the technology to extract. So this argument reduces to a low probability high risk endeavor with many ifs, if we find a planet, if we we are technologically developed enough, etc. which proves the point of capitalism not being sustainable in the first place. ** {{Objection}} Even assuming constant growth is required to sustain capitalism, this is constant economic growth, which is not equivalent to a constant increase in resource consumption. Economic growth based on intellectual property and more efficient use of existing resources (asymptotically approaching perfect efficiency) can be maintained in a finite system. *** {{Objection}} Economic growth based on intellectual property, which manifest as physical inventions and digital goods, still requires resources: people eating, using computers, servers running, etc. energy in general. To try to most efficiently use resources one would need to put the natural environment in a central role, capitalism abstracts and obfuscates the value of natural resources as it detaches them from the communities that learned to survive with those resources, it does not asymptotically approach perfect efficiency, it breaks the ecosystemic chain, almost always running counter to energy, eg. a plastic cup which costs one dollar and takes enormous effort, machinery and workers to produce. It prioritizes growth of only capital, it establishes an asymmetric relation that benefits a few, immensely more than the remaining majority. The energy in the system is finite, it is just distributed unequally, and it's systems crystalize future distribution, leading to non optimal use of resources and permanent destruction of others. In it's "pure" ideological form capitalism completely disregards the natural environment, even paints it as an obstacle or enemy, in the name of individual or market "freedom". * {{Argument against}} Capitalism breaks the second law of thermodynamics. Disregards energy and the natural environment over capital growth. The universe does not care though, it just reflects back, therefore becoming a recipe for destruction to the ones using it as their ultimate rule. == See also == * [[Should we colonize Mars?]] == Notes and references == {{Reflist}} [[Category:Economics]] dqrbeh0u05pu4ds9nlukserikwsanu2 2 222546 2408142 2391229 2022-07-20T09:34:39Z Bert Niehaus 2387134 /* Wiki Redirect */ wikitext text/x-wiki {{#babel:de-N|en-3|nl-2}} <!-- {{userboxtop}} {{User Wikiversity custodian}} {{userboxbottom}} --> Engelbert Niehaus is full Professor for Mathematics and Mathematics Education at the University Koblenz-Landau and is head of the Computer Science Centre in Landau (Germany). Supports * [[Open Community Approach]] of [http://at6fui.weebly.com EFG-SGH/AT6FUI], * [[Open Educational Resources]] for [[w:Capacity Building|Capacity Building]] and [[Risk Management]] {{userpage}} == Direct Links to Work in Progress == * [[Wiki2Reveal]] * [[v:de:Kurs:Stochastik|Kurs:Stochastik]] * [[v:de:Kurs:Funktionentheorie|Kurs:Funktionentheorie]] * [[v:de:Digitale Lernumgebung|Digitale Lernumgebungen]] * [[Water]] * [[3D Modelling]] * [[Space and Global Health]] == Tools and Informations for my Work == === Audio in Wiki Articles === * '''(Inline Audio)''' see [[Wikipedia:Template:Audio]] for inline audio :: '''Alabama''' ({{Audio|en-us-Alabama.ogg|pronunciation}}) is a state located in... : <code><nowiki>'''Alabama''' ({{Audio|en-us-Alabama.ogg|pronunciation}}) is a state located in...</nowiki></code> * '''(Audio Player)''' import audio file just like an image as media file. Now embedded audio file will be displayed with an audio player in the right column. [[File:Accordion chords-01.ogg|thumb|Accordion Audio Sample with Chords]] : <code><nowiki>[[File:Accordion chords-01.ogg|thumb|Accordion Audio Sample with Chords]]</nowiki></code> * '''(Slide Audio Comments)''' Audio comments can be used as slide comments to generate [[PanDocElectron|PanDoc-Presentations]] with audio comments for a single slide. Parsing of Wiki source text must be adapted (see also [https://github.com/spencermountain/wtf_wikipedia#wiki2reveal---on-the-fly-cross-compilation-into-a-presentation wtf_wikipedia.js] repository of Spencer Kelly. * '''([[/Wiki2Reveal/|Wiki2Reveal Audio Demo]])''' The Wiki2Reveal-Audio demo is a test page which includes audio comments in the slides === Wiki Redirect === * [https://en.wikipedia.org/wiki/Wikipedia:Redirect Redirect] <code><nowiki>#REDIRECT&nbsp;[[3D Modelling]]</nowiki></code> === Wiki Quiz === [[/Quiz/|Example Quiz]] showing the basic quiz elements. === Wiki Translations of Pages === * [https://en.wikipedia.org/wiki/Help:Interlanguage_links Interlanguage Links]: To add a new interlanguage link to a learning resource visible in the language menu on the right, add the following code at the end e.g. of the Wikiversity page [[Water]]: <pre> <noinclude>[[de:Wasser]]</noinclude> </pre> After saving the article in Wikiversity an interlanguage link will be shown on the left in the menu to the translation. Vice versa add the following interlanguage link to the german article about water "[[v:de:Wasser|Wasser]]" === Tools === Tools, that are created for Wikiversity support of learning resources are created as privacy friendly [[AppLSAC]] software, that runs online and offline in a modern browser. * '''[https://niebert.github.io/Wikipedia2Wikiversity Wikipedia2Wikiversity]''' Link converter, that converts the Wikipedia links to interwiki links when you want to use Wikipedia content in a learning resouce (always a citation to the source wikipedia version of the article, if you use the the tool for learning resources - see "cite this page" in MediaWiki menu) * '''Wikipedia to Wikiversity Import:''' [[Special:Import]] for converting a Wikipedia article into a learning resource. * '''[https://niebert.github.io/imgmap ImageMap Editor]''' for using [[Image Map]]s in Wikiversity (forked HTML5 tool that removed server dependencies - runs offline as ZIP-download) * '''[[PanDocElectron]]''' Wrapper for PanDoc developed by John MacFarlane to convert Wikipedia sources into Office documents, webbased presentations PDF documents, LaTeX documents, and many other output formats (see [https://www.pandoc.org/try PanDoc Try ...]) * '''[https://tools.wmflabs.org/videoconvert/ Wikiversity Video Upload]''' including WEBM conversion (see [https://commons.wikimedia.org/wiki/Help:Converting_video Help:Converting Videos]) * '''[https://commons.wikimedia.org/wiki/Commons:Commonist Commonist Video Uploader to Wikimedia Commons]''' - an open source upload load tool for media to [https://commons.wikimedia.org/wiki/Main_Page WikiMedia Commons] written in Java. * '''[https://niebert.github.io/TranslationCorrection4Wiki Syntax Correction after G00GLE-Translation]''' - translation corrupts Wiki syntax by injection of unnecessary blanks. This tool correct this Media Wiki parsing errors especially for mathematical formulas. * '''[[Wiki2Reveal]]''' Create RevealJS presenation on-the-fly from Wikiversity articles. Maintaining the presentation is done just by editing the the source page in Wikiversity. Pilot was performed in a [[v:de:Kurs:Funktionalanalysis|german Mathematics lecture]], Presentations are create in conjunction with [https://niebert.github.io/Wikipedia2Wikiversity Wikipedia2Wikiversity] to create a raw version for the lecture, that kept the references to the encyclopedic definitions in Wikiversity so that the learner can click on the links even in the presentation and the learner can look up specific definitions in the lectures they my not know in detail. [[Wiki2Reveal]] is an OpenSource tool for Wikiversity learning resources [https://www.github.com/niebert7Wiki2Reveal deployed on GitHub]. It is designed as an [[AppLSAC]] so that you can [download the tool an run that on the client === Shell Commands === [[File:PanDoc_Wikiversity.webm|thumb|WEBM Video - final size 22MB]] Convert a '''mp4'''-Video with audio into a '''webm''' that can: : <code>ffmpeg -i input.mp4 -vcodec vp9 -acodec libopus output.webm</code> or without conversion of audio stream : <code>ffmpeg -i input.mp4 -vcodec vp9 output.webm</code> Code Compression example for PanDocElectron * Recorded Screencast with [https://obsproject.com/ OBS] in mov-Format (size 198MB) * Converted MOV into MPEG4 with [https://handbrake.fr/ HandBrake] (size 25MB) * Converted MPEG4 into WEBM format with ffmpeg (size 21MB) File size matters to reduce network traffic costs for the WikiFoundation. Encourage students to minimize Video for learning resources in seminars, even if they comment that transcoding with ffmpeg takes very long. == Quiz Examples in Wikiversity == * [[Plasmas/Plasma objects/Auroras/Quiz|Sun Aurora Quiz]] == PanDoc Presentations == * [[/OER und PanDoc/]] (german presentation) * [[/OER and Wikiversity/|Open Educational Resources and Wikiversity - From Scientific Results to tailored Educational Support]] * [[/KnitR-Example/]] == Selected Contributions == * Started the [[Expert Focus Group for Space and Global Health]] in Wikiversity as part of the [[Expert_Focus_Group_for_Space_and_Global_Health/Community_of_Practice|Community of Practice]] * [[Water]] - Assigned to [[Sustainable Development Goals]] and showed application of topic for different target groups of learners.  == Analysis of Community Feedback == * [[/2017/]] * [[/2021/]] == Resources == * [https://en.wikiversity.org/w/index.php?title=Special:PrefixIndex&prefix=User:Bert+Niehaus/Books/ WikiBooks] - Tests and Releases == Used Tools == * '''[[Special:Import]]''' - fork wikipdia resources and create a learning resources. ** This avoids typsetting of mathematical formulas over and over again. ** the previous history of the imported document will be accessible. ** '''Remark:''' Import is not possible for all users. The community must decide how and if forking of [[Open Educational Resources]] should or will be supported in general. The '''primary driver for forking''' is the provision of '''tailored educational resources''' for the requirements and constraints of the target group of learners or institutional requirements that determine the adaption of learning resources. * '''[[/Syntax Highlight/]]''' are useful to provide a way to implement a mathematical algorithm e.g. in a specific language. The syntax highlight helps the learner to understand the structure of the code and do their own coding experiments e.g. in Octace, Python, Maxima or perform a learning task based on the documented code. == Acknowledgements == Special thanks to: * Prof. Dr. Marlien Herselman ([[Living Lab]] Support) * Dr. Adele Botha ([https://openbadges.org/ Open Badges]) for Digital Certificates for Capacity Building * [https://de.wikiversity.org/wiki/Benutzer:Platzm Dr. Melanie Platz] ([https://de.wikiversity.org/wiki/Spezial:Beitr%C3%A4ge/Platzm Contributions]) * [[User:Dave Braunschweig|Prof. Dr. Dave Braunschweig]] (Wikiversity Support for Risk Management, [[OER]]) * Jörg Rapp * Matthias Größler * Svenja Müller (Hundemer) * Anna Fath-Streb Furthermore see [http://at6fui.weebly.com/acknowledgements.html EFG-SGH/AT6FUI Acknowledgements] <noinclude>[[de:User:Bert_Niehaus]]</noinclude> 8cz2vu3kurfairnmmwwyfx5vfvsa9ix 2408145 2408142 2022-07-20T10:05:22Z Bert Niehaus 2387134 /* Wiki Quiz */ wikitext text/x-wiki {{#babel:de-N|en-3|nl-2}} <!-- {{userboxtop}} {{User Wikiversity custodian}} {{userboxbottom}} --> Engelbert Niehaus is full Professor for Mathematics and Mathematics Education at the University Koblenz-Landau and is head of the Computer Science Centre in Landau (Germany). Supports * [[Open Community Approach]] of [http://at6fui.weebly.com EFG-SGH/AT6FUI], * [[Open Educational Resources]] for [[w:Capacity Building|Capacity Building]] and [[Risk Management]] {{userpage}} == Direct Links to Work in Progress == * [[Wiki2Reveal]] * [[v:de:Kurs:Stochastik|Kurs:Stochastik]] * [[v:de:Kurs:Funktionentheorie|Kurs:Funktionentheorie]] * [[v:de:Digitale Lernumgebung|Digitale Lernumgebungen]] * [[Water]] * [[3D Modelling]] * [[Space and Global Health]] == Tools and Informations for my Work == === Audio in Wiki Articles === * '''(Inline Audio)''' see [[Wikipedia:Template:Audio]] for inline audio :: '''Alabama''' ({{Audio|en-us-Alabama.ogg|pronunciation}}) is a state located in... : <code><nowiki>'''Alabama''' ({{Audio|en-us-Alabama.ogg|pronunciation}}) is a state located in...</nowiki></code> * '''(Audio Player)''' import audio file just like an image as media file. Now embedded audio file will be displayed with an audio player in the right column. [[File:Accordion chords-01.ogg|thumb|Accordion Audio Sample with Chords]] : <code><nowiki>[[File:Accordion chords-01.ogg|thumb|Accordion Audio Sample with Chords]]</nowiki></code> * '''(Slide Audio Comments)''' Audio comments can be used as slide comments to generate [[PanDocElectron|PanDoc-Presentations]] with audio comments for a single slide. Parsing of Wiki source text must be adapted (see also [https://github.com/spencermountain/wtf_wikipedia#wiki2reveal---on-the-fly-cross-compilation-into-a-presentation wtf_wikipedia.js] repository of Spencer Kelly. * '''([[/Wiki2Reveal/|Wiki2Reveal Audio Demo]])''' The Wiki2Reveal-Audio demo is a test page which includes audio comments in the slides === Wiki Redirect === * [https://en.wikipedia.org/wiki/Wikipedia:Redirect Redirect] <code><nowiki>#REDIRECT&nbsp;[[3D Modelling]]</nowiki></code> === Wiki Quiz === [[/Quiz/|Example Quiz]] showing the basic quiz elements - see also [[Help:Quiz]]. === Wiki Translations of Pages === * [https://en.wikipedia.org/wiki/Help:Interlanguage_links Interlanguage Links]: To add a new interlanguage link to a learning resource visible in the language menu on the right, add the following code at the end e.g. of the Wikiversity page [[Water]]: <pre> <noinclude>[[de:Wasser]]</noinclude> </pre> After saving the article in Wikiversity an interlanguage link will be shown on the left in the menu to the translation. Vice versa add the following interlanguage link to the german article about water "[[v:de:Wasser|Wasser]]" === Tools === Tools, that are created for Wikiversity support of learning resources are created as privacy friendly [[AppLSAC]] software, that runs online and offline in a modern browser. * '''[https://niebert.github.io/Wikipedia2Wikiversity Wikipedia2Wikiversity]''' Link converter, that converts the Wikipedia links to interwiki links when you want to use Wikipedia content in a learning resouce (always a citation to the source wikipedia version of the article, if you use the the tool for learning resources - see "cite this page" in MediaWiki menu) * '''Wikipedia to Wikiversity Import:''' [[Special:Import]] for converting a Wikipedia article into a learning resource. * '''[https://niebert.github.io/imgmap ImageMap Editor]''' for using [[Image Map]]s in Wikiversity (forked HTML5 tool that removed server dependencies - runs offline as ZIP-download) * '''[[PanDocElectron]]''' Wrapper for PanDoc developed by John MacFarlane to convert Wikipedia sources into Office documents, webbased presentations PDF documents, LaTeX documents, and many other output formats (see [https://www.pandoc.org/try PanDoc Try ...]) * '''[https://tools.wmflabs.org/videoconvert/ Wikiversity Video Upload]''' including WEBM conversion (see [https://commons.wikimedia.org/wiki/Help:Converting_video Help:Converting Videos]) * '''[https://commons.wikimedia.org/wiki/Commons:Commonist Commonist Video Uploader to Wikimedia Commons]''' - an open source upload load tool for media to [https://commons.wikimedia.org/wiki/Main_Page WikiMedia Commons] written in Java. * '''[https://niebert.github.io/TranslationCorrection4Wiki Syntax Correction after G00GLE-Translation]''' - translation corrupts Wiki syntax by injection of unnecessary blanks. This tool correct this Media Wiki parsing errors especially for mathematical formulas. * '''[[Wiki2Reveal]]''' Create RevealJS presenation on-the-fly from Wikiversity articles. Maintaining the presentation is done just by editing the the source page in Wikiversity. Pilot was performed in a [[v:de:Kurs:Funktionalanalysis|german Mathematics lecture]], Presentations are create in conjunction with [https://niebert.github.io/Wikipedia2Wikiversity Wikipedia2Wikiversity] to create a raw version for the lecture, that kept the references to the encyclopedic definitions in Wikiversity so that the learner can click on the links even in the presentation and the learner can look up specific definitions in the lectures they my not know in detail. [[Wiki2Reveal]] is an OpenSource tool for Wikiversity learning resources [https://www.github.com/niebert7Wiki2Reveal deployed on GitHub]. It is designed as an [[AppLSAC]] so that you can [download the tool an run that on the client === Shell Commands === [[File:PanDoc_Wikiversity.webm|thumb|WEBM Video - final size 22MB]] Convert a '''mp4'''-Video with audio into a '''webm''' that can: : <code>ffmpeg -i input.mp4 -vcodec vp9 -acodec libopus output.webm</code> or without conversion of audio stream : <code>ffmpeg -i input.mp4 -vcodec vp9 output.webm</code> Code Compression example for PanDocElectron * Recorded Screencast with [https://obsproject.com/ OBS] in mov-Format (size 198MB) * Converted MOV into MPEG4 with [https://handbrake.fr/ HandBrake] (size 25MB) * Converted MPEG4 into WEBM format with ffmpeg (size 21MB) File size matters to reduce network traffic costs for the WikiFoundation. Encourage students to minimize Video for learning resources in seminars, even if they comment that transcoding with ffmpeg takes very long. == Quiz Examples in Wikiversity == * [[Plasmas/Plasma objects/Auroras/Quiz|Sun Aurora Quiz]] == PanDoc Presentations == * [[/OER und PanDoc/]] (german presentation) * [[/OER and Wikiversity/|Open Educational Resources and Wikiversity - From Scientific Results to tailored Educational Support]] * [[/KnitR-Example/]] == Selected Contributions == * Started the [[Expert Focus Group for Space and Global Health]] in Wikiversity as part of the [[Expert_Focus_Group_for_Space_and_Global_Health/Community_of_Practice|Community of Practice]] * [[Water]] - Assigned to [[Sustainable Development Goals]] and showed application of topic for different target groups of learners.  == Analysis of Community Feedback == * [[/2017/]] * [[/2021/]] == Resources == * [https://en.wikiversity.org/w/index.php?title=Special:PrefixIndex&prefix=User:Bert+Niehaus/Books/ WikiBooks] - Tests and Releases == Used Tools == * '''[[Special:Import]]''' - fork wikipdia resources and create a learning resources. ** This avoids typsetting of mathematical formulas over and over again. ** the previous history of the imported document will be accessible. ** '''Remark:''' Import is not possible for all users. The community must decide how and if forking of [[Open Educational Resources]] should or will be supported in general. The '''primary driver for forking''' is the provision of '''tailored educational resources''' for the requirements and constraints of the target group of learners or institutional requirements that determine the adaption of learning resources. * '''[[/Syntax Highlight/]]''' are useful to provide a way to implement a mathematical algorithm e.g. in a specific language. The syntax highlight helps the learner to understand the structure of the code and do their own coding experiments e.g. in Octace, Python, Maxima or perform a learning task based on the documented code. == Acknowledgements == Special thanks to: * Prof. Dr. Marlien Herselman ([[Living Lab]] Support) * Dr. Adele Botha ([https://openbadges.org/ Open Badges]) for Digital Certificates for Capacity Building * [https://de.wikiversity.org/wiki/Benutzer:Platzm Dr. Melanie Platz] ([https://de.wikiversity.org/wiki/Spezial:Beitr%C3%A4ge/Platzm Contributions]) * [[User:Dave Braunschweig|Prof. Dr. Dave Braunschweig]] (Wikiversity Support for Risk Management, [[OER]]) * Jörg Rapp * Matthias Größler * Svenja Müller (Hundemer) * Anna Fath-Streb Furthermore see [http://at6fui.weebly.com/acknowledgements.html EFG-SGH/AT6FUI Acknowledgements] <noinclude>[[de:User:Bert_Niehaus]]</noinclude> ekhrbaonokb400s5ky8m3o2qnhg3n7r 0 232469 2408106 2407548 2022-07-20T04:20:35Z Young1lim 21186 /* ARM Assembly Programming (II) */ wikitext text/x-wiki == '''Background''' == '''Combinational and Sequential Circuits''' * [[Media:DD2.B.4..Adder.20131007.pdf |Adder]] * [[Media:DD3.A.1.LatchFF.20160308.pdf |Latches and Flipflops]] '''FSM''' * [[Media:DD3.A.3.FSM.20131030.pdf |FSM]] * [[Media:CArch.2.A.Bubble.20131021.pdf |FSM Example]] '''Tiny CPU Example''' * [[Media:CDsgn6.TinyCPU.2.A.ISA.20160511.pdf |Instruction Set]] * [[Media:CDsgn6.TinyCPU.2.B.DPath.20160502.pdf |Data Path]] * [[Media:CDsgn6.TinyCPU.2.C.CPath.20160427.pdf |Control Path]] * [[Media:CDsgn6.TinyCPU.2.D.Implement.20160513.pdf |FPGA Implementation]] </br> == '''Microprocessor Architecture''' == * ARM Architecture : - Programmer's Model ([[Media:ARM.1Arch.1A.Model.20180321.pdf |pdf]]) : - Pipelined Architecture ([[Media:ARM.1Arch.2A.Pipeline.20180419.pdf |pdf]]) * ARM Organization * ARM Cortex-M Processor Architecture * ARM Processor Cores </br> == '''Instruction Set Architecture''' == * ARM Instruction Set : - Overview ([[Media:ARM.2ISA.1A.Overview.20190611.pdf |pdf]]) : - Addressing Modes ([[Media:ARM.2ISA.2A.AddrMode.20191108.pdf |pdf]]) : - Multiple Transfer ([[Media:ARM.2ISA.3A.MTransfer.20190903.pdf |pdf]]) : - Assembler Format :: - Data Processing ([[Media:ARM.2ISA.4A.Proc.Format.20200204.pdf |pdf]]) :: - Data Transfer ([[Media:ARM.2ISA.4B.Trans.Format.20200205.pdf |pdf]]) :: - Coprocessor ([[Media:ARM.2ISA.4C.CoProc.Format.20191214.pdf |pdf]]) :: - Summary ([[Media:ARM.2ISA.4D.Summary.Format.20200205.pdf |pdf]]) : - Binary Encoding ([[Media:ARM.2ISA.5A.Encoding.201901105.pdf |pdf]]) * Thumb Instruction Set </br> == '''Assembly Programming''' == === ARM Assembly Programming (I) === * 1. Overview ([[Media:ARM.2ASM.1A.Overview.20200101.pdf |pdf]]) * 2. Example Programs ([[Media:ARM.2ASM.2A.Program.20200108.pdf |pdf]]) * 3. Addressing Modes ([[Media:ARM.2ASM.3A.Address.20200127.pdf |pdf]]) * 4. Data Transfer ([[Media:ARM.2ASM.4A.DTransfer.20200206.pdf |pdf]]) * 5. Data Processing ([[Media:ARM.2ASM.5A.DProcess.20200208.pdf |pdf]]) * 6. Control ([[Media:ARM.2ASM.6A.Control.20200215.pdf |pdf]]) * 7. Arrays ([[Media:ARM.2ASM.7A.Array.20200311.pdf |pdf]]) * 8. Data Structures ([[Media:ARM.2ASM.8A.DataStruct.20200718.pdf |pdf]]) * 9. Finite State Machines ([[Media:ARM.2ASM.9A.FSM.20200417.pdf |pdf]]) * 10. Functions ([[Media:ARM.2ASM.10A.Function.20210115.pdf |pdf]]) * 11. Parameter Passing ([[Media:ARM.2ASM.11A.Parameter.20210106.pdf |pdf]]) * 12. Stack Frames ([[Media:ARM.2ASM.12A.StackFrame.20210611.pdf |pdf]]) :: :: === ARM Assembly Programming (II) === :: * 1. Thumb instruction programming ([[Media:ARM.2ASM.Thumb.20210612.pdf |pdf]]) * 2. Exceptions ([[Media:ARM.2ASM.Exception.20220718.pdf |pdf]]) * 3. Exception Programming ([[Media:ARM.2ASM.ExceptionProg.20220311.pdf |pdf]]) * 4. Exception Handlers ([[Media:ARM.2ASM.ExceptionHandler.20220131.pdf |pdf]]) * 5. Interrupt Programming ([[Media:ARM.2ASM.InterruptProg.20211030.pdf |pdf]]) * 6. Interrupt Handlers ([[Media:ARM.2ASM.InterruptHandler.20211030.pdf |pdf]]) </br> * ARM Assembly Exercises ([[Media:ESys.3.A.ARM-ASM-Exercise.20160608.pdf |A.pdf]], [[Media:ESys.3.B.Assembly.20160716.pdf |B.pdf]]) :: === ARM Assembly Programming (III) === * 1. Fixed point arithmetic (integer division) * 2. Floating point arithmetic * 3. Matrix multiply === ARM Linking === * arm link ([[Media:arm_link.20211208.pdf |pdf]]) </br> === ARM Microcontroller Programming === * 1. Input / Output * 2. Serial / Parallel Port Interfacing * 3. Analog I/O Interfacing * 4. Communication </br> == '''Architectural Support''' == </br> '''ARM Architectural Support''' * High Level Languages * System Development * Operating Systems </br> == '''Memory and Peripheral Architecture''' == </br> == '''System and Peripheral Buses''' == </br> == '''Serial Bus''' == </br> == '''Interrupts and Exceptions ''' == </br> == '''Timers ''' == </br> == '''Synchrnoization'''== </br> === H/W and S/W Synchronization === * busy wait synchronization * handshake interface </br> === Interrupt Synchronization === * interrupt synchronization * reentrant programming * buffered IO * periodic interrupt * periodic polling </br> ==''' Interfacing '''== </br> === Time Interfacing === * input capture * output compare </br> === Serial Interfacing === * Programming UART * Programming SPI * Programming I2C * Programming USB </br> === Analog Interfacing === * OP Amp * Filters * ADC * DAC </br>== '''Instruction Set Architecture''' == * ARM Instruction Set :: - Overview ([[Media:ARM.2ISA.1A.Overview.20180528.pdf |pdf]]) :: - Binary Encoding ([[Media:ARM.2ISA.2A.Encoding.20180528.pdf |pdf]]) :: - Assembler Format ([[Media:ARM.2ISA.3A.Format.20180528.pdf |pdf]]) * Thumb Instruction Set * ARM Assembly Language ([[Media:ESys3.1A.Assembly.20160608.pdf |pdf]]) * ARM Machine Language ([[Media:ESys3.2A.Machine.20160615.pdf |pdf]]) </br> </br> go to [ [[Electrical_%26_Computer_Engineering_Studies]] ] a646l17w7tphfgqy7lchshee00mazg3 2408108 2408106 2022-07-20T04:22:09Z Young1lim 21186 /* ARM Assembly Programming (II) */ wikitext text/x-wiki == '''Background''' == '''Combinational and Sequential Circuits''' * [[Media:DD2.B.4..Adder.20131007.pdf |Adder]] * [[Media:DD3.A.1.LatchFF.20160308.pdf |Latches and Flipflops]] '''FSM''' * [[Media:DD3.A.3.FSM.20131030.pdf |FSM]] * [[Media:CArch.2.A.Bubble.20131021.pdf |FSM Example]] '''Tiny CPU Example''' * [[Media:CDsgn6.TinyCPU.2.A.ISA.20160511.pdf |Instruction Set]] * [[Media:CDsgn6.TinyCPU.2.B.DPath.20160502.pdf |Data Path]] * [[Media:CDsgn6.TinyCPU.2.C.CPath.20160427.pdf |Control Path]] * [[Media:CDsgn6.TinyCPU.2.D.Implement.20160513.pdf |FPGA Implementation]] </br> == '''Microprocessor Architecture''' == * ARM Architecture : - Programmer's Model ([[Media:ARM.1Arch.1A.Model.20180321.pdf |pdf]]) : - Pipelined Architecture ([[Media:ARM.1Arch.2A.Pipeline.20180419.pdf |pdf]]) * ARM Organization * ARM Cortex-M Processor Architecture * ARM Processor Cores </br> == '''Instruction Set Architecture''' == * ARM Instruction Set : - Overview ([[Media:ARM.2ISA.1A.Overview.20190611.pdf |pdf]]) : - Addressing Modes ([[Media:ARM.2ISA.2A.AddrMode.20191108.pdf |pdf]]) : - Multiple Transfer ([[Media:ARM.2ISA.3A.MTransfer.20190903.pdf |pdf]]) : - Assembler Format :: - Data Processing ([[Media:ARM.2ISA.4A.Proc.Format.20200204.pdf |pdf]]) :: - Data Transfer ([[Media:ARM.2ISA.4B.Trans.Format.20200205.pdf |pdf]]) :: - Coprocessor ([[Media:ARM.2ISA.4C.CoProc.Format.20191214.pdf |pdf]]) :: - Summary ([[Media:ARM.2ISA.4D.Summary.Format.20200205.pdf |pdf]]) : - Binary Encoding ([[Media:ARM.2ISA.5A.Encoding.201901105.pdf |pdf]]) * Thumb Instruction Set </br> == '''Assembly Programming''' == === ARM Assembly Programming (I) === * 1. Overview ([[Media:ARM.2ASM.1A.Overview.20200101.pdf |pdf]]) * 2. Example Programs ([[Media:ARM.2ASM.2A.Program.20200108.pdf |pdf]]) * 3. Addressing Modes ([[Media:ARM.2ASM.3A.Address.20200127.pdf |pdf]]) * 4. Data Transfer ([[Media:ARM.2ASM.4A.DTransfer.20200206.pdf |pdf]]) * 5. Data Processing ([[Media:ARM.2ASM.5A.DProcess.20200208.pdf |pdf]]) * 6. Control ([[Media:ARM.2ASM.6A.Control.20200215.pdf |pdf]]) * 7. Arrays ([[Media:ARM.2ASM.7A.Array.20200311.pdf |pdf]]) * 8. Data Structures ([[Media:ARM.2ASM.8A.DataStruct.20200718.pdf |pdf]]) * 9. Finite State Machines ([[Media:ARM.2ASM.9A.FSM.20200417.pdf |pdf]]) * 10. Functions ([[Media:ARM.2ASM.10A.Function.20210115.pdf |pdf]]) * 11. Parameter Passing ([[Media:ARM.2ASM.11A.Parameter.20210106.pdf |pdf]]) * 12. Stack Frames ([[Media:ARM.2ASM.12A.StackFrame.20210611.pdf |pdf]]) :: :: === ARM Assembly Programming (II) === :: * 1. Thumb instruction programming ([[Media:ARM.2ASM.Thumb.20210612.pdf |pdf]]) * 2. Exceptions ([[Media:ARM.2ASM.Exception.20220719.pdf |pdf]]) * 3. Exception Programming ([[Media:ARM.2ASM.ExceptionProg.20220311.pdf |pdf]]) * 4. Exception Handlers ([[Media:ARM.2ASM.ExceptionHandler.20220131.pdf |pdf]]) * 5. Interrupt Programming ([[Media:ARM.2ASM.InterruptProg.20211030.pdf |pdf]]) * 6. Interrupt Handlers ([[Media:ARM.2ASM.InterruptHandler.20211030.pdf |pdf]]) </br> * ARM Assembly Exercises ([[Media:ESys.3.A.ARM-ASM-Exercise.20160608.pdf |A.pdf]], [[Media:ESys.3.B.Assembly.20160716.pdf |B.pdf]]) :: === ARM Assembly Programming (III) === * 1. Fixed point arithmetic (integer division) * 2. Floating point arithmetic * 3. Matrix multiply === ARM Linking === * arm link ([[Media:arm_link.20211208.pdf |pdf]]) </br> === ARM Microcontroller Programming === * 1. Input / Output * 2. Serial / Parallel Port Interfacing * 3. Analog I/O Interfacing * 4. Communication </br> == '''Architectural Support''' == </br> '''ARM Architectural Support''' * High Level Languages * System Development * Operating Systems </br> == '''Memory and Peripheral Architecture''' == </br> == '''System and Peripheral Buses''' == </br> == '''Serial Bus''' == </br> == '''Interrupts and Exceptions ''' == </br> == '''Timers ''' == </br> == '''Synchrnoization'''== </br> === H/W and S/W Synchronization === * busy wait synchronization * handshake interface </br> === Interrupt Synchronization === * interrupt synchronization * reentrant programming * buffered IO * periodic interrupt * periodic polling </br> ==''' Interfacing '''== </br> === Time Interfacing === * input capture * output compare </br> === Serial Interfacing === * Programming UART * Programming SPI * Programming I2C * Programming USB </br> === Analog Interfacing === * OP Amp * Filters * ADC * DAC </br>== '''Instruction Set Architecture''' == * ARM Instruction Set :: - Overview ([[Media:ARM.2ISA.1A.Overview.20180528.pdf |pdf]]) :: - Binary Encoding ([[Media:ARM.2ISA.2A.Encoding.20180528.pdf |pdf]]) :: - Assembler Format ([[Media:ARM.2ISA.3A.Format.20180528.pdf |pdf]]) * Thumb Instruction Set * ARM Assembly Language ([[Media:ESys3.1A.Assembly.20160608.pdf |pdf]]) * ARM Machine Language ([[Media:ESys3.2A.Machine.20160615.pdf |pdf]]) </br> </br> go to [ [[Electrical_%26_Computer_Engineering_Studies]] ] os37o5r0ed3ip1armfeuxjifapbx95y 1 248615 2407999 2124611 2022-07-19T13:29:19Z HariSinghw 2937420 /* Request to Become member of Editorial Board */ new section wikitext text/x-wiki #REDIRECT [[Talk:WikiJournal of Humanities/Editors]] == Request to Become member of Editorial Board == ==Editorial board application of Dr. Raj Kumar Yadav== {{WikiJournal editor application submitted | position =Editorial board | name =Dr. Raj Kumar Yadav | qualifications =PhD | link =http://cup.edu.in/rajkumaryadav.php | areas_of_expertise =Criminal Law, Clinical Legal Education | professional_experience =14 Years | publishing_experience =11 Years | open_experience =Wikipedia | policy_confirm =I confirm that I will act in accordance with the policies of the WikiJournal of Humanities. [[User:HariSinghw|HariSinghw]] ([[User talk:HariSinghw|discuss]] • [[Special:Contributions/HariSinghw|contribs]]) 13:29, 19 July 2022 (UTC) }} 8z6ysrekjiltnedi4bd722i6txsa29v 0 249885 2408007 2406222 2022-07-19T14:40:19Z Parodda 2936296 Added a more detailed and accurate description of the address as part of the 996 Wiki grant through HGAPS wikitext text/x-wiki == '''Addresses''' == === '''''Future Directions Address 1: "Future Directions in Adversity and Mental Health"''''' === '''Presented by Dr. Kate McLaughlin, Ph.D.''' ==== Description ==== An increasing body of research has shown that experiences of childhood adversity are more common than previously thought among children in the US. Furthermore, there is a classic dose/response relationship between childhood adversity and psychopathology, with children who have experienced more than six instances of childhood adversity being five times more likely to develop at least one clinical manifestation of psychopathology by adulthood. Yet, many current approaches to child psychopathology have a tendency to lump vastly different experiences of adversity together - a practice that has likely served to further complicate efforts to identify an underlying neurobiological mechanism linking childhood adversity and trauma. In , McLaughlin presents a novel perspective on this issue: identifying low/high threat and low/high deprivation as two distinct contextual axes of childhood adversity, influencing underlying neurobiological mechanisms and eventual manifestation of psychopathology in distinctly different ways. The low/high threat exposure axis pertains to the harm or threat of harm that a child may experience during their developmental years. As McLaughlin discusses, threat exposure influences neural systems involved in fear learning and salience processing, including the amygdala, hippocampus, and medial PFC. Such an adaptive response to growing up in a dangerous environment can be essential for the child’s survival in the short term, but as children grow up these changes in emotional learning can result in increased emotional reactivity and poor emotion regulation. Using brain maps, McLaughlin details how her lab tracked these observable behavioral characteristics to the presence of a drastically heightened amygdala response, specifically in response to negative emotional cues. McLaughlin then contextualizes her work within the existing psychological framework of the general psychopathology (p) factor, hypothesizing the p factor as a transdiagnostic mechanism, and explaining that the neurological changes her lab mapped served to explain a significant portion of the relationship between trauma and the p factor. Pulling in additional data from a bell conditioning task where fear response (SCR amplitude) was measured, McLaughlin explains that sustained childhood exposure to threat results in children having a harder time distinguishing between what is safe and what is dangerous, and likely perceiving a broader set of stimuli to be potentially dangerous compared to children who have never experienced trauma. Continuing on, McLaughlin discusses how data reflects that maps of the ACC, thalamus, aINS, and amygdala respond preferentially to threat cues and fail to habilitate over time to threat vs safety cues. McLaughlin concludes the segment of her address on trauma by stating that a key additional implication of this data is that the poor cross talk between the amygdala and hippocampus that occurs as a result of trauma serves as a direct predictor of higher levels of psychopathology across the board. Returning to her key point, that the mechanisms that link experiences of threat to psychopathology are fundamentally distinct from those that link deprivation to psychopathology, McLaughlin shifts the focus of her discussion to identified neurologic mechanisms stemming from deprivation during key developmental years. McLaughlin begins by stating that children with inadequate exposure to caregivers are not exposed to many of the stimuli necessary for optimal learning and development, including language, nurturance, and complex interpersonal stimulation. McLaughlin then hypothesizes that the result of this deprivation in social and cognitive inputs is an exaggerated experience of synaptic pruning, wherein unused neural circuits are destroyed. While synaptic pruning is an important component of neural development, exaggerated synaptic pruning in the case of childhood deprivation can lead to low cortical grey matter density, a dramatic reduction in areas of the brain relating to language processing, social cognition, attention, executive function, and working memory. As McLaughlin explains from her data, exaggerated synaptic pruning as a result of childhood deprivation may also be linked to increased prevalence of ADHD in children. Contextualizing her findings further, McLaughlin describes how these data can be replicated to apply to children growing up in poverty in the US. In conclusion of her address, McLaughlin discusses the importance of identifying neural mechanisms stemming distinct axes of childhood adversity as they provide psychologists with the tools to understand and help children throughout their development, meeting them within their unique societal contexts to hopefully reduce the prevalence of child and adolescent psychopathology. Watch the YouTube video recording of the address [https://www.youtube.com/watch?v=ceZUPrRHxlo here]. === '''''Future Directions Address 2: "Future Directions in Mediators of Treatment"''''' === '''Presented by [[wikipedia:Philip_C._Kendall|Dr. Philip Kendall, Ph.D]].''' ==== Description ==== How do psychological therapies work? How can we enhance treatment to improve outcomes? Questions of mediation lie at the heart of these inquiries. In this address, Dr. Philip Kendall delineates some of the issues confronting tests of treatment mediation in youth mental health and suggests future directions in research on addressing these issues. Watch the YouTube video recording of the address [https://www.youtube.com/watch?v=0w0ul3YH17o here]. === '''''Future Directions Address 3: "Future Directions in Immunology and Mental Health"''''' === '''Presented by Dr. Greg Miller, Ph.D.''' ==== Description ==== In this address, Dr. Gregory Miller provides an overview of the recently developed neuroimmune network hypothesis and highlights implications and future directions for theory and empirical research on early-life stress and its links with physical and emotional health problems. Watch the YouTube video recording of the address [https://www.youtube.com/watch?v=kgu3lnyZNmA&feature=youtu.be here]. === '''''Future Directions Address 4: "Future Directions in Parent-Child Separation"''''' === ''' Presented by Dr. Kathryn Humphreys, Ph.D.''' ==== Description ==== In this address, Dr. Kate Humphreys reviews salient emerging themes in the scientific literature related to the study and treatment of parent-child separation. Watch the YouTube video recording of the address [https://www.youtube.com/watch?v=fq_OHfGyF0o&feature=youtu.be here]. == '''Workshops''' == === '''''Strategies for Improving Writing Clarity''''' === '''Presented by Dr. Andres De Los Reyes, Ph.D.''' ===== Description ===== People tend to be drawn to and understand information best when it is communicated to them in the form of a narrative or “story” rather than a list of facts. However, researchers rarely receive formal training on leveraging narrative tools when writing about their academic work. In this workshop, Dr. Andres De Los Reyes describes evidence-based strategies for consistently applying narrative structure to academic work, with a focus on preparing manuscripts for submission to peer-reviewed academic journals. This includes his description of the and-but-therefore approach to writing and how this narrative structure can be utilized in academic writing as a way to make scientific information more interesting to consume and memorable to the audience. === '''''Job Options in Academia''''' === '''Presented by Dr. Susan White, Ph.D and Dr. Matthew Lerner, Ph.D. ''' ===== Description ===== Graduate training in fields relevant to child and adolescent mental health (e.g., Education, Psychiatry, Psychology, and Social Work) prepares trainees for careers in a variety of policy, research, and practice settings. While there are many options one can take with a career in mental health, academic jobs are among the most common and include traditional academic settings such as R1 research universities and research positions in a medical school, the government, or a research center. Another big consideration is whether or not to go for a job with tenure track (which is like a probationary period that typically lasts about 6 years) especially because these positions are very difficult to come by. There are also considerations to be made on whether to take a position that requires/allows teaching and service work like serving on an editorial board. Research finds that the best predictor of success in academia is: department reputation. Drs. White and Lerner give advice on the timeline of when to apply and resources to use on your applications such as your advisor, organization, and practice. They also provide brief discussion on job interviews which mostly consist of job talks in academia. Lastly, the give advice on negotiating a job offer with the most important piece of advice being to '''get everything in writing''' when negotiating a position. === '''''Preparing a Training Grant''''' === '''Presented by Dr. Deborah A.G. Drabick, Ph.D. and Dr. Tara Peris, Ph.D. ''' ===== Description ===== Submitting a training grant involves considering multiple factors that focus on not only a proposed study but also a concrete plan for developing the skills needed to execute this study. By construction, these applications carry many expectations, requirements, and complicated forms. In this workshop, Drs. Deborah Drabick and Tara Peris leverage their years of experience with extramural funding to clarify the process of submitting a training grant, and provide attendees with concrete tools for submitting successful training grant applications. Training grants are important because they offer opportunities to graduate students and post-docs that may not otherwise be available and provide additional mentorship and consultation. There are several types of training grants that typically fall into either F grant class or K grant class. Based on the type of grant you are applying for, the information needed to apply will vary; however, picking your topic and telling your story will always be required. In doing this, you should describe what you are interested in researching, the current state of the field, and how your research will address gaps you have identified in the current research. Grants are typically reviewed on a scale of 1-9 in 5 areas which are then compiled into an overall impact score. Reviewers then meet and discuss the top 50% of the grant applications and make a decision on who will receive funding. === '''''Responding to Peer Review''''' === '''Presented by Dr. Andres De Los Reyes, Ph.D.''' ===== Description ===== Publishing academic work often involves submitting scholarly manuscripts to peer-reviewed journals. A key component of the publishing process involves receiving commentary about your work from peers in your field and satisfactorily responding to such commentary. Despite it being a core feature of the publishing process, researchers rarely receive formal training on responding to peer review commentary. In this workshop, Dr. Andres De Los Reyes describes evidence-based strategies for responding to peer review commentary, including strategies for how to compose cover letters for responding to such commentary. Along these lines, Dr. De Los Reyes details how to respond to peer reviews line by line to ensure all comments have been addressed. Additionally, he outlines how to respectfully respond to and address comments from a reviewer that you may not agree with. === '''''Job Search and Negotiation''''' === ''' Presented by Dr. Deborah A.G. Drabick, Ph.D. and Dr. Tara Peris, Ph.D. ''' ===== Description ===== In this workshop Drs. Deborah Drabick and Tara Peris provide advice when it comes to searching for jobs and negotiating job offers. They give practical advice for determining when to go on the job market, where are the best places to search for job openings, how to write a good cover letter that will catch an employer's attention, and where to find resources that will assist in the preparation for a job interview. It is always good to monitor list-servs from APA, ABCT, and other relevant groups for job postings as well as checking APA psyc careers and following up via word of mouth. When applying for jobs, you should have your CV up to date and a cover letter ready that details your experiences and qualifications. They also detail how to advocate for yourself, negotiate salary and benefits, and how to get a lab startup package when given a job offer. When negotiating you can negotiate on salary, title, space, start-up funds, time between moving from your current place to your new job, protected time, parking, childcare, and housing. You should always ask for more than what you want since you are negotiating and will not get everything you ask for. Lastly, the remind you to always be gracious when interviewing and negotiating job offers as well as to send thank you notes to those you interact with during the process. === '''''Preparing a Grant Post-Ph.D''''' === ''' Presented by Dr. Joshua Langberg, Ph.D. and Dr. Susan White, Ph.D. ''' ===== Description ===== Submitting your first grant as a Ph.D. can appear on the surface to be a daunting task, with many expectations, requirements, and complicated forms. In this workshop, we leverage years of experience with extramural funding to explain the grant submission process, and provide attendees with concrete tools for submitting successful applications via multiple post-Ph.D. mechanisms, including project grants and K Series, F Series, and T Series applications. K Series grants are most often used to fund early career research, F Series are individual fellowships, and T Series are institutional training grants. Each grant will have different elements specific to that grant; however, each will require picking a topic/telling your story, showing preliminary data, forming a team, and budgeting. It is important to establish a timeline for writing the grant and submitting materials to ensure that everything is submitted on time. You should ideally have multiple grants under review at one time to maximize the chance of having a successfully funded grant. Once you have written one, it is easy to tweak it to meet the requirements of other grant applications. Lastly, ask others in the field for examples of grants they have written and ask them to review yours before submitting. === '''''Strategies for Developing a Research Program''''' === ''' Presented by Dr. Andres De Los Reyes, Ph.D. ''' ===== Description ===== Our first two writing workshops dealt with applying narrative tools to academic work and responding to peer review commentary, with the key goal of publishing a single journal article. How might you use these tools to connect separate articles together into a larger story? In research, our larger stories are the “research programs” we build from years of work and multiple articles. These are the stories we take with us “on the road” when interviewing for jobs and applying for grants. In this workshop, we discover how narrative devices commonly used in filmmaking actually help us weave related but distinct articles together into the “story” of an entire body of work. === '''''Networking at Conferences''''' === ''' Presented by Dr. Deborah A.G. Drabick, Ph.D. and Dr. Matthew Lerner, Ph.D. ''' ===== Description ===== To an early career scientist, attending professional meetings can be an overwhelming experience, with many opportunities to not only learn new things but also connect with like-minded scholars in the field. In this workshop, Drs. Deborah Drabick and Matthew Lerner demystify the process of networking at conferences, and provide attendees with concrete tools for developing and maintaining professional relationships with conference attendees. The presenters discuss how to approach a researcher who you are interested in building a connection with and how to maximize the time you have to speak with them and to make yourself stand out. Drs. Drabick and Lerner also discuss how to have a meaningful discussion that can carry into a long-term professional relationship such as collaborations on research projects. It is also important to be mindful of how you are carrying yourself and what your interactions look like as you never know who is around and watching. Having a go to question can be a good way to start the conversation such as asking what the current state of that person's research is or discussing the current state of the literature in their field of study. Always make sure you know about the person's research before approaching them and consider how their work can inform yours. It is also important to attend their session if they are speaking at the conference or event so you can be informed on their current work and research goals. === '''''Work-Life Balance''''' === '''Presented by Dr. Joshua Langberg, Ph.D. and Dr. Sarah Racz, Ph.D.''' ===== Description ===== Sometimes it feels like everyone in our field is “always on task” and unable to “unplug”. But is that a realistic view of how we balance our work lives with our lives outside of work? In this workshop, Drs. Joshua Langberg and Sarah Racz discuss the competing demands placed on us across our various work, family, and social spheres; and strategies to manage these demands in the necessary pursuit of healthy, balanced lives. They begin with practical advice such as knowing what your priorities are and how you operationalize them. Then map your schedule so you have a clear picture of your time and your commitments. From there you will need to make choices out of the time items you have left on your priorities and what time you have left in the day. By having routine and structure for each day, you are able to maximize your time and make conscious choices of what you are spending your day doing. They also recommend being flexible, but organized when creating a work-life balance as sometimes things in your schedule may shift and you need to quickly adjust. Being organized may look like keeping a calendar and/or to do list as well as using family management apps. It is also important to communicate with others in your household about your schedule and set up a plan that works for all of you. Lastly, it is important to advocate for yourself and to know your rights and responsibilities if you are a working parent when it comes to parental leave and time off. == '''Ceremony for the ''Future Directions Launch Award''''' == === John L. Cooley === * Received Ph.D. from the University of Kansas ====== About the award recipient ====== John is a recipient of the 2019 Future Directions Launch Award in Adversity.  After receiving his Ph.D. in Clinical Child Psychology from University of Kansas in 2018, he worked as a NIMH T32 postdoctoral fellow in the Department of Psychiatry at the University of Colorado Anschutz Medical Campus. He is currently a tenure-track Assistant Professor in the Department of Psychological Sciences at Texas Tech University, where his lab is guided by two overarching questions: “Why are some children and adolescents more impacted by peer victimization/bullying than others?” and “How can we address the mental health needs of peer-victimized/bullied youth?" More specifically, John’s lab is focused on investigating a) factors that influence risk for peer victimization/bullying and their associated negative outcomes, b) methods for identifying victims of peer aggression in need of intervention, and c) prevention and intervention approaches. Learn more about John's lab here: [https://www.peerrelationslab.com www.peerrelationslab.com] Watch the YouTube video recording of the remarks [https://www.youtube.com/watch?v=Jq6k0URJ1es here]. === Erin Kang === * Ph.D. Candidate at Stony Brook University at the time of the award ====== About the award recipient ====== Erin received the 2019 Future Directions Launch Award in Treatment. She earned her Ph.D. in Clinical Psychology in 2020 at Stony Brook University under the mentorship of Dr. Matthew Lerner. She is currently a tenure-track Assistant Professor in the Psychology Department at Montclair State University, where her lab focuses on understanding how the processing of social information shapes, and is shaped by, social experience in autistic youth and those with related neurodevelopmental disorders. This focus on social plasticity, or capacity to learn from and adapt to their complex social environments, includes the role of social experiences, affective processing, and neural plasticity that underlie this capacity. Learn more about Erin's lab here: [https://www.erinkanglab.com www.erinkanglab.com] Watch the YouTube video recording of the remarks [https://www.youtube.com/watch?v=oaK14hoO3UI here]. === Nicole Lorenzo === * Ph.D. candidate at Florida International University at the time of the award ====== About the award recipient ====== Nicole received the 2019 Future Directions Launch Award in Treatment. After receiving her Ph.D. in Clinical Science at Florida International University in 2019, she worked as a post-doctoral fellow at the University of Maryland, College Park. Currently, she is a tenure-track Assistant Professor in the psychology department at American University. Her research focuses on the transactional processes involved in parent-child interactions, examining how these processes develop and the impact of factors like temperament and parent mental health. This developmental work informs her intervention work which seeks to understand how we can refine and individualize treatment targets to develop early intervention programs that are accessible and scalable for families and providers, particularly those from underserved and underrepresented backgrounds. Learn more about Nicole's work here: [https://www.researchgate.net/profile/Nicole&#x20;Lorenzo www.researchgate.net/profile/Nicole_Lorenzo] Watch the YouTube video recording of the remarks [https://www.youtube.com/watch?v=3T53yHtdcqY here]. au5ticm5u1mhksqynohjru4jzzxwjmh 2408014 2408007 2022-07-19T14:43:04Z Parodda 2936296 added the name of the address in bold wikitext text/x-wiki == '''Addresses''' == === '''''Future Directions Address 1: "Future Directions in Adversity and Mental Health"''''' === '''Presented by Dr. Kate McLaughlin, Ph.D.''' ==== Description ==== An increasing body of research has shown that experiences of childhood adversity are more common than previously thought among children in the US. Furthermore, there is a classic dose/response relationship between childhood adversity and psychopathology, with children who have experienced more than six instances of childhood adversity being five times more likely to develop at least one clinical manifestation of psychopathology by adulthood. Yet, many current approaches to child psychopathology have a tendency to lump vastly different experiences of adversity together - a practice that has likely served to further complicate efforts to identify an underlying neurobiological mechanism linking childhood adversity and trauma. In '''Neurodevelopmental Mechanisms Linking Childhood Adversity with Psychopathology Across the Life-Course''', McLaughlin presents a novel perspective on this issue: identifying low/high threat and low/high deprivation as two distinct contextual axes of childhood adversity, influencing underlying neurobiological mechanisms and eventual manifestation of psychopathology in distinctly different ways. The low/high threat exposure axis pertains to the harm or threat of harm that a child may experience during their developmental years. As McLaughlin discusses, threat exposure influences neural systems involved in fear learning and salience processing, including the amygdala, hippocampus, and medial PFC. Such an adaptive response to growing up in a dangerous environment can be essential for the child’s survival in the short term, but as children grow up these changes in emotional learning can result in increased emotional reactivity and poor emotion regulation. Using brain maps, McLaughlin details how her lab tracked these observable behavioral characteristics to the presence of a drastically heightened amygdala response, specifically in response to negative emotional cues. McLaughlin then contextualizes her work within the existing psychological framework of the general psychopathology (p) factor, hypothesizing the p factor as a transdiagnostic mechanism, and explaining that the neurological changes her lab mapped served to explain a significant portion of the relationship between trauma and the p factor. Pulling in additional data from a bell conditioning task where fear response (SCR amplitude) was measured, McLaughlin explains that sustained childhood exposure to threat results in children having a harder time distinguishing between what is safe and what is dangerous, and likely perceiving a broader set of stimuli to be potentially dangerous compared to children who have never experienced trauma. Continuing on, McLaughlin discusses how data reflects that maps of the ACC, thalamus, aINS, and amygdala respond preferentially to threat cues and fail to habilitate over time to threat vs safety cues. McLaughlin concludes the segment of her address on trauma by stating that a key additional implication of this data is that the poor cross talk between the amygdala and hippocampus that occurs as a result of trauma serves as a direct predictor of higher levels of psychopathology across the board. Returning to her key point, that the mechanisms that link experiences of threat to psychopathology are fundamentally distinct from those that link deprivation to psychopathology, McLaughlin shifts the focus of her discussion to identified neurologic mechanisms stemming from deprivation during key developmental years. McLaughlin begins by stating that children with inadequate exposure to caregivers are not exposed to many of the stimuli necessary for optimal learning and development, including language, nurturance, and complex interpersonal stimulation. McLaughlin then hypothesizes that the result of this deprivation in social and cognitive inputs is an exaggerated experience of synaptic pruning, wherein unused neural circuits are destroyed. While synaptic pruning is an important component of neural development, exaggerated synaptic pruning in the case of childhood deprivation can lead to low cortical grey matter density, a dramatic reduction in areas of the brain relating to language processing, social cognition, attention, executive function, and working memory. As McLaughlin explains from her data, exaggerated synaptic pruning as a result of childhood deprivation may also be linked to increased prevalence of ADHD in children. Contextualizing her findings further, McLaughlin describes how these data can be replicated to apply to children growing up in poverty in the US. In conclusion of her address, McLaughlin discusses the importance of identifying neural mechanisms stemming distinct axes of childhood adversity as they provide psychologists with the tools to understand and help children throughout their development, meeting them within their unique societal contexts to hopefully reduce the prevalence of child and adolescent psychopathology. Watch the YouTube video recording of the address [https://www.youtube.com/watch?v=ceZUPrRHxlo here]. === '''''Future Directions Address 2: "Future Directions in Mediators of Treatment"''''' === '''Presented by [[wikipedia:Philip_C._Kendall|Dr. Philip Kendall, Ph.D]].''' ==== Description ==== How do psychological therapies work? How can we enhance treatment to improve outcomes? Questions of mediation lie at the heart of these inquiries. In this address, Dr. Philip Kendall delineates some of the issues confronting tests of treatment mediation in youth mental health and suggests future directions in research on addressing these issues. Watch the YouTube video recording of the address [https://www.youtube.com/watch?v=0w0ul3YH17o here]. === '''''Future Directions Address 3: "Future Directions in Immunology and Mental Health"''''' === '''Presented by Dr. Greg Miller, Ph.D.''' ==== Description ==== In this address, Dr. Gregory Miller provides an overview of the recently developed neuroimmune network hypothesis and highlights implications and future directions for theory and empirical research on early-life stress and its links with physical and emotional health problems. Watch the YouTube video recording of the address [https://www.youtube.com/watch?v=kgu3lnyZNmA&feature=youtu.be here]. === '''''Future Directions Address 4: "Future Directions in Parent-Child Separation"''''' === ''' Presented by Dr. Kathryn Humphreys, Ph.D.''' ==== Description ==== In this address, Dr. Kate Humphreys reviews salient emerging themes in the scientific literature related to the study and treatment of parent-child separation. Watch the YouTube video recording of the address [https://www.youtube.com/watch?v=fq_OHfGyF0o&feature=youtu.be here]. == '''Workshops''' == === '''''Strategies for Improving Writing Clarity''''' === '''Presented by Dr. Andres De Los Reyes, Ph.D.''' ===== Description ===== People tend to be drawn to and understand information best when it is communicated to them in the form of a narrative or “story” rather than a list of facts. However, researchers rarely receive formal training on leveraging narrative tools when writing about their academic work. In this workshop, Dr. Andres De Los Reyes describes evidence-based strategies for consistently applying narrative structure to academic work, with a focus on preparing manuscripts for submission to peer-reviewed academic journals. This includes his description of the and-but-therefore approach to writing and how this narrative structure can be utilized in academic writing as a way to make scientific information more interesting to consume and memorable to the audience. === '''''Job Options in Academia''''' === '''Presented by Dr. Susan White, Ph.D and Dr. Matthew Lerner, Ph.D. ''' ===== Description ===== Graduate training in fields relevant to child and adolescent mental health (e.g., Education, Psychiatry, Psychology, and Social Work) prepares trainees for careers in a variety of policy, research, and practice settings. While there are many options one can take with a career in mental health, academic jobs are among the most common and include traditional academic settings such as R1 research universities and research positions in a medical school, the government, or a research center. Another big consideration is whether or not to go for a job with tenure track (which is like a probationary period that typically lasts about 6 years) especially because these positions are very difficult to come by. There are also considerations to be made on whether to take a position that requires/allows teaching and service work like serving on an editorial board. Research finds that the best predictor of success in academia is: department reputation. Drs. White and Lerner give advice on the timeline of when to apply and resources to use on your applications such as your advisor, organization, and practice. They also provide brief discussion on job interviews which mostly consist of job talks in academia. Lastly, the give advice on negotiating a job offer with the most important piece of advice being to '''get everything in writing''' when negotiating a position. === '''''Preparing a Training Grant''''' === '''Presented by Dr. Deborah A.G. Drabick, Ph.D. and Dr. Tara Peris, Ph.D. ''' ===== Description ===== Submitting a training grant involves considering multiple factors that focus on not only a proposed study but also a concrete plan for developing the skills needed to execute this study. By construction, these applications carry many expectations, requirements, and complicated forms. In this workshop, Drs. Deborah Drabick and Tara Peris leverage their years of experience with extramural funding to clarify the process of submitting a training grant, and provide attendees with concrete tools for submitting successful training grant applications. Training grants are important because they offer opportunities to graduate students and post-docs that may not otherwise be available and provide additional mentorship and consultation. There are several types of training grants that typically fall into either F grant class or K grant class. Based on the type of grant you are applying for, the information needed to apply will vary; however, picking your topic and telling your story will always be required. In doing this, you should describe what you are interested in researching, the current state of the field, and how your research will address gaps you have identified in the current research. Grants are typically reviewed on a scale of 1-9 in 5 areas which are then compiled into an overall impact score. Reviewers then meet and discuss the top 50% of the grant applications and make a decision on who will receive funding. === '''''Responding to Peer Review''''' === '''Presented by Dr. Andres De Los Reyes, Ph.D.''' ===== Description ===== Publishing academic work often involves submitting scholarly manuscripts to peer-reviewed journals. A key component of the publishing process involves receiving commentary about your work from peers in your field and satisfactorily responding to such commentary. Despite it being a core feature of the publishing process, researchers rarely receive formal training on responding to peer review commentary. In this workshop, Dr. Andres De Los Reyes describes evidence-based strategies for responding to peer review commentary, including strategies for how to compose cover letters for responding to such commentary. Along these lines, Dr. De Los Reyes details how to respond to peer reviews line by line to ensure all comments have been addressed. Additionally, he outlines how to respectfully respond to and address comments from a reviewer that you may not agree with. === '''''Job Search and Negotiation''''' === ''' Presented by Dr. Deborah A.G. Drabick, Ph.D. and Dr. Tara Peris, Ph.D. ''' ===== Description ===== In this workshop Drs. Deborah Drabick and Tara Peris provide advice when it comes to searching for jobs and negotiating job offers. They give practical advice for determining when to go on the job market, where are the best places to search for job openings, how to write a good cover letter that will catch an employer's attention, and where to find resources that will assist in the preparation for a job interview. It is always good to monitor list-servs from APA, ABCT, and other relevant groups for job postings as well as checking APA psyc careers and following up via word of mouth. When applying for jobs, you should have your CV up to date and a cover letter ready that details your experiences and qualifications. They also detail how to advocate for yourself, negotiate salary and benefits, and how to get a lab startup package when given a job offer. When negotiating you can negotiate on salary, title, space, start-up funds, time between moving from your current place to your new job, protected time, parking, childcare, and housing. You should always ask for more than what you want since you are negotiating and will not get everything you ask for. Lastly, the remind you to always be gracious when interviewing and negotiating job offers as well as to send thank you notes to those you interact with during the process. === '''''Preparing a Grant Post-Ph.D''''' === ''' Presented by Dr. Joshua Langberg, Ph.D. and Dr. Susan White, Ph.D. ''' ===== Description ===== Submitting your first grant as a Ph.D. can appear on the surface to be a daunting task, with many expectations, requirements, and complicated forms. In this workshop, we leverage years of experience with extramural funding to explain the grant submission process, and provide attendees with concrete tools for submitting successful applications via multiple post-Ph.D. mechanisms, including project grants and K Series, F Series, and T Series applications. K Series grants are most often used to fund early career research, F Series are individual fellowships, and T Series are institutional training grants. Each grant will have different elements specific to that grant; however, each will require picking a topic/telling your story, showing preliminary data, forming a team, and budgeting. It is important to establish a timeline for writing the grant and submitting materials to ensure that everything is submitted on time. You should ideally have multiple grants under review at one time to maximize the chance of having a successfully funded grant. Once you have written one, it is easy to tweak it to meet the requirements of other grant applications. Lastly, ask others in the field for examples of grants they have written and ask them to review yours before submitting. === '''''Strategies for Developing a Research Program''''' === ''' Presented by Dr. Andres De Los Reyes, Ph.D. ''' ===== Description ===== Our first two writing workshops dealt with applying narrative tools to academic work and responding to peer review commentary, with the key goal of publishing a single journal article. How might you use these tools to connect separate articles together into a larger story? In research, our larger stories are the “research programs” we build from years of work and multiple articles. These are the stories we take with us “on the road” when interviewing for jobs and applying for grants. In this workshop, we discover how narrative devices commonly used in filmmaking actually help us weave related but distinct articles together into the “story” of an entire body of work. === '''''Networking at Conferences''''' === ''' Presented by Dr. Deborah A.G. Drabick, Ph.D. and Dr. Matthew Lerner, Ph.D. ''' ===== Description ===== To an early career scientist, attending professional meetings can be an overwhelming experience, with many opportunities to not only learn new things but also connect with like-minded scholars in the field. In this workshop, Drs. Deborah Drabick and Matthew Lerner demystify the process of networking at conferences, and provide attendees with concrete tools for developing and maintaining professional relationships with conference attendees. The presenters discuss how to approach a researcher who you are interested in building a connection with and how to maximize the time you have to speak with them and to make yourself stand out. Drs. Drabick and Lerner also discuss how to have a meaningful discussion that can carry into a long-term professional relationship such as collaborations on research projects. It is also important to be mindful of how you are carrying yourself and what your interactions look like as you never know who is around and watching. Having a go to question can be a good way to start the conversation such as asking what the current state of that person's research is or discussing the current state of the literature in their field of study. Always make sure you know about the person's research before approaching them and consider how their work can inform yours. It is also important to attend their session if they are speaking at the conference or event so you can be informed on their current work and research goals. === '''''Work-Life Balance''''' === '''Presented by Dr. Joshua Langberg, Ph.D. and Dr. Sarah Racz, Ph.D.''' ===== Description ===== Sometimes it feels like everyone in our field is “always on task” and unable to “unplug”. But is that a realistic view of how we balance our work lives with our lives outside of work? In this workshop, Drs. Joshua Langberg and Sarah Racz discuss the competing demands placed on us across our various work, family, and social spheres; and strategies to manage these demands in the necessary pursuit of healthy, balanced lives. They begin with practical advice such as knowing what your priorities are and how you operationalize them. Then map your schedule so you have a clear picture of your time and your commitments. From there you will need to make choices out of the time items you have left on your priorities and what time you have left in the day. By having routine and structure for each day, you are able to maximize your time and make conscious choices of what you are spending your day doing. They also recommend being flexible, but organized when creating a work-life balance as sometimes things in your schedule may shift and you need to quickly adjust. Being organized may look like keeping a calendar and/or to do list as well as using family management apps. It is also important to communicate with others in your household about your schedule and set up a plan that works for all of you. Lastly, it is important to advocate for yourself and to know your rights and responsibilities if you are a working parent when it comes to parental leave and time off. == '''Ceremony for the ''Future Directions Launch Award''''' == === John L. Cooley === * Received Ph.D. from the University of Kansas ====== About the award recipient ====== John is a recipient of the 2019 Future Directions Launch Award in Adversity.  After receiving his Ph.D. in Clinical Child Psychology from University of Kansas in 2018, he worked as a NIMH T32 postdoctoral fellow in the Department of Psychiatry at the University of Colorado Anschutz Medical Campus. He is currently a tenure-track Assistant Professor in the Department of Psychological Sciences at Texas Tech University, where his lab is guided by two overarching questions: “Why are some children and adolescents more impacted by peer victimization/bullying than others?” and “How can we address the mental health needs of peer-victimized/bullied youth?" More specifically, John’s lab is focused on investigating a) factors that influence risk for peer victimization/bullying and their associated negative outcomes, b) methods for identifying victims of peer aggression in need of intervention, and c) prevention and intervention approaches. Learn more about John's lab here: [https://www.peerrelationslab.com www.peerrelationslab.com] Watch the YouTube video recording of the remarks [https://www.youtube.com/watch?v=Jq6k0URJ1es here]. === Erin Kang === * Ph.D. Candidate at Stony Brook University at the time of the award ====== About the award recipient ====== Erin received the 2019 Future Directions Launch Award in Treatment. She earned her Ph.D. in Clinical Psychology in 2020 at Stony Brook University under the mentorship of Dr. Matthew Lerner. She is currently a tenure-track Assistant Professor in the Psychology Department at Montclair State University, where her lab focuses on understanding how the processing of social information shapes, and is shaped by, social experience in autistic youth and those with related neurodevelopmental disorders. This focus on social plasticity, or capacity to learn from and adapt to their complex social environments, includes the role of social experiences, affective processing, and neural plasticity that underlie this capacity. Learn more about Erin's lab here: [https://www.erinkanglab.com www.erinkanglab.com] Watch the YouTube video recording of the remarks [https://www.youtube.com/watch?v=oaK14hoO3UI here]. === Nicole Lorenzo === * Ph.D. candidate at Florida International University at the time of the award ====== About the award recipient ====== Nicole received the 2019 Future Directions Launch Award in Treatment. After receiving her Ph.D. in Clinical Science at Florida International University in 2019, she worked as a post-doctoral fellow at the University of Maryland, College Park. Currently, she is a tenure-track Assistant Professor in the psychology department at American University. Her research focuses on the transactional processes involved in parent-child interactions, examining how these processes develop and the impact of factors like temperament and parent mental health. This developmental work informs her intervention work which seeks to understand how we can refine and individualize treatment targets to develop early intervention programs that are accessible and scalable for families and providers, particularly those from underserved and underrepresented backgrounds. Learn more about Nicole's work here: [https://www.researchgate.net/profile/Nicole&#x20;Lorenzo www.researchgate.net/profile/Nicole_Lorenzo] Watch the YouTube video recording of the remarks [https://www.youtube.com/watch?v=3T53yHtdcqY here]. hn5o5bv2dj7fep01itpb6gd8u3ecwbe 0 251850 2408050 2215284 2022-07-19T22:22:29Z Bobamnertiopsis 24451 +dois where available, other small reference tidying wikitext text/x-wiki {{Article info | first1 = Jouko | last1 = Tuomisto | orcid1 = 0000-0003-1710-0377 | affiliation1 = National Institute for Health and Welfare, Kuopio, Finland | correspondence1 = j.tuomisto@dnainternet.net | journal = WikiJournal of Medicine | keywords = dioxins; TCDD; polychlorinated dibenzo-p-dioxins; AH receptor; developmental toxicity; cancer | submitted = 2019-08-05 | accepted = 2019-12-12 | doi = 10.15347/wjm/2019.008 | abstract = '''Dioxins and dioxin-like compounds''' comprise a group of chemicals including polychlorinated dibenzo''-p-''dioxins (PCDD) and polychlorinated dibenzofurans (PCDF), as well as certain dioxin-like polychlorinated biphenyls (dl-PCB), and potentially others. They act via a common mechanism, stimulation of aryl hydrocarbon receptor (AH receptor, AHR), a vital transcription factor in cells. There are very high differences in potency among these compounds, i.e. in the ability to stimulate the receptor. This leads to ten thousand fold or higher differences in doses causing similar toxic effects. Most of these compounds are eliminated very slowly in the environment, animals, or humans, which makes them persistent. They are much more soluble in fat than in water, and therefore they tend to accumulate in lipid or fatty tissues, and concentrate along the food web (bioaccumulation and biomagnification). PCDD/PCDFs are formed mostly as side products in burning processes, but PCBs were oils manufactured for many purposes. Because of toxicity and persistence, dioxin-like compounds have been regulated strictly since 1980s, and their levels in the environment and animals have decreased by an order of magnitude or more. Therefore the effects on wildlife have clearly decreased, and even populations at the top of the food web such as fish-eating birds or seals have recovered after serious effects on their reproductive capacity and developmental effects in their young especially in 1970s and 1980s. This does not exclude the possibility of some remaining effects. In humans the intake is mostly from food of animal sources, but because our diet is much more diverse than that of such hallmark animals as white-tailed eagles or seals, the concentrations never increased to similar levels. However, during 1970s and 1980s effects were probably also seen in humans, including developmental effects in teeth, sexual organs, and the development of immune systems. Both scientists and administrative bodies debate at the moment about the importance of remaining risks. This is very important, because the AH receptors seem to be physiologically important regulators of growth and development of organs, immunological development, food intake and hunger, and in addition regulate enzymes protecting us from many chemicals. Thus a certain level of activation is needed, although inappropriate stimulation of the receptor is harmful. This dualism emphasizes the importance of benefit versus risk analysis. As a whole, regulating the emissions to the environment is still highly important, but one should be very cautious in limiting consumption of important and otherwise healthy food items and e.g. breast feeding. Distinct toxic effects of high doses of dioxins in humans have been clearly demonstrated by frank poisonings and the highest occupational exposures. Hallmark effects have been skin lesions called chloracne, various developmental effects of children, and a slightly increased risk of total cancer rate. The highest dioxin levels have been ten thousand fold higher than those seen in the general population today. |note= '''Note:''' This review is based on original studies and scientific reviews, independently of existing Wikipedia articles, and as interpreted by author's 35 year experience in dioxin research. However, pieces of similar information can be found in Wikipedia articles [[w:Dioxins and dioxin-like compounds|Dioxins and dioxin-like compounds]], [[w:2,3,7,8-Tetrachlorodibenzodioxin|2,3,7,8-tetrachlorodibenzodioxin]], [[w:Polychlorinated dibenzodioxins|Polychlorinated dibenzodioxins]], [[w:Polychlorinated dibenzofurans|Polychlorinated dibenzofurans]], [[w:Polychlorinated biphenyl|Polychlorinated biphenyl]], and [[w:Persistent organic pollutant|Persistent organic pollutant]]. }} == General introduction == “Dioxins” is an imprecise term including structurally related groups of chemicals such as polychlorinated dibenzo-''p''-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). Certain polychlorinated biphenyls (dl-PCBs) and many other chemicals<ref name=Poland82>{{cite journal |last1=Poland |first1=A |last2=Knutson |first2=JC |title=2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. |journal=Annual review of pharmacology and toxicology |date=1982 |volume=22 |pages=517-54 |doi=10.1146/annurev.pa.22.040182.002505 |pmid=6282188}}</ref><ref name=Pohjanvirta94>{{cite journal |last1=Pohjanvirta |first1=R |last2=Tuomisto |first2=J |title=Short-term toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in laboratory animals: effects, mechanisms, and animal models. |journal=Pharmacological reviews |date=December 1994 |volume=46 |issue=4 |pages=483-549 |pmid=7899475}}</ref><ref name=Denison03>{{cite journal |last1=Denison |first1=MS |last2=Nagy |first2=SR |title=Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. |journal=Annual review of pharmacology and toxicology |date=2003 |volume=43 |pages=309-34 |doi=10.1146/annurev.pharmtox.43.100901.135828 |pmid=12540743}}</ref><ref name=TuomistoSynopsis>{{Cite report|last=Tuomisto|first=Jouko|last2=Vartiainen|first2=Terttu|last3=Tuomisto|first3=Jouni T.|date=2011|title=Synopsis on dioxins and PCBs|url=https://www.julkari.fi/bitstream/handle/10024/80313/81322e2c-e9b6-4003-bb13-995dcd1b68cb.pdf?sequence=1&isAllowed=y|issn=1798-0089|publisher=National Institute for Health and Welfare|language=en}}</ref> have dioxin-like properties. The term “dioxin-like” is used because these chemicals have a common mechanism of action, i.e. inappropriate stimulation of aryl hydrocarbon receptor (AH receptor, AHR, “dioxin receptor”).<ref name=Poland82/><ref name=Pohjanvirta94/><ref>{{cite journal |last1=Denison |first1=MS |last2=Faber |first2=SC |title=And Now for Something Completely Different: Diversity in Ligand-Dependent Activation of Ah Receptor Responses. |journal=Current opinion in toxicology |date=February 2017 |volume=2 |pages=124-131 |doi=10.1016/j.cotox.2017.01.006 |pmid=28845473}}</ref><ref name=Rothhammer19>{{cite journal |last1=Rothhammer |first1=V |last2=Quintana |first2=FJ |title=The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. |journal=Nature reviews. Immunology |date=March 2019 |volume=19 |issue=3 |pages=184-197 |doi=10.1038/s41577-019-0125-8 |pmid=30718831}}</ref> Among compounds binding to the AH receptor, the higher the binding affinity, the higher will be the toxicity. High toxicity means that even low doses or low exposure levels are sufficient to produce toxic responses. Compounds with lower affinity for the AH receptor require higher doses to elicit similar toxic effects. Low-affinity compounds (e.g. some PCBs, usually at relatively high doses) can elicit toxic effects that are different from those of characteristic dioxin-like effects of chemicals such as 2,3,7,8-tetrachlorodibenzo-''p''-dioxin (TCDD). Dioxins are a puzzling group of chemicals that have widely diverse effects in different cell-types, tissues and animal species. Many lay people consider them only dreaded environmental “superpoisons”. But they are also highly interesting tools for studying the mechanisms of intracellular receptors, gene expression, growth and development of organs, metabolism of chemicals in the body, carcinogenesis, food intake and hunger, as well as interactions of chemicals, microbes and immunological systems. The AH receptor, the mediator of dioxin toxicity seems to be an important physiological actor in the body, a ligand-activated transcription factor functionally similar but structurally unrelated to intracellular receptors such as steroid or thyroid receptors. This reminds us of the ultimate principle of Paracelsus: all things are poisons, only the dose makes that a thing is not a poison. AH receptors are necessary for many normal biological functions,<ref>{{Cite journal|last=Barouki|first=Robert|last2=Coumoul|first2=Xavier|last3=Fernandez-Salguero|first3=Pedro M.|date=2007-03-30|title=The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein|url=http://dx.doi.org/10.1016/j.febslet.2007.03.046|journal=FEBS Letters|volume=581|issue=19|pages=3608–3615|doi=10.1016/j.febslet.2007.03.046|issn=0014-5793}}</ref><ref name=Rothhammer19/> and their physiological activation regulates our wellbeing, but their inappropriate activation leads to multiple forms of toxicity. The best studied compound is the most toxic 2,3,7,8-tetrachlorodibenzo''-p-''dioxin (TCDD). The toxicity of other compounds is compared with this prototype. TCDD is assigned a toxicity equivalence factor (TEF) of 1. The potency and toxicokinetics of other compounds vary over orders of magnitude, and therefore each compound is assigned its own TEF that may range from 1 to 0.000 03 (or lower for fish, see below). The TEF for each compound forms the basis for defining toxic equivalency (TEQ) when assessing the toxicity of mixtures. The metabolism and excretion of dioxins in mammals is generally very slow. Dioxins are also persistent and accumulate in the biosphere. Due to slow accumulation to animals and humans, delayed toxicity is the typical mode of harmful effects and the delay between exposure and effect complicates the assessment of risk from dioxins. Developmental adverse effects are seen at the lowest doses. A few dramatic cases of accidental or deliberate acute poisoning are known. Two women were poisoned in Vienna, Austria, in 1998 by large doses of TCDD. In 2004 Victor Yushchenko, then presidential candidate of Ukraine, was deliberately poisoned with a huge dose of TCDD. A widely known dioxin accident took place in Seveso, Italy in 1976. These and similar high-dose incidents have delineated the acute effects on humans. As described in detail later in this article it is more difficult to ascertain, precisely, what are the human health effects of chronic low-dose exposures to dioxin-like compounds. This remains a contentious issue of importance to regulatory agencies as well as to the general public. For a short account of historical legacies of dioxins see Weber et al.<ref name=Weber08>{{cite journal |last1=Weber |first1=R |last2=Tysklind |first2=M |last3=Gaus |first3=C |title=Dioxin--contemporary and future challenges of historical legacies. Dedicated to Prof. Dr. Otto Hutzinger, the founder of the DIOXIN Conference Series. |journal=Environmental science and pollution research international |date=March 2008 |volume=15 |issue=2 |pages=96-100 |pmid=18380226|doi=10.1065/espr2008.01.473}}</ref> Due to intensive research efforts dioxin toxicity is known and understood better than that of most environmental toxic agents. On the other hand, it is beguilingly complicated. == Chemistry == There are 75 possible congeners of polychlorinated dibenzo-''p-''dioxins (PCDD) and 135 possible congeners of polychlorinated dibenzofurans (PCDF). So-called lateral chlorine substitutions at the positions 2,3,7, and 8 (Fig. 1) allow the dioxins to bind to the AH receptor with high affinity. They also prevent enzymatic attacks on the molecule causing persistence both in human body and in the environment. Such compounds are particularly toxic and constitute the prototype for dioxin-like toxicity. TEF values have been assigned to 17 congeners (seven dibenzo''-p-''dioxins and ten dibenzofurans) having four to eight chlorine substitutions. Chlorines in excess of the four (2,3,7 and 8) decrease the potency, but the type of toxic effects remains mainly the same.<ref name=Berg06>{{cite journal |last1=Van den Berg |first1=M |last2=Birnbaum |first2=LS |last3=Denison |first3=M |last4=De Vito |first4=M |last5=Farland |first5=W |last6=Feeley |first6=M |last7=Fiedler |first7=H |last8=Hakansson |first8=H |last9=Hanberg |first9=A |last10=Haws |first10=L |last11=Rose |first11=M |last12=Safe |first12=S |last13=Schrenk |first13=D |last14=Tohyama |first14=C |last15=Tritscher |first15=A |last16=Tuomisto |first16=J |last17=Tysklind |first17=M |last18=Walker |first18=N |last19=Peterson |first19=RE |title=The 2005 World Health Organization reevaluation of human and Mammalian toxic equivalency factors for dioxins and dioxin-like compounds. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=October 2006 |volume=93 |issue=2 |pages=223-41 |doi=10.1093/toxsci/kfl055 |pmid=16829543}}</ref> {{Fig | number = 1 | width = 400px | image = Structures of dibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,3,4,7,8-pentachlorodibenzofurane.jpg | caption = Structures of dibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,3,4,7,8-pentachlorodibenzofurane | attribution = }} There are 209 PCB-compounds. Four non-ortho compounds that have no chlorine substitution in any o-position to the inter-ring C-C-bridge (2, 2’, 6 or 6’) have the greatest dioxin-like potency (Fig. 2). The toxicity of 3,3’,4,4’,5-penta-CB (PCB126) is comparable to those dioxins assigned the TEF value<ref name=Berg06/> although high toxicity in humans has been challenged.<ref name=Larsson15>{{cite journal |last1=Larsson |first1=M |last2=van den Berg |first2=M |last3=Brenerová |first3=P |last4=van Duursen |first4=MB |last5=van Ede |first5=KI |last6=Lohr |first6=C |last7=Luecke-Johansson |first7=S |last8=Machala |first8=M |last9=Neser |first9=S |last10=Pěnčíková |first10=K |last11=Poellinger |first11=L |last12=Schrenk |first12=D |last13=Strapáčová |first13=S |last14=Vondráček |first14=J |last15=Andersson |first15=PL |title=Consensus toxicity factors for polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls combining in silico models and extensive in vitro screening of AhR-mediated effects in human and rodent cells. |journal=Chemical research in toxicology |date=20 April 2015 |volume=28 |issue=4 |pages=641-50 |doi=10.1021/tx500434j |pmid=25654323}}</ref> Eight mono-ortho PCBs have very low activity. All other PCBs are devoid of noticeable dioxin-like effects. Only compounds that are able to assume a planar (flat) conformation can bind to the AH receptor. Non-ortho compounds rotate relatively freely along the C-C-bridge between the rings, but each o-chlorine causes a steric hindrance and makes it more difficult for the molecule to assume a planar conformation (Fig. 2). {{Fig | number = 2 | image = Structures of biphenyl and 3,3’,4,4’,5-pentachlorobiphenyl.jpg | caption = Structures of biphenyl and 3,3’,4,4’,5-pentachlorobiphenyl (PCB 126) }} Brominated dioxins, furans and biphenyls, as well as mixed halogenated congeners, may share the toxicity and the ability to bind to AH receptor. They probably deserve TEF values as well, but lack sufficient data.<ref name=Berg13>{{cite journal |last1=van den Berg |first1=M |last2=Denison |first2=MS |last3=Birnbaum |first3=LS |last4=Devito |first4=MJ |last5=Fiedler |first5=H |last6=Falandysz |first6=J |last7=Rose |first7=M |last8=Schrenk |first8=D |last9=Safe |first9=S |last10=Tohyama |first10=C |last11=Tritscher |first11=A |last12=Tysklind |first12=M |last13=Peterson |first13=RE |title=Polybrominated dibenzo-p-dioxins, dibenzofurans, and biphenyls: inclusion in the toxicity equivalency factor concept for dioxin-like compounds. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=June 2013 |volume=133 |issue=2 |pages=197-208 |doi=10.1093/toxsci/kft070 |pmid=23492812}}</ref> Many other compounds bind to the AH receptor, e.g. polyaromatic hydrocarbons and polychlorinated azoxy-benzenes and naphthalenes.<ref name=Poland82/> Surprisingly, many natural compounds have very high affinity to AH receptors. These include e.g. indoles, flavones, benzoflavones, imidazoles and pyridines (for review, see Denison and Nagy<ref name=Denison03/>; DeGroot et al.<ref>{{cite book |last1=DeGroot |first1=Danica |last2=He |first2=Guochun |last3=Fraccalvieri |first3=Domenico |last4=Bonati |first4=Laura |last5=Pandini |first5=Allesandro |last6=Denison |first6=Michael S. |title=The AH Receptor in Biology and Toxicology |date=2011 |publisher=John Wiley & Sons, Ltd |isbn=9781118140574 |pages=63–79 |url=https://onlinelibrary.wiley.com/doi/10.1002/9781118140574.ch4 |language=en |chapter=AHR Ligands: Promiscuity in Binding and Diversity in Response|doi=10.1002/9781118140574.ch4}}</ref>). They are usually metabolized rapidly, but due to continuous intake from food, especially vegetables, they may cause receptor activation at the same level as or higher than the present background concentrations of contaminant dioxins.<ref>{{cite journal |last1=Connor |first1=KT |last2=Harris |first2=MA |last3=Edwards |first3=MR |last4=Budinsky |first4=RA |last5=Clark |first5=GC |last6=Chu |first6=AC |last7=Finley |first7=BL |last8=Rowlands |first8=JC |title=AH receptor agonist activity in human blood measured with a cell-based bioassay: evidence for naturally occurring AH receptor ligands in vivo. |journal=Journal of exposure science & environmental epidemiology |date=July 2008 |volume=18 |issue=4 |pages=369-80 |doi=10.1038/sj.jes.7500607 |pmid=17912254}}</ref> Short-acting stimulations of the receptor may, however, be qualitatively different from the persistent stimulation of dioxins.<ref>{{Cite journal|last=Gouedard|first=C.|last2=Barouki|first2=R.|last3=Morel|first3=Y.|date=2004-05-28|title=Dietary Polyphenols Increase Paraoxonase 1 Gene Expression by an Aryl Hydrocarbon Receptor-Dependent Mechanism|url=http://dx.doi.org/10.1128/mcb.24.12.5209-5222.2004|journal=Molecular and Cellular Biology|volume=24|issue=12|pages=5209–5222|doi=10.1128/mcb.24.12.5209-5222.2004|issn=0270-7306}}</ref><ref>{{Cite journal|last=Mahiout|first=Selma|last2=Lindén|first2=Jere|last3=Esteban|first3=Javier|last4=Sánchez-Pérez|first4=Ismael|last5=Sankari|first5=Satu|last6=Pettersson|first6=Lars|last7=Håkansson|first7=Helen|last8=Pohjanvirta|first8=Raimo|date=2017-07|title=Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats|url=http://dx.doi.org/10.1016/j.taap.2017.04.020|journal=Toxicology and Applied Pharmacology|volume=326|pages=54–65|doi=10.1016/j.taap.2017.04.020|issn=0041-008X}}</ref> Intriguingly many of these vegetables are considered very healthy. == Sources == Sources of different dioxin-like chemicals are different depending upon the chemical class. PCDD/F compounds are unwanted side products in burning processes or are impurities in the synthesis of PCBs, chlorophenol fungicides and phenoxy acid herbicides.<ref name=Kanan>{{cite journal |last1=Kanan |first1=Sofian |last2=Samara |first2=Fatin |title=Dioxins and furans: A review from chemical and environmental perspectives |journal=Trends in Environmental Analytical Chemistry |date=January 2018 |volume=17 |pages=1–13 |doi=10.1016/j.teac.2017.12.001}}</ref> Due to control measures, main sources are very different today than they were 30 or 40 years ago. The decrease in environmental levels was clearly demonstrated in sea bottom sediment core studies: the peak concentrations are in sediments layered in about 1980s.<ref name=Assefa>{{Cite journal|last=Assefa|first=Anteneh T.|last2=Sobek|first2=Anna|last3=Sundqvist|first3=Kristina L.|last4=Cato|first4=Ingemar|last5=Jonsson|first5=Per|last6=Tysklind|first6=Mats|last7=Wiberg|first7=Karin|date=2013-12-24|title=Temporal Trends of PCDD/Fs in Baltic Sea Sediment Cores Covering the 20th Century|url=http://dx.doi.org/10.1021/es404599z|journal=Environmental Science & Technology|volume=48|issue=2|pages=947–953|doi=10.1021/es404599z|issn=0013-936X}}</ref><ref>{{cite journal |last1=Sobek |first1=A |last2=Sundqvist |first2=KL |last3=Assefa |first3=AT |last4=Wiberg |first4=K |title=Baltic Sea sediment records: unlikely near-future declines in PCBs and HCB. |journal=The Science of the total environment |date=15 June 2015 |volume=518-519 |pages=8-15 |doi=10.1016/j.scitotenv.2015.02.093 |pmid=25747358}}</ref> However, further reduction especially of air emissions is needed.<ref name=Assefa/> Any burning will produce PCDD/Fs if chlorine (particularly along with metal catalysts) is available, even burning wood<ref>{{Cite journal|last=Northcross|first=Amanda L.|last2=Katharine Hammond|first2=S.|last3=Canuz|first3=Eduardo|last4=Smith|first4=Kirk R.|date=2012-03|title=Dioxin inhalation doses from wood combustion in indoor cookfires|url=http://dx.doi.org/10.1016/j.atmosenv.2011.11.054|journal=Atmospheric Environment|volume=49|pages=415–418|doi=10.1016/j.atmosenv.2011.11.054|issn=1352-2310}}</ref> and burning incense.<ref>{{Cite journal|last=Hu|first=Ming-Tsan|last2=Chen|first2=Shen-Jen|last3=Huang|first3=Kuo-Lin|last4=Lin|first4=Yuan-Chung|last5=Lee|first5=Wen-Jhy|last6=Chang-Chien|first6=Guo-Ping|last7=Tsai|first7=Jen-Hsiung|last8=Lee|first8=Jia-Twu|last9=Chiu|first9=Chuen-Huey|date=2009-08|title=Characteritization of, and health risks from, polychlorinated dibenzo-p-dioxins/dibenzofurans from incense burned in a temple|url=https://linkinghub.elsevier.com/retrieve/pii/S0048969709005026|journal=Science of The Total Environment|language=en|volume=407|issue=17|pages=4870–4875|doi=10.1016/j.scitotenv.2009.05.027}}</ref> Poorly controlled urban waste incineration was one of the most important sources in past. This can be technically solved by ensuring high incineration temperature (1,000 °C or higher), long burning time, and effective flue gas filtration. In modern good-quality incinerators PCDD/Fs are effectively removed.<ref name=Zhang17>{{cite journal |last1=Zhang |first1=Mengmei |last2=Buekens |first2=Alfons |last3=Li |first3=Xiaodong |title=Open burning as a source of dioxins |journal=Critical Reviews in Environmental Science and Technology |date=22 June 2017 |volume=47 |issue=8 |pages=543–620 |doi=10.1080/10643389.2017.1320154}}</ref> On the other hand, accidental dumpsite fires and backyard burning of waste are much more problematic and poorly controlled. In poor burning conditions the production of PCDD/Fs can be very high.<ref name=Dopico15>{{cite journal |last1=Dopico |first1=M |last2=Gómez |first2=A |title=Review of the current state and main sources of dioxins around the world. |journal=Journal of the Air & Waste Management Association (1995) |date=September 2015 |volume=65 |issue=9 |pages=1033-49 |doi=10.1080/10962247.2015.1058869 |pmid=26068294}}</ref><ref name=Zhang17/> Many previous sources of PCDD/Fs are presently in reasonable control (e.g. decreased chlorine bleaching of pulp, syntheses of PCBs, chlorophenols and phenoxy acids etc.). Metal industries and local burning of solid fuels remain as sources.<ref name=Zhang17/> Emissions decreased between 1985 and 2004 by about 80 % in Europe (from 14 kg per year I-TEQ{{efn|I-TEQ (international TEQ for PCDD/Fs) was used before present TEQs were agreed under the auspices of the World Health Organization. The differences are minor. The TEQs used in this text are sometimes called WHO-TEQs.}} to 2–4 kg),<ref>{{cite journal |last1=Quass |first1=U |last2=Fermann |first2=M |last3=Bröker |first3=G |title=The European dioxin air emission inventory project--final results. |journal=Chemosphere |date=March 2004 |volume=54 |issue=9 |pages=1319-27 |doi=10.1016/S0045-6535(03)00251-0 |pmid=14659425}}</ref> in the USA between 1987 and 2000 even more (from 14 kg to 1.4 kg)<ref>{{Cite web|url=https://cfpub.epa.gov/ncea/risk/recordisplay.cfm?deid=159286|title=An Inventory Of Sources And Environmental Releases Of Dioxin-Like Compounds In The U.S. For The Years 1987, 1995, And 2000 (Final, Nov 2006)|publisher=US EPA National Center for Environmental Assessment,Washington DC|website=cfpub.epa.gov|language=en|access-date=2019-12-16}}</ref> (Fig. 3). In the USA the top three current sources of dioxin emissions to air are forest fires, backyard burning of trash, and medical waste incinerators.<ref name=USEPA13>{{Cite web|url=https://cfpub.epa.gov/ncea/dioxin/recordisplay.cfm?deid=235432|title=Update to An Inventory of Sources and Environmental Releases of Dioxin-Like Compounds in the United States for the Years 1987, 1995, and 2000 (2013, External Review Draft)|publisher=US EPA National Center for Environmental Assessment, Washington DC|website=cfpub.epa.gov|language=en|access-date=2019-12-16}}</ref> The trend is not satisfactory in all countries, however.<ref>{{cite journal |last1=Momeniha |first1=F |last2=Faridi |first2=S |last3=Amini |first3=H |last4=Shamsipour |first4=M |last5=Naddafi |first5=K |last6=Yunesian |first6=M |last7=Niazi |first7=S |last8=Gohari |first8=K |last9=Farzadfar |first9=F |last10=Nabizadeh |first10=R |last11=Mokammel |first11=A |last12=Mahvi |first12=AH |last13=Mesdaghinia |first13=A |last14=Kashani |first14=H |last15=Nasseri |first15=S |last16=Gholampour |first16=A |last17=Saeedi |first17=R |last18=Hassanvand |first18=MS |title=Estimating national dioxins and furans emissions, major sources, intake doses, and temporal trends in Iran from 1990-2010. |journal=Journal of environmental health science & engineering |date=2017 |volume=15 |pages=20 |doi=10.1186/s40201-017-0283-1 |pmid=29051819}}</ref><ref name=Kanan/> Electronic waste recycling in poorly-controlled conditions is a recent additional concern as a source of dioxin-like compounds.<ref>{{cite journal |last1=Zhang |first1=J |last2=Jiang |first2=Y |last3=Zhou |first3=J |last4=Wu |first4=B |last5=Liang |first5=Y |last6=Peng |first6=Z |last7=Fang |first7=D |last8=Liu |first8=B |last9=Huang |first9=H |last10=He |first10=C |last11=Wang |first11=C |last12=Lu |first12=F |title=Elevated body burdens of PBDEs, dioxins, and PCBs on thyroid hormone homeostasis at an electronic waste recycling site in China. |journal=Environmental science & technology |date=15 May 2010 |volume=44 |issue=10 |pages=3956-62 |doi=10.1021/es902883a |pmid=20408536}}</ref><ref>{{cite journal |last1=Hu |first1=Jianfang |last2=Xiao |first2=Xiao |last3=Peng |first3=Ping'an |last4=Huang |first4=Weilin |last5=Chen |first5=Deyi |last6=Cai |first6=Ying |title=Spatial distribution of polychlorinated dibenzo-p-dioxins and dibenzo-furans (PCDDs/Fs) in dust, soil, sediment and health risk assessment from an intensive electronic waste recycling site in Southern China |journal=Environmental Science: Processes & Impacts |date=2013 |volume=15 |issue=10 |pages=1889 |doi=10.1039/c3em00319a |pmid=23955158}}</ref> It should be noted that there are also natural sources of PCDD/Fs such as kaolinic clay and volcanic eruptions.<ref name=Hoogenboom15>{{cite journal |last1=Hoogenboom |first1=Ron |last2=Traag |first2=Wim |last3=Fernandes |first3=Alwyn |last4=Rose |first4=Martin |title=European developments following incidents with dioxins and PCBs in the food and feed chain |journal=Food Control |date=April 2015 |volume=50 |pages=670–683 |doi=10.1016/j.foodcont.2014.10.010}}</ref><ref>{{cite journal |last1=Jin |first1=LJ |last2=Chen |first2=BL |title=Natural origins, concentration levels, and formation mechanisms of organohalogens in the environment |journal=Progr Chemistry |date=2017 |volume=29 |pages=1093-1114 |doi=10.7536/PC170563 |url=http://manu56.magtech.com.cn/progchem/EN/abstract/abstract11961.shtml}}</ref><ref name=Rathna18>{{cite journal |last1=Rathna |first1=R |last2=Varjani |first2=S |last3=Nakkeeran |first3=E |title=Recent developments and prospects of dioxins and furans remediation. |journal=Journal of environmental management |date=1 October 2018 |volume=223 |pages=797-806 |doi=10.1016/j.jenvman.2018.06.095 |pmid=29986327}}</ref> {{Fig | number = 3 | width = 400px | image = Decrease of dioxins in ambient air over 20 years.jpg | caption = Decrease of dioxins in ambient air in different regions | attribution = (redrawn from Dopico and Gomez, 2015).<ref name=Dopico15/> }} PCB compounds were in wide use from 1930s to 1980s for multiple purposes because they are technically excellent oils, resistant to pressure, chemically resistant, non-flammable, and do not conduct electricity. Although their production was discontinued in most countries in the 1980s, these compounds still linger in many products such as electrical transformers and plastic materials. Some of it ends up to the general environment. Only a minor portion of PCBs in mixtures are dioxin-like, depending on the matrix, for example non-ortho congeners are of the order of 0.1 % and mono-ortho congeners 10 % of the total amount of PCBs.<ref>{{cite journal |last1=Kiviranta |first1=H |last2=Ovaskainen |first2=ML |last3=Vartiainen |first3=T |title=Market basket study on dietary intake of PCDD/Fs, PCBs, and PBDEs in Finland. |journal=Environment international |date=September 2004 |volume=30 |issue=7 |pages=923-32 |doi=10.1016/j.envint.2004.03.002 |pmid=15196840}}</ref> {{notelist}} == Environmental fate == Dioxins tend to accumulate in the environment, because they are persistent and not easily degraded by environmental microbes. Because dioxins are much more soluble in lipids than in water, they tend to accumulate in e.g. plankton (bioaccumulation). The concentration tends to magnify at each trophic level (biomagnification), which leads to high concentrations at the highest trophic levels, e.g. seals and predatory birds. Human concentrations are not nearly as high as in the most endangered wild species, because human diet is quite diverse. However, there have been concerns regarding the safety of wild and farmed fish in our diet (see below). TCDD has been long known to be sensitive to photochemical dechlorination. If exposed to direct sunlight or UV-radiation, it will decompose in a matter of hours.<ref>{{Cite journal|last=Crosby|first=D.|last2=Wong|first2=A.|date=1977-03-25|title=Environmental degradation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)|url=http://dx.doi.org/10.1126/science.841331|journal=Science|volume=195|issue=4284|pages=1337–1338|doi=10.1126/science.841331|issn=0036-8075}}</ref> Photocatalysis and other methods have also been tested in attempts to remove dioxins in soils and other environments.<ref name=Kanan/><ref name=Rathna18/> Because dioxins adsorb tightly to soil particles, and microbial degradation (mostly via dehalogenation) of dioxins is very slow, researchers have actively tried to search for mechanisms to increase degradation<ref>{{Cite journal|last=Isosaari|first=Pirjo|last2=Tuhkanen|first2=Tuula|last3=Vartiainen|first3=Terttu|date=2004-05|title=Photodegradation of polychlorinated dibenzo-p-dioxins and dibenzofurans in soil with vegetable oil|url=http://dx.doi.org/10.1007/bf02979673|journal=Environmental Science and Pollution Research|volume=11|issue=3|pages=181–185|doi=10.1007/bf02979673|issn=0944-1344}}</ref> or to find especially active microbial species for the purposes of bioremediation.<ref>{{cite journal |last1=Smidt |first1=H |last2=de Vos |first2=WM |title=Anaerobic microbial dehalogenation. |journal=Annual review of microbiology |date=2004 |volume=58 |pages=43-73 |doi=10.1146/annurev.micro.58.030603.123600 |pmid=15487929}}</ref><ref name=Kanan/><ref name=Rathna18/> By and large, this has not been very successful. Also interactions with the microbiome in the intestines are poorly known.<ref name=Atashgani18>{{cite journal |last1=Atashgahi |first1=S |last2=Shetty |first2=SA |last3=Smidt |first3=H |last4=de Vos |first4=WM |title=Flux, Impact, and Fate of Halogenated Xenobiotic Compounds in the Gut. |journal=Frontiers in physiology |date=2018 |volume=9 |pages=888 |doi=10.3389/fphys.2018.00888 |pmid=30042695}}</ref> {| class="wikitable" |Dioxin literature is confusing to many readers, because units used may be less known and they are sometimes used in a confusing manner. Some dioxins are very potent and therefore the amounts of our concern are very small, usually measured as picograms or nanograms. Picogram is 0.000 000 000 001 g. Concentrations in animal or human tissues are usually expressed as pg/g lipid or ng/kg lipid. Some authors use non-standard expression ppt (parts per trillion). This is confusing and should be avoided, since trillion may mean 10¹² or 10¹⁸ in different countries depending on the use of [[w:Long and short scales|short scale or long scale]] system, resp. To make it clear, weight units are g (gram), mg (milligram, 10^-3 g), μg (microgram, 10^-6 g), ng (nanogram, 10^-9 g), pg (picogram, 10^-12 g), fg (femtogram, 10^-15 g). |} == Toxicokinetics: absorption, distribution and elimination == The main source of dioxins in animals and humans is food.<ref name=Liem00>{{cite journal |last1=Liem |first1=AK |last2=Fürst |first2=P |last3=Rappe |first3=C |title=Exposure of populations to dioxins and related compounds. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=241-59 |doi=10.1080/026520300283324 |pmid=10912239}}</ref><ref>{{cite journal |last1=Fernández-González |first1=R |last2=Yebra-Pimentel |first2=I |last3=Martínez-Carballo |first3=E |last4=Simal-Gándara |first4=J |title=A Critical Review about Human Exposure to Polychlorinated Dibenzo-p-Dioxins (PCDDs), Polychlorinated Dibenzofurans (PCDFs) and Polychlorinated Biphenyls (PCBs) through Foods. |journal=Critical reviews in food science and nutrition |date=2015 |volume=55 |issue=11 |pages=1590-617 |doi=10.1080/10408398.2012.710279 |pmid=24279584}}</ref> Oral absorption of dioxins depends on the carrier. Dioxins in the fat of fish or meat are well absorbed, but those in e.g. soils poorly. Also dermal absorption depends on the carrier.<ref name=Pohjanvirta94/> After absorption they are distributed mostly to adipose tissue and to the liver.<ref name=Pohjanvirta94/><ref>{{cite journal |last1=Warenik-Bany |first1=M |last2=Strucinski |first2=P |last3=Piskorska-Pliszczynska |first3=J |title=Dioxins and PCBs in game animals: Interspecies comparison and related consumer exposure. |journal=Environment international |date=NaN |volume=89-90 |pages=21-9 |doi=10.1016/j.envint.2016.01.007 |pmid=26826359}}</ref><ref>{{Cite journal|last=La Merrill|first=Michele|last2=Emond|first2=Claude|last3=Kim|first3=Min Ji|last4=Antignac|first4=Jean-Philippe|last5=Le Bizec|first5=Bruno|last6=Clément|first6=Karine|last7=Birnbaum|first7=Linda S.|last8=Barouki|first8=Robert|date=2013-02|title=Toxicological Function of Adipose Tissue: Focus on Persistent Organic Pollutants|url=http://dx.doi.org/10.1289/ehp.1205485|journal=Environmental Health Perspectives|volume=121|issue=2|pages=162–169|doi=10.1289/ehp.1205485|issn=0091-6765}}</ref> Liver sequestration increases at high dose levels due to induction of CYP1A2 binding dioxins.<ref>{{cite journal |last1=van Birgelen |first1=AP |last2=van den Berg |first2=M |title=Toxicokinetics. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=267-73 |doi=10.1080/026520300283342 |pmid=10912241}}</ref> Elimination of dioxins is slow, because they are not easily metabolized and urinary excretion is negligible. Elimination is mainly via faeces after slow metabolism in the liver, followed by biliary excretion into the gut. Variation between species is large, e.g. the half-life of TCDD in rats is about 3 weeks, in man about 7 years.<ref name=Pohjanvirta94/> Elimination half-lives of various congeners in people may vary tenfold (Table 1). There may be high individual variation.<ref name=Mitoma15>{{cite journal |last1=Mitoma |first1=C |last2=Uchi |first2=H |last3=Tsukimori |first3=K |last4=Yamada |first4=H |last5=Akahane |first5=M |last6=Imamura |first6=T |last7=Utani |first7=A |last8=Furue |first8=M |title=Yusho and its latest findings-A review in studies conducted by the Yusho Group. |journal=Environment international |date=September 2015 |volume=82 |pages=41-8 |doi=10.1016/j.envint.2015.05.004 |pmid=26010306}}</ref> Very high concentrations seem to induce metabolizing enzymes and shorten the half-lives.<ref>{{cite journal |last1=Aylward |first1=LL |last2=Brunet |first2=RC |last3=Carrier |first3=G |last4=Hays |first4=SM |last5=Cushing |first5=CA |last6=Needham |first6=LL |last7=Patterson DG |first7=Jr |last8=Gerthoux |first8=PM |last9=Brambilla |first9=P |last10=Mocarelli |first10=P |title=Concentration-dependent TCDD elimination kinetics in humans: toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort. |journal=Journal of exposure analysis and environmental epidemiology |date=January 2005 |volume=15 |issue=1 |pages=51-65 |doi=10.1038/sj.jea.7500370 |pmid=15083163}}</ref><ref name=Sorg09>{{cite journal |last1=Sorg |first1=O |last2=Zennegg |first2=M |last3=Schmid |first3=P |last4=Fedosyuk |first4=R |last5=Valikhnovskyi |first5=R |last6=Gaide |first6=O |last7=Kniazevych |first7=V |last8=Saurat |first8=JH |title=2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites. |journal=Lancet (London, England) |date=3 October 2009 |volume=374 |issue=9696 |pages=1179-85 |doi=10.1016/S0140-6736(09)60912-0 |pmid=19660807}}</ref> '''Table 1 {{!}}''' Elimination half-lives in humans of some PCDD/Fs.<ref>{{cite journal |last1=Milbrath |first1=MO |last2=Wenger |first2=Y |last3=Chang |first3=CW |last4=Emond |first4=C |last5=Garabrant |first5=D |last6=Gillespie |first6=BW |last7=Jolliet |first7=O |title=Apparent half-lives of dioxins, furans, and polychlorinated biphenyls as a function of age, body fat, smoking status, and breast-feeding. |journal=Environmental health perspectives |date=March 2009 |volume=117 |issue=3 |pages=417-25 |doi=10.1289/ehp.11781 |pmid=19337517}}</ref> {| class="wikitable sortable" !Congener !Half-life, years |- |2,3,7,8-TCDD |7.2 |- |1,2,3,7,8-PeCDD |11.2 |- |1,2,3,4,7,8-HxCDD |9.8 |- |1,2,3,6,7,8-HxCDD |13.1 |- |1,2,3,7,8,9-HxCDD |5.1 |- |1,2,3,4,6,7,8-HpCDD |4.9 |- |OCDD |6.7 |- |2,3,7,8-TCDF |2.1 |- |1,2,3,7,8-PeCDF |3.5 |- |2,3,4,7,8-PeCDF |7.0 |- |1,2,3,4,7,8-HxCDF |6.4 |- |1,2,3,6,7,8-HxCDF |7.2 |- |1,2,3,7,8,9-HxCDF |7.2 |- |2,3,4,6,7,8-HxCDF |2.8 |- |1,2,3,4,6,7,8-HpCDF |3.1 |- |1,2,3,4,7,8,9-HpCDF |4.6 |- |OCDF |1.4 |} Nursing mothers excrete dioxins in milk fat at approximately the same concentrations as their own level in body fat. This means that maternal dioxin levels decrease during the lactation period (even by 20%).<ref>{{cite journal |last1=Vartiainen |first1=T |last2=Jaakkola |first2=JJ |last3=Saarikoski |first3=S |last4=Tuomisto |first4=J |title=Birth weight and sex of children and the correlation to the body burden of PCDDs/PCDFs and PCBs of the mother. |journal=Environmental health perspectives |date=February 1998 |volume=106 |issue=2 |pages=61-6 |doi=10.1289/ehp.9810661 |pmid=9432971}}</ref> Also placental PCDD/F concentrations are in the same range as in maternal body or breast milk (as pg/g fat)<ref name=Virtanen12>{{cite journal |last1=Virtanen |first1=HE |last2=Koskenniemi |first2=JJ |last3=Sundqvist |first3=E |last4=Main |first4=KM |last5=Kiviranta |first5=H |last6=Tuomisto |first6=JT |last7=Tuomisto |first7=J |last8=Viluksela |first8=M |last9=Vartiainen |first9=T |last10=Skakkebaek |first10=NE |last11=Toppari |first11=J |title=Associations between congenital cryptorchidism in newborn boys and levels of dioxins and PCBs in placenta. |journal=International journal of andrology |date=June 2012 |volume=35 |issue=3 |pages=283-93 |doi=10.1111/j.1365-2605.2011.01233.x |pmid=22150420}}</ref> and placental transfer to the foetus occurs.<ref>{{cite journal |last1=Feeley |first1=M |last2=Brouwer |first2=A |title=Health risks to infants from exposure to PCBs, PCDDs and PCDFs. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=325-33 |doi=10.1080/026520300283397 |pmid=10912246}}</ref> Each delivery and lactation decreases the mother's body burden by 25–30%. In children elimination is faster than in adults, initially with a half-life of months rather than years,<ref>{{cite journal |last1=Kreuzer |first1=PE |last2=Csanády |first2=GA |last3=Baur |first3=C |last4=Kessler |first4=W |last5=Päpke |first5=O |last6=Greim |first6=H |last7=Filser |first7=JG |title=2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition. |journal=Archives of toxicology |date=1997 |volume=71 |issue=6 |pages=383-400 |pmid=9195020|doi=10.1007/s002040050402}}</ref><ref>{{cite journal |last1=Kerger |first1=BD |last2=Leung |first2=HW |last3=Scott |first3=P |last4=Paustenbach |first4=DJ |last5=Needham |first5=LL |last6=Patterson DG |first6=Jr |last7=Gerthoux |first7=PM |last8=Mocarelli |first8=P |title=Age- and concentration-dependent elimination half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso children. |journal=Environmental health perspectives |date=October 2006 |volume=114 |issue=10 |pages=1596-602 |doi=10.1289/ehp.8884 |pmid=17035149}}</ref><ref>{{cite journal |last1=Leung |first1=HW |last2=Kerger |first2=BD |last3=Paustenbach |first3=DJ |last4=Ryan |first4=JJ |last5=Masuda |first5=Y |title=Concentration and age-dependent elimination kinetics of polychlorinated dibenzofurans in Yucheng and Yusho patients. |journal=Toxicology and industrial health |date=September 2007 |volume=23 |issue=8 |pages=493-501 |doi=10.1177/0748233708089024 |pmid=18669171}}</ref> probably due to several factors, faster rate of faecal lipid excretion, and increased metabolism.<ref>{{cite journal |last1=Kerger |first1=BD |last2=Leung |first2=HW |last3=Scott |first3=PK |last4=Paustenbach |first4=DJ |title=Refinements on the age-dependent half-life model for estimating child body burdens of polychlorodibenzodioxins and dibenzofurans. |journal=Chemosphere |date=April 2007 |volume=67 |issue=9 |pages=S272-8 |doi=10.1016/j.chemosphere.2006.05.108 |pmid=17207842}}</ref> Rapid growth and dilution decrease the concentrations as well, even if the body burden does not change to the same extent. == Mechanism of action: the Aryl Hydrocarbon Receptor == Most biological actions of dioxins, including their toxicity, are mediated by the AHR (Fig. 4). The AHR is an evolutionarily ancient receptor, an over 600-million-year old protein occurring in all vertebrates. Homologs of the AHR have also been discovered in invertebrates and insects. These primitive AHR-homologs do not bind dioxins or other external ligands. They seem to play important developmental roles in neuronal differentiation and regulation of feeding-related aggregation behaviour or in regulation of normal morphogenesis.<ref name=Linden10>{{cite journal |last1=Lindén |first1=J |last2=Lensu |first2=S |last3=Tuomisto |first3=J |last4=Pohjanvirta |first4=R |title=Dioxins, the aryl hydrocarbon receptor and the central regulation of energy balance. |journal=Frontiers in neuroendocrinology |date=October 2010 |volume=31 |issue=4 |pages=452-78 |doi=10.1016/j.yfrne.2010.07.002 |pmid=20624415}}</ref><ref>{{cite book |last1=Hahn |first1=Mark E. |last2=Karchner |first2=Sibel I. |title=The AH Receptor in Biology and Toxicology |date=2011 |publisher=John Wiley & Sons, Ltd |isbn=9781118140574 |pages=387–403 |url=https://onlinelibrary.wiley.com/doi/10.1002/9781118140574.ch27 |language=en|doi=10.1002/9781118140574.ch27 |chapter=Structural and Functional Diversification of AHRs during Metazoan Evolution}}</ref><ref>{{cite book |last1=Powell‐Coffman |first1=Jo Anne |last2=Qin |first2=Hongtao |title=The AH Receptor in Biology and Toxicology |date=2011 |publisher=John Wiley & Sons, Ltd |isbn=9781118140574 |pages=405–411 |url=https://onlinelibrary.wiley.com/doi/abs/10.1002/9781118140574.ch28|doi=10.1002/9781118140574.ch28 |language=en |chapter=Invertebrate AHR Homologs: Ancestral Functions in Sensory Systems}}</ref><ref>{{cite journal |last1=Tian |first1=J |last2=Feng |first2=Y |last3=Fu |first3=H |last4=Xie |first4=HQ |last5=Jiang |first5=JX |last6=Zhao |first6=B |title=The Aryl Hydrocarbon Receptor: A Key Bridging Molecule of External and Internal Chemical Signals |journal=Environmental science & technology |date=18 August 2015 |volume=49 |issue=16 |pages=9518-31 |doi=10.1021/acs.est.5b00385 |pmid=26079192}}</ref><ref name=Bock17>{{cite journal |last1=Bock |first1=KW |title=Human and rodent aryl hydrocarbon receptor (AHR): from mediator of dioxin toxicity to physiologic AHR functions and therapeutic options. |journal=Biological chemistry |date=1 April 2017 |volume=398 |issue=4 |pages=455-464 |doi=10.1515/hsz-2016-0303 |pmid=27805907}}</ref> {{Fig | number = 4 | width = 400px | image = AHR functional domains.svg | caption = The structure of AHR. The approximate sites for DNA binding, ligand binding, HSP90 binding, heterodimerization, and transactivation are shown | attribution = Jeff Dahl, CC BY-SA 4.0 }} The AHR belongs to the family of basic Helix–Loop–Helix-PAS (bHLH/PAS) proteins, which have important roles in e.g. regulation of neural development, in generation and maintenance of circadian rhythms, in sensing cellular environment, and as transcriptional partners and co-activators. Although it is structurally different, the AHR acts as a transcription factor analogously to the nuclear receptors such as steroid receptors or thyroid receptors. The AHR is a ligand-activated transcription factor that integrates environmental, dietary, microbial and metabolic cues to control complex transcriptional programmes in a ligand-specific, cell-type-specific and context-specific manner.<ref name=Rothhammer19/> The AHR exists in the cytosol in a protein complex including several proteins (Fig. 5). These chaperones keep the AHR in a conformation able to bind a ligand but unable to enter the nucleus. After ligand binding, the protein complex enters into the nucleus. The AHR releases its chaperones and heterodimerizes with another bHLH/PAS protein, ARNT (AHR nuclear translocator). The AHR/ARNT dimer binds to DNA at the major groove of the DNA helix at specific sites, AHR response elements (also known as dioxin response elements, DREs, or xenobiotic response elements XREs). {{Fig | number = 5 | width = 400px | image = AHR pathways in cell.jpg | caption = A schematic diagram of some AHR signaling pathways. The canonical pathway is depicted with solid black arrows, alternative pathways with dashed arrows, and an intersection of these two with a solid red arrow. The green bars represent the AHR, red bars ARNT, yellow bars ARA9 (AIP, Xap2), blue bars HSP90 and the blue ovals p23. Dioxin binding to the AHR (1.) leads to its translocation into the nucleus by importin-β, (2.) heterodimerization with ARNT and binding to the DNA at DREs, (3.) modulating expression levels of target genes (green arrows). One of the gene products elevated by this mechanism is AHRR, a repressor protein which forms a feedback loop that inhibits AHR action. The AHR is finally degraded by the ubiquitin–proteasome system (4.). AHR activation can also rapidly increase intracellular Ca2+ concentration (5.) which in turn may ultimately result in augmented Cox2 gene expression. Elevation of Ca2+ activates CaMKs, which appear to have a critical role in the translocation of the AHR. Another example of effects mediated by the AHR via non-canonical pathways is suppression of acute-phase proteins (6.) which does not involve DNA binding. | attribution = (simplified and modified from Lindén et al.).<ref name=Linden10/>, Jouko Tuomisto }} In addition to this canonical pathway, some actions of dioxins and AHR are mediated via non-canonical pathways. These may be involved e.g. in interactions with other receptors, such as estrogen receptor, other transcription factors such as NFκB signalling complex, different kinases, and various epigenetic mechanisms.<ref name=Linden10/><ref name=Brunnberg2012>{{Cite book|url=http://dx.doi.org/10.1002/9781118140574.ch9|title=The AH Receptor in Biology and Toxicology|last=Brunnberg|first=Sara|last2=Swedenborg|first2=Elin|last3=Gustafsson|first3=Jan-Åke|date=2011-11-10|editor-first=R|editor-last=Pohjanvirta|publisher=John Wiley & Sons, Inc.|isbn=978-1-118-14057-4|location=Hoboken, NJ, USA|pages=127–141|doi=10.1002/9781118140574.ch9|chapter=Functional Interactions of AHR with other Receptors}}</ref><ref name=Ko2012>{{Cite book|url=http://dx.doi.org/10.1002/9781118140574.ch11|chapter=Epigenetic mechanisms in AHR function|doi=10.1002/9781118140574.ch11|title=The AH Receptor in Biology and Toxicology|last=Ko|first=Chia-I|last2=Puga|first2=Alvaro|editor-first=R|editor-last=Pohjanvirta|date=2011-11-10|publisher=John Wiley & Sons, Inc.|isbn=978-1-118-14057-4|location=Hoboken, NJ, USA|pages=157–178}}</ref><ref>{{cite journal |last1=Patrizi |first1=B |last2=Siciliani de Cumis |first2=M |title=TCDD Toxicity Mediated by Epigenetic Mechanisms |journal=International journal of molecular sciences |date=18 December 2018 |volume=19 |issue=12 |doi=10.3390/ijms19124101 |pmid=30567322}}</ref><ref name=Rothhammer19/><ref name=Viluksela19>{{cite journal |last1=Viluksela |first1=M |last2=Pohjanvirta |first2=R |title=Multigenerational and Transgenerational Effects of Dioxins. |journal=International journal of molecular sciences |date=17 June 2019 |volume=20 |issue=12 |doi=10.3390/ijms20122947 |pmid=31212893}}</ref><ref>{{cite book |last1=Matsumura |first1=Fumio |title=The AH Receptor in Biology and Toxicology |date=2011 |publisher=John Wiley & Sons, Ltd |isbn=9781118140574 |pages=197–215 |url=https://onlinelibrary.wiley.com/doi/10.1002/9781118140574.ch13 |language=en |chapter=Nongenomic route of action of TCDD: Identity, characteristics, and toxicological significance|doi=10.1002/9781118140574.ch13|editor-first=R|editor-last=Pohjanvirta}}</ref> Interactions with the retinoid system are especially interesting, because some effects of dioxins are similar to symptoms of vitamin A deficiency (e.g. retarded growth, problems in reproduction) and some resemble the toxic effects of vitamin A (such as developmental malformations).<ref name=Nilsson2002>{{Cite journal|last=Nilsson|first=Charlotte B.|last2=Håkansson|first2=Helen|date=2002-01|title=The Retinoid Signaling System — A Target in Dioxin Toxicity|url=http://dx.doi.org/10.1080/20024091064228|journal=Critical Reviews in Toxicology|volume=32|issue=3|pages=211–232|doi=10.1080/20024091064228|issn=1040-8444}}</ref> It seems that dioxins are involved both in metabolic steps of retinoid activation and metabolism as well as in molecular interactions of retinoid receptors and AHR in the transactivation machinery. <ref name=Nilsson2002/><ref name=Brunnberg2012/> In response to activation by dioxins, the AHR signalling pathway modifies the expression levels of numerous genes. The best characterized of these at the molecular level is the induction of the gene for a Phase I cytochrome P-450 drug-metabolizing enzyme, CYP1A1.<ref><{{cite journal |last1=Okey |first1=AB |last2=Franc |first2=MA |last3=Moffat |first3=ID |last4=Tijet |first4=N |last5=Boutros |first5=PC |last6=Korkalainen |first6=M |last7=Tuomisto |first7=J |last8=Pohjanvirta |first8=R |title=Toxicological implications of polymorphisms in receptors for xenobiotic chemicals: the case of the aryl hydrocarbon receptor. |journal=Toxicology and applied pharmacology |date=1 September 2005 |volume=207 |issue=2 Suppl |pages=43-51 |doi=10.1016/j.taap.2004.12.028 |pmid=15993909}}</ref><ref name=Okey07>{{cite journal |last1=Okey |first1=AB |title=An aryl hydrocarbon receptor odyssey to the shores of toxicology: the Deichmann Lecture, International Congress of Toxicology-XI. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=July 2007 |volume=98 |issue=1 |pages=5-38 |doi=10.1093/toxsci/kfm096 |pmid=17569696}}</ref><ref>{{cite book |last1=Ma |first1=Qiang |title=The AH Receptor in Biology and Toxicology |date=2011 |publisher=John Wiley & Sons, Ltd |isbn=9781118140574 |pages=33–45 |url=https://onlinelibrary.wiley.com/doi/10.1002/9781118140574.ch2 |language=en |chapter=Overview of AHR Functional Domains and the Classical AHR Signaling Pathway: Induction of Drug Metabolizing Enzymes|editor-first=R|editor-last=Pohjanvirta|doi=10.1002/9781118140574.ch2}}</ref> Dioxin-activated AHR induces other Phase I and II enzymes that metabolize chemicals in the liver including CYP1A2, CYP1B1, CYP2S1, CYP2A5, ALDH3, GSTA1, UGT1A1, UGT1A6, UGT1A7 and NQO1. Probably this induction system evolved as a mechanism to enhance the elimination of foreign fat-soluble chemicals. In addition to xenobiotic-metabolizing enzymes, TCDD exposure modifies the expression of a large number of other genes. For example, in adult mouse or rat liver, hundreds of genes are affected.<ref>{{cite journal |last1=Tijet |first1=N |last2=Boutros |first2=PC |last3=Moffat |first3=ID |last4=Okey |first4=AB |last5=Tuomisto |first5=J |last6=Pohjanvirta |first6=R |title=Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries. |journal=Molecular pharmacology |date=January 2006 |volume=69 |issue=1 |pages=140-53 |doi=10.1124/mol.105.018705 |pmid=16214954}}</ref><ref name=Linden10/><ref name=Rothhammer19/> It is still unclear which genes are the most important for the toxic effects such as lethality, anorexia and wasting syndrome, and various hyperplastic and atrophic tissue changes. The role of AH receptor predominantly as an inducer of metabolic enzymes to protect us from xenobiotics is rapidly changing. Mice lacking AHR (AHR knockout) have clearly demonstrated the necessity of AHR activation for normal physiology, and these animals are severely sick with e.g. cardiac hypertrophy, liver fibrosis, reproductive problems, and impaired immunology. AH receptors participate in many regulatory functions in the body (the reader is referred to recent reviews).<ref name=Linden10/><ref>{{cite journal |last1=Casado |first1=FL |last2=Singh |first2=KP |last3=Gasiewicz |first3=TA |title=The aryl hydrocarbon receptor: regulation of hematopoiesis and involvement in the progression of blood diseases. |journal=Blood cells, molecules & diseases |date=15 April 2010 |volume=44 |issue=4 |pages=199-206 |doi=10.1016/j.bcmd.2010.01.005 |pmid=20171126}}</ref><ref name=Pohjanvirta12>{{cite book |editor1-last=Pohjanvirta |editor1-first=Raimo |title=The AH Receptor in Biology and Toxicology |date=2011 |publisher=Wiley |url=https://onlinelibrary.wiley.com/doi/book/10.1002/9781118140574 |language=en|doi=10.1002/9781118140574}}</ref><ref>{{cite journal |last1=Van Voorhis |first1=M |last2=Fechner |first2=JH |last3=Zhang |first3=X |last4=Mezrich |first4=JD |title=The aryl hydrocarbon receptor: a novel target for immunomodulation in organ transplantation. |journal=Transplantation |date=27 April 2013 |volume=95 |issue=8 |pages=983-90 |doi=10.1097/TP.0b013e31827a3d1d |pmid=23263608}}</ref><ref>{{cite journal |last1=Esser |first1=C |last2=Rannug |first2=A |title=The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology. |journal=Pharmacological reviews |date=2015 |volume=67 |issue=2 |pages=259-79 |doi=10.1124/pr.114.009001 |pmid=25657351}}</ref><ref>{{cite journal |last1=Lahoti |first1=TS |last2=Boyer |first2=JA |last3=Kusnadi |first3=A |last4=Muku |first4=GE |last5=Murray |first5=IA |last6=Perdew |first6=GH |title=Aryl Hydrocarbon Receptor Activation Synergistically Induces Lipopolysaccharide-Mediated Expression of Proinflammatory Chemokine (c-c motif) Ligand 20. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=November 2015 |volume=148 |issue=1 |pages=229-40 |doi=10.1093/toxsci/kfv178 |pmid=26259605}}</ref><ref>{{cite journal |last1=Sibilano |first1=R |last2=Pucillo |first2=CE |last3=Gri |first3=G |title=Allergic responses and aryl hydrocarbon receptor novel pathway of mast cell activation. |journal=Molecular immunology |date=January 2015 |volume=63 |issue=1 |pages=69-73 |doi=10.1016/j.molimm.2014.02.015 |pmid=24656327}}</ref><ref>{{cite journal |last1=Kawajiri |first1=K |last2=Fujii-Kuriyama |first2=Y |title=The aryl hydrocarbon receptor: a multifunctional chemical sensor for host defense and homeostatic maintenance. |journal=Experimental animals |date=3 May 2017 |volume=66 |issue=2 |pages=75-89 |doi=10.1538/expanim.16-0092 |pmid=27980293}}</ref><ref name=Kolluri17>{{cite journal |last1=Kolluri |first1=SK |last2=Jin |first2=UH |last3=Safe |first3=S |title=Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target. |journal=Archives of toxicology |date=July 2017 |volume=91 |issue=7 |pages=2497-2513 |doi=10.1007/s00204-017-1981-2 |pmid=28508231}}</ref><ref name=Bock17/> An important area seems to be antibacterial and antiviral defence mechanisms<ref name=MouraAlves14/><ref name=Boule18>{{cite journal |last1=Boule |first1=Lisbeth A. |last2=Burke |first2=Catherine G. |last3=Jin |first3=Guang-Bi |last4=Lawrence |first4=B. Paige |title=Aryl hydrocarbon receptor signaling modulates antiviral immune responses: ligand metabolism rather than chemical source is the stronger predictor of outcome |journal=Scientific Reports |date=29 January 2018 |volume=8 |issue=1 |doi=10.1038/s41598-018-20197-4}}</ref> and the regulation of innate immunity.<ref name=Schiering17>{{cite journal |last1=Schiering |first1=C |last2=Wincent |first2=E |last3=Metidji |first3=A |last4=Iseppon |first4=A |last5=Li |first5=Y |last6=Potocnik |first6=AJ |last7=Omenetti |first7=S |last8=Henderson |first8=CJ |last9=Wolf |first9=CR |last10=Nebert |first10=DW |last11=Stockinger |first11=B |title=Feedback control of AHR signalling regulates intestinal immunity. |journal=Nature |date=9 February 2017 |volume=542 |issue=7640 |pages=242-245 |doi=10.1038/nature21080 |pmid=28146477}}</ref><ref>{{cite journal |last1=Gutiérrez-Vázquez |first1=C |last2=Quintana |first2=FJ |title=Regulation of the Immune Response by the Aryl Hydrocarbon Receptor. |journal=Immunity |date=16 January 2018 |volume=48 |issue=1 |pages=19-33 |doi=10.1016/j.immuni.2017.12.012 |pmid=29343438}}</ref><ref name=Rothhammer19/> AHR ligands are important at intestinal epithelial cells which serve as gatekeepers for their supply, and if AHR activation is too low, loss of important lymphoid cells and subsequent susceptibility to infections follow. == Toxicity equivalents == Dioxins and dioxin-like compounds vary in their potency and fate in the organisms. The toxicity of mixtures cannot be assessed by simply adding up the amounts or concentrations of all chemicals in the mixture. However, if the amount of a compound is standardized to the toxicologically equivalent amount of TCDD, chemicals with different potencies can be summed up and this equivalent quantity is very useful for regulatory and even some scientific purposes.<ref name=Berg06/><ref name=Tuomisto12>{{cite book |last1=Tuomisto |first1=Jouko |title=The AH Receptor in Biology and Toxicology |date=2011 |publisher=John Wiley & Sons, Ltd |isbn=9781118140574 |pages=317–330 |url=https://onlinelibrary.wiley.com/doi/10.1002/9781118140574.ch23 |language=en |chapter=The Toxic Equivalency Principle and its Application in Dioxin Risk Assessment|doi=10.1002/9781118140574.ch23|editor-first=R|editor-last=Pohjanvirta}}</ref> Several versions of TEF have been used since 1984, proposed by Ontario Ministry of Environment, U.S. Environmental Protection Agency, and the Nordic Countries, respectively. International harmonization was undertaken by NATO/CCMS, and most recently the World Health Organization organized re-evaluations of TEF values in 1998, 2005 and 2013.<ref name=Tuomisto12/><ref name=Berg13/> Brominated dioxins, furans and biphenyls, as well as mixed halogenated congeners, share many aspects of toxicity and the ability to bind to AH receptor. They probably deserve TEF values as well, but lack sufficient data. On interim basis the TEFs of respective chlorinated compounds has been recommended.<ref name=Berg13/> The toxicities can vary by a factor of 30,000, and TCDD is assigned a TEF of 1. Other chemicals are given TEF values of 1 to 0.000 03 (in fish down to <0.000 005) (Table 2). The amount of a given compound is multiplied by its TEF, resulting in the amount toxicologically equivalent to that of TCDD. These partial equivalent amounts are then added up to make the sum toxic equivalent (TEQ) of the mixture. This can be used as a proxy of the total dose of dioxin-like compounds. This is a consensus value based on several assumptions and not a strictly scientific fact.<ref name=Berg06/> Therefore they should be regularly updated to reflect new and more accurate information. This is because there are a number of uncertainties regarding kinetics, additivity, species differences, and slopes of dose-response curves.<ref name=Berg00>{{Cite journal|last=De Berg|first=Martin Vann|last2=Peterson|first2=Richard E.|last3=Schrenk|first3=Dieter|date=2000-04|title=Human risk assessment and TEFs|url=http://dx.doi.org/10.1080/026520300283414|journal=Food Additives and Contaminants|volume=17|issue=4|pages=347–358|doi=10.1080/026520300283414|issn=0265-203X}}</ref> '''Table 2 {{!}}''' Toxic equivalency factors for PCDD/Fs and PCBs. Other congeners are not assumed to have dioxin-like effects. IUPAC numbers for PCBs are given in parenthesis.<ref name=Berg98>{{cite journal |last1=Van den Berg |first1=M |last2=Birnbaum |first2=L |last3=Bosveld |first3=AT |last4=Brunström |first4=B |last5=Cook |first5=P |last6=Feeley |first6=M |last7=Giesy |first7=JP |last8=Hanberg |first8=A |last9=Hasegawa |first9=R |last10=Kennedy |first10=SW |last11=Kubiak |first11=T |last12=Larsen |first12=JC |last13=van Leeuwen |first13=FX |last14=Liem |first14=AK |last15=Nolt |first15=C |last16=Peterson |first16=RE |last17=Poellinger |first17=L |last18=Safe |first18=S |last19=Schrenk |first19=D |last20=Tillitt |first20=D |last21=Tysklind |first21=M |last22=Younes |first22=M |last23=Waern |first23=F |last24=Zacharewski |first24=T |title=Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. |journal=Environmental health perspectives |date=December 1998 |volume=106 |issue=12 |pages=775-92 |doi=10.1289/ehp.98106775 |pmid=9831538}}</ref><ref name=Berg06/> {| class="wikitable sortable" !Class !Congener !WHO-TEF 2005 !WHO-TEF fish 1998 !WHO-TEF birds 1998 |- | rowspan="7" |PCDDs |2,3,7,8-TCDD |1 |1 |1 |- |1,2,3,7,8-PeCDD |1 |1 |1 |- |1,2,3,4,7,8-HxCDD |0.1 |0.5 |0.05 |- |1,2,3,6,7,8-HxCDD |0.1 |0.01 |0.01 |- |1,2,3,7,8,9-HxCDD |0.1 |0.01 |0.1 |- |1,2,3,4,6,7,8-HpCDD |0.01 |0.0001 |<0.001 |- |OCDD |0.0003 |<0.0001 |0.0001 |- | rowspan="10" |PCDFs |2,3,7,8-TCDF |0.1 |0.05 |1 |- |1,2,3,7,8-PeCDF |0.03 |0.05 |0.1 |- |2,3,4,7,8-PeCDF |0.3 |0.5 |1 |- |1,2,3,4,7,8-HxCDF |0.1 |0.1 |0.1 |- |1,2,3,6,7,8-HxCDF |0.1 |0.1 |0.1 |- |1,2,3,7,8,9-HxCDF |0.1 |0.1 |0.1 |- |2,3,4,6,7,8-HxCDF |0.1 |0.1 |0.1 |- |1,2,3,4,6,7,8-HpCDF |0.01 |0.01 |0.01 |- |1,2,3,4,7,8,9-HpCDF |0.01 |0.01 |0.01 |- |OCDF |0.0003 |<0.0001 |0.0001 |- | rowspan="4" |Non-ortho-PCBs |3,3’,4,4’-TCB (77) |0.0001 |0.0005 |0.1 |- |3,4,4’,5-TCB (81) |0.0003 |0.0001 |0.05 |- |3,3’,4,4’,5-PeCB (126) |0.1 |0.005 |0.1 |- |3,3’,4,4’,5,5’-HxCB (169) |0.03 |0.00005 |0.001 |- | rowspan="8" |Mono-ortho-PCBs |2,3,3’,4,4’-PeCB (105) |0.00003 |<0.000005 |0.0001 |- |2,3,4,4’,5-PeCB (114) |0.00003 |<0.000005 |0.0001 |- |2,3’,4,4’,5-PeCB (118) |0.00003 |<0.000005 |0.00001 |- |2’,3,4,4’,5-PeCB (123) |0.00003 |<0.000005 |0.00001 |- |2,3,3’,4,4’,5-HxCB (156) |0.00003 |<0.000005 |0.0001 |- |2,3,3’,4,4’,5’-HxCB (157) |0.00003 |<0.000005 |0.0001 |- |2,3’,4,4’,5,5’-HxCB (167) |0.00003 |<0.000005 |0.00001 |- |2,3,3’,4,4’,5,5’-HpCB (189) |0.00003 |<0.000005 |0.00001 |} PCDD/F congeners usually seem to act additively, which justifies the use of TEFs.<ref>{{cite journal |last1=Viluksela |first1=M |last2=Stahl |first2=BU |last3=Birnbaum |first3=LS |last4=Schramm |first4=KW |last5=Kettrup |first5=A |last6=Rozman |first6=KK |title=Subchronic/chronic toxicity of a mixture of four chlorinated dibenzo-p-dioxins in rats. I. Design, general observations, hematology,and liver concentrations. |journal=Toxicology and applied pharmacology |date=July 1998 |volume=151 |issue=1 |pages=57-69 |doi=10.1006/taap.1998.8384 |pmid=9705887}}</ref> With less potent compounds, partial antagonism is possible.<ref>{{cite journal |last1=Safe |first1=SH |title=Hazard and risk assessment of chemical mixtures using the toxic equivalency factor approach. |journal=Environmental health perspectives |date=August 1998 |volume=106 Suppl 4 |pages=1051-8 |doi=10.1289/ehp.98106s41051 |pmid=9703492}}</ref><ref name=Berg00/><ref>{{cite journal |last1=Peters |first1=AK |last2=Leonards |first2=PE |last3=Zhao |first3=B |last4=Bergman |first4=A |last5=Denison |first5=MS |last6=Van den Berg |first6=M |title=Determination of in vitro relative potency (REP) values for mono-ortho polychlorinated biphenyls after purification with active charcoal. |journal=Toxicology letters |date=10 September 2006 |volume=165 |issue=3 |pages=230-41 |doi=10.1016/j.toxlet.2006.04.005 |pmid=16750337}}</ref><ref name=Howard10>{{cite journal |last1=Howard |first1=GJ |last2=Schlezinger |first2=JJ |last3=Hahn |first3=ME |last4=Webster |first4=TF |title=Generalized concentration addition predicts joint effects of aryl hydrocarbon receptor agonists with partial agonists and competitive antagonists. |journal=Environmental health perspectives |date=May 2010 |volume=118 |issue=5 |pages=666-72 |doi=10.1289/ehp.0901312 |pmid=20435555}}</ref> This may lead to overestimation of the total toxicity.<ref name=Howard10/> In fact, some in vitro results indicate that there may be significant deviations in human sensitivity from the TEF values based mostly on rodent data.<ref name=Larsson15/> If toxicity studies, such as on lethality, immunotoxicity and reproductive toxicity, are available, TEF values are based on them. If they are lacking, it may be necessary to base the values on ''in vitro'' information. Most studies are based on oral intake, so the values correlate best with oral toxicity. Internal TEF values based on concentrations in the body would be preferable, but there is not enough data to formulate them. Different endpoints of toxicity may lead to different TEF values; hence the values are always balanced compromises and show only the order of magnitude. Slightly different TEF values have been assessed for fish and birds, in addition to those of humans and other mammals (Table 2).<ref name=Berg98/> == Wildlife: exposures and toxic effects == Toxic effects in wildlife are difficult to sort out, because usually the exposures have been to mixtures of quite different chemicals such as PCDD/Fs, dioxin-like PCBs as well as simultaneous exposure to non-dioxin-like PCBs, DDT and other chlorinated insecticides such as aldrin, dieldrin, lindane and others. Effects of individual chemicals on animals have been studied in laboratory conditions, but ecological impact is more difficult to assess. Effects on wildlife and domestic animals have been reviewed, e.g.<ref name=White09>{{cite journal |last1=White |first1=SS |last2=Birnbaum |first2=LS |title=An overview of the effects of dioxins and dioxin-like compounds on vertebrates, as documented in human and ecological epidemiology. |journal=Journal of environmental science and health. Part C, Environmental carcinogenesis & ecotoxicology reviews |date=October 2009 |volume=27 |issue=4 |pages=197-211 |doi=10.1080/10590500903310047 |pmid=19953395}}</ref> Developmental and embryotoxicity are the most sensitive effects of dioxins. Trout and other salmonids are the most sensitive species of fish. Sensitivities among fish species vary up to 120-fold.<ref>{{cite journal |last1=Elonen |first1=Gregory E. |last2=Spehar |first2=Robert L. |last3=Holcombe |first3=Gary W. |last4=Johnson |first4=Rodney D. |last5=Fernandez |first5=Joseph D. |last6=Erickson |first6=Russell J. |last7=Tietge |first7=Joseph E. |last8=Cook |first8=Philip M. |title=Comparative toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin to seven freshwater fish species during early life-stage development |journal=Environmental Toxicology and Chemistry |date=March 1998 |volume=17 |issue=3 |pages=472–483 |doi=10.1002/etc.5620170319}}</ref><ref name=KingHeiden12>{{cite journal |last1=King-Heiden |first1=TC |last2=Mehta |first2=V |last3=Xiong |first3=KM |last4=Lanham |first4=KA |last5=Antkiewicz |first5=DS |last6=Ganser |first6=A |last7=Heideman |first7=W |last8=Peterson |first8=RE |title=Reproductive and developmental toxicity of dioxin in fish. |journal=Molecular and cellular endocrinology |date=6 May 2012 |volume=354 |issue=1-2 |pages=121-38 |doi=10.1016/j.mce.2011.09.027 |pmid=21958697}}</ref> Typical findings are excess mortality, oedema, haemorrhages, and craniofacial malformations. So-called blue sac disease of early embryos is associated with high concentrations of TCDD<ref>{{cite journal |last1=Walker |first1=Mary K. |last2=Spitsbergen |first2=Jan M. |last3=Olson |first3=James R. |last4=Peterson |first4=Richard E. |title=2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Toxicity during Early Life Stage Development of Lake Trout ( ) |journal=Canadian Journal of Fisheries and Aquatic Sciences |date=May 1991 |volume=48 |issue=5 |pages=875–883 |doi=10.1139/f91-104}}</ref> and other dioxin-like compounds.<ref>{{Cite journal|last=Vuorinen|first=P|date=2002-06|title=PCDD, PCDF, PCB and thiamine in Baltic herring (Clupea harengus L.) and sprat [ Sprattus sprattus (L.)] as a background to the M74 syndrome of Baltic salmon (Salmo salar L.)|url=http://dx.doi.org/10.1006/jmsc.2002.1200|journal=ICES Journal of Marine Science|volume=59|issue=3|pages=480–496|doi=10.1006/jmsc.2002.1200|issn=1054-3139}}</ref> Adult fish are less susceptible showing wasting syndrome, fin necrosis, liver toxicity, and loss of weight at high doses, and impaired reproduction especially in females.<ref name=KingHeiden12/> Dioxins, along with overfishing, are considered a reason for the lake trout population crash in the Great Lakes in the U.S.A. and Canada in mid-twentieth century. Experimentally it is possible to pinpoint the results at a specific chemical, and the mechanisms of toxicity in fish have been studied in zebrafish, especially cardiovascular toxicity, craniofacial malformations, and reproductive toxicity (reviewed by King-Heiden ''et al''.).<ref name=KingHeiden12/> A number of bird species have also been shown to be sensitive to embryonal toxicity and problems in reproduction. High concentrations of dioxins, PCBs and DDT in fish have threatened the populations of fish-eating birds, especially eagles and ospreys with incredible total PCB levels of up to 1,000 μg/g in fat, due to the position of these birds at the top of the food chain.<ref name=Helander08>{{cite journal |last1=Helander |first1=B |last2=Bignert |first2=A |last3=Asplund |first3=L |title=Using raptors as environmental sentinels: monitoring the white-tailed sea eagle Haliaeetus albicilla in Sweden. |journal=Ambio |date=September 2008 |volume=37 |issue=6 |pages=425-31 |doi=10.1579/0044-7447(2008)37[425:uraesm]2.0.co;2 |pmid=18833795}}</ref> Marine mammals are also on top of the food chain, highest are polar bears. On the other hand, polar bears also metabolize polychlorinated compounds fairly effectively.<ref name=Braune05>{{cite journal |last1=Braune |first1=BM |last2=Outridge |first2=PM |last3=Fisk |first3=AT |last4=Muir |first4=DC |last5=Helm |first5=PA |last6=Hobbs |first6=K |last7=Hoekstra |first7=PF |last8=Kuzyk |first8=ZA |last9=Kwan |first9=M |last10=Letcher |first10=RJ |last11=Lockhart |first11=WL |last12=Norstrom |first12=RJ |last13=Stern |first13=GA |last14=Stirling |first14=I |title=Persistent organic pollutants and mercury in marine biota of the Canadian Arctic: an overview of spatial and temporal trends. |journal=The Science of the total environment |date=1 December 2005 |volume=351-352 |pages=4-56 |doi=10.1016/j.scitotenv.2004.10.034 |pmid=16109439}}</ref> PCB concentrations seem to be 2–5-fold higher than in seals, their main food source. In Canadian seals total PCB levels vary from 300 to 1,000 ng/g (wet weight in blubber), and TEQs are of the order of 0.5–0.6 pg/g.<ref name=Braune05/> In the Baltic Sea, which is the most contaminated brackish water area in the world, total PCB levels in ringed seals are presently about 5,000 ng/g (in fat) and PCDD/F levels about 40 pg/g TEQ (in fat). The levels were 8-fold and 20-fold higher, resp., in 1970s, and at that time POPs are considered having been an important reason for their poor reproductive success.<ref name=Bjurlid18>{{cite journal |last1=Bjurlid |first1=F |last2=Roos |first2=A |last3=Ericson Jogsten |first3=I |last4=Hagberg |first4=J |title=Temporal trends of PBDD/Fs, PCDD/Fs, PBDEs and PCBs in ringed seals from the Baltic Sea (Pusa hispida botnica) between 1974 and 2015. |journal=The Science of the total environment |date=March 2018 |volume=616-617 |pages=1374-1383 |doi=10.1016/j.scitotenv.2017.10.178 |pmid=29066193}}</ref> POPs are also implicated in bone deformities in seals<ref>{{cite journal |last1=Olsson |first1=Mats |last2=Karlsson |first2=Börje |last3=Ahnland |first3=Eva |title=Diseases and environmental contaminants in seals from the Baltic and the Swedish west coast |journal=Science of The Total Environment |date=September 1994 |volume=154 |issue=2-3 |pages=217–227 |doi=10.1016/0048-9697(94)90089-2}}</ref> and polar bears.<ref>{{cite journal |last1=Sonne |first1=C |last2=Dietz |first2=R |last3=Born |first3=EW |last4=Riget |first4=FF |last5=Kirkegaard |first5=M |last6=Hyldstrup |first6=L |last7=Letcher |first7=RJ |last8=Muir |first8=DC |title=Is bone mineral composition disrupted by organochlorines in east Greenland polar bears (Ursus maritimus)? |journal=Environmental health perspectives |date=December 2004 |volume=112 |issue=17 |pages=1711-6 |doi=10.1289/ehp.7293 |pmid=15579418}}</ref> In addition to marine mammals, developmental effects were shown in bank voles living in an environment contaminated by chlorophenols and their dioxin impurities: they had third molars reduced in size.<ref>{{cite journal |last1=Murtomaa |first1=M |last2=Tervaniemi |first2=OM |last3=Parviainen |first3=J |last4=Ruokojärvi |first4=P |last5=Tuukkanen |first5=J |last6=Viluksela |first6=M |title=Dioxin exposure in contaminated sawmill area: the use of molar teeth and bone of bank vole (Clethrionomys glareolus) and field vole (Microtus agrestis) as biomarkers. |journal=Chemosphere |date=June 2007 |volume=68 |issue=5 |pages=951-7 |doi=10.1016/j.chemosphere.2007.01.030 |pmid=17335869}}</ref> In laboratory rats, TCDD reduces dose-dependently the size of molars, most severely the third lower molars.<ref name=Kattainen01>{{cite journal |last1=Kattainen |first1=H |last2=Tuukkanen |first2=J |last3=Simanainen |first3=U |last4=Tuomisto |first4=JT |last5=Kovero |first5=O |last6=Lukinmaa |first6=PL |last7=Alaluusua |first7=S |last8=Tuomisto |first8=J |last9=Viluksela |first9=M |title=In utero/lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure impairs molar tooth development in rats. |journal=Toxicology and applied pharmacology |date=1 August 2001 |volume=174 |issue=3 |pages=216-24 |doi=10.1006/taap.2001.9216 |pmid=11485382}}</ref> As in humans, the concentrations of dioxins (as well as DDT and its metabolites) in wildlife have clearly decreased over the years,<ref name=Braune05/> e.g. in seals of the Baltic sea,<ref name=Bjurlid18/> in eggs of herring gulls of the Great Lakes,<ref>{{cite journal |last1=Norstrom |first1=RJ |last2=Hebert |first2=CE |title=Comprehensive re-analysis of archived herring gull eggs reconstructs historical temporal trends in chlorinated hydrocarbon contamination in Lake Ontario and Green Bay, Lake Michigan, 1971-1982. |journal=Journal of environmental monitoring : JEM |date=August 2006 |volume=8 |issue=8 |pages=835-47 |doi=10.1039/b602378a |pmid=16896467}}</ref><ref>{{cite journal |last1=de Solla |first1=Shane R.|last2=Weseloh |first2=D. V. Chip |last3=Hughes |first3=Kimberley D. |last4=Moore |first4=David J. |title=Forty-Year Decline of Organic Contaminants in Eggs of Herring Gulls ( ) from the Great Lakes, 1974 to 2013 |journal=Waterbirds |date=April 2016 |volume=39 |issue=sp1 |pages=166–179 |doi=10.1675/063.039.sp117}}</ref> in eggs around contaminated harbour sites,<ref>{{cite journal |last1=Hughes |first1=K. D. |last2=de Solla |first2=S. R. |last3=Weseloh |first3=D. V. C. |last4=Martin |first4=P. A. |title=Long-term trends in legacy contaminants in aquatic wildlife in the Hamilton Harbour Area of Concern |journal=Aquatic Ecosystem Health & Management |date=9 May 2016 |volume=19 |issue=2 |pages=171–180 |doi=10.1080/14634988.2016.1150113}}</ref> and guillemot eggs of the Baltic sea,<ref>{{cite journal |last1=Miller |first1=A |last2=Nyberg |first2=E |last3=Danielsson |first3=S |last4=Faxneld |first4=S |last5=Haglund |first5=P |last6=Bignert |first6=A |title=Comparing temporal trends of organochlorines in guillemot eggs and Baltic herring: advantages and disadvantage for selecting sentinel species for environmental monitoring. |journal=Marine environmental research |date=September 2014 |volume=100 |pages=38-47 |doi=10.1016/j.marenvres.2014.02.007 |pmid=24680644}}</ref> in white-tailed eagles in Scandinavia,<ref name=Helander08/> as well as in salmon and Baltic herring in the Baltic sea.<ref name=Airaksinen14>{{cite journal |last1=Airaksinen |first1=R |last2=Hallikainen |first2=A |last3=Rantakokko |first3=P |last4=Ruokojärvi |first4=P |last5=Vuorinen |first5=PJ |last6=Parmanne |first6=R |last7=Verta |first7=M |last8=Mannio |first8=J |last9=Kiviranta |first9=H |title=Time trends and congener profiles of PCDD/Fs, PCBs, and PBDEs in Baltic herring off the coast of Finland during 1978-2009. |journal=Chemosphere |date=November 2014 |volume=114 |pages=165-71 |doi=10.1016/j.chemosphere.2014.03.097 |pmid=25113198}}</ref><ref>{{cite journal |last1=Miller |first1=A |last2=Hedman |first2=JE |last3=Nyberg |first3=E |last4=Haglund |first4=P |last5=Cousins |first5=IT |last6=Wiberg |first6=K |last7=Bignert |first7=A |title=Temporal trends in dioxins (polychlorinated dibenzo-p-dioxin and dibenzofurans) and dioxin-like polychlorinated biphenyls in Baltic herring (Clupea harengus). |journal=Marine pollution bulletin |date=15 August 2013 |volume=73 |issue=1 |pages=220-30 |doi=10.1016/j.marpolbul.2013.05.015 |pmid=23806670}}</ref><ref>{{cite journal |last1=Vuorinen |first1=Pekka J. |last2=Roots |first2=Ott |last3=Keinänen |first3=Marja |title=Review of organohalogen toxicants in fish from the Gulf of Finland |journal=Journal of Marine Systems |date=July 2017 |volume=171 |pages=141–150 |doi=10.1016/j.jmarsys.2016.12.002}}</ref> When the organochlorine levels have decreased, populations have recovered, e.g. white-tailed eagle<ref name=Helander08/><ref>{{cite journal |last1=Sulawa |first1=Justine |last2=Robert |first2=Alexandre |last3=Köppen |first3=Ulrich |last4=Hauff |first4=Peter |last5=Krone |first5=Oliver |title=Recovery dynamics and viability of the white-tailed eagle (Haliaeetus albicilla) in Germany |journal=Biodiversity and Conservation |date=13 August 2009 |volume=19 |issue=1 |pages=97–112 |doi=10.1007/s10531-009-9705-4}}</ref> and osprey.<ref>{{cite journal |last1=Rattner |first1=BA |last2=Lazarus |first2=RS |last3=Bean |first3=TG |last4=McGowan |first4=PC |last5=Callahan |first5=CR |last6=Erickson |first6=RA |last7=Hale |first7=RC |title=Examination of contaminant exposure and reproduction of ospreys (Pandion haliaetus) nesting in Delaware Bay and River in 2015. |journal=The Science of the total environment |date=15 October 2018 |volume=639 |pages=596-607 |doi=10.1016/j.scitotenv.2018.05.068 |pmid=29800853}}</ref> Brominated compounds have not decreased much so far, but they only contribute about 1 % of TEQs.<ref name=Bjurlid18/> Concentrations in fish and in birds are dependent on the age of the animal. Correcting for this is necessary to reliably calculate time trends in trout.<ref>{{cite journal |last1=Pagano |first1=JJ |last2=Garner |first2=AJ |last3=McGoldrick |first3=DJ |last4=Crimmins |first4=BS |last5=Hopke |first5=PK |last6=Milligan |first6=MS |last7=Holsen |first7=TM |title=Age-Corrected Trends and Toxic Equivalence of PCDD/F and CP-PCBs in Lake Trout and Walleye from the Great Lakes: 2004-2014. |journal=Environmental science & technology |date=16 January 2018 |volume=52 |issue=2 |pages=712-721 |doi=10.1021/acs.est.7b05568 |pmid=29249152}}</ref> In Baltic herring, concentrations of both PCBs and PCDD/Fs increase several fold from age 1 year to age 8–15 years.<ref>{{cite journal |last1=Kiviranta |first1=H |last2=Vartiainen |first2=T |last3=Parmanne |first3=R |last4=Hallikainen |first4=A |last5=Koistinen |first5=J |title=PCDD/Fs and PCBs in Baltic herring during the 1990s. |journal=Chemosphere |date=March 2003 |volume=50 |issue=9 |pages=1201-16 |pmid=12547334|doi=10.1016/S0045-6535(02)00481-2}}</ref><ref name=Airaksinen14/> In adult glaucous gulls, however, no age-correlation was found, suggesting that steady state levels are reached early in life.<ref>{{cite journal |last1=Bustnes |first1=JO |last2=Bakken |first2=V |last3=Skaare |first3=JU |last4=Erikstad |first4=KE |title=Age and accumulation of persistent organochlorines: a study of Arctic-breeding glaucous gulls (Larus hyperboreus)|doi=10.1897/02-456 |journal=Environmental toxicology and chemistry |date=September 2003 |volume=22 |issue=9 |pages=2173-9 |pmid=12959547}}</ref> This implies relatively rapid elimination and a short half-life. In eagle nestlings, PCB concentrations decrease after hatching<ref>{{cite journal |last1=Løseth |first1=ME |last2=Briels |first2=N |last3=Eulaers |first3=I |last4=Nygård |first4=T |last5=Malarvannan |first5=G |last6=Poma |first6=G |last7=Covaci |first7=A |last8=Herzke |first8=D |last9=Bustnes |first9=JO |last10=Lepoint |first10=G |last11=Jenssen |first11=BM |last12=Jaspers |first12=VLB |title=Plasma concentrations of organohalogenated contaminants in white-tailed eagle nestlings - The role of age and diet. |journal=Environmental pollution (Barking, Essex : 1987) |date=March 2019 |volume=246 |pages=527-534 |doi=10.1016/j.envpol.2018.12.028 |pmid=30583161}}</ref> indicating that maternal load transferred to eggs is initially more important than the content of PCBs in their diet during the rapid growth. == Human intake and concentrations == Animal source food is the most important source of dioxins for humans.<ref name=Liem00/> Fish is very important, and although meat and milk products have dominated in most countries, the concentrations in farming products have now declined due to active emission controls.<ref name=EFSAPanel18>{{cite journal |last1=EFSA Panel on Contaminants in the Food Chain |title=Risk for animal and human health related to the presence of dioxins and dioxin-like PCBs in feed and food |journal=EFSA Journal |date=2018 |volume=16 |page=5333 |doi=10.2903/j.efsa.2018.5333 |url=https://www.efsa.europa.eu/en/efsajournal/pub/5333}}</ref> In all foods the concentrations have decreased remarkably in the Western countries during the last 30 to 40 years, and the present daily intake is 1–2 pg/kg bw (TEQ). Human exposure from contaminated soil is very limited.<ref>{{cite journal |last1=Demond |first1=A |last2=Franzblau |first2=A |last3=Garabrant |first3=D |last4=Jiang |first4=X |last5=Adriaens |first5=P |last6=Chen |first6=Q |last7=Gillespie |first7=B |last8=Hao |first8=W |last9=Hong |first9=B |last10=Jolliet |first10=O |last11=Lepkowski |first11=J |title=Human exposure from dioxins in soil. |journal=Environmental science & technology |date=7 February 2012 |volume=46 |issue=3 |pages=1296-302 |doi=10.1021/es2022363 |pmid=22136605}}</ref> Dioxins accumulate during the whole lifetime, because their half-lives are very long (Fig. 6). PCDD/F concentrations in young people are 5–10 pg/g TEQ in fat, but 40–100 pg/g in older generations.<ref>{{cite journal |last1=Kiviranta |first1=H |last2=Tuomisto |first2=JT |last3=Tuomisto |first3=J |last4=Tukiainen |first4=E |last5=Vartiainen |first5=T |title=Polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls in the general population in Finland. |journal=Chemosphere |date=August 2005 |volume=60 |issue=7 |pages=854-69 |doi=10.1016/j.chemosphere.2005.01.064 |pmid=15992592}}</ref> Additionally, there is carry-over in older generations from earlier decades when the intake was 5 to 10 times higher than presently.<ref name=TuomistoSTS>{{cite journal |last1=Tuomisto |first1=JT |last2=Pekkanen |first2=J |last3=Kiviranta |first3=H |last4=Tukiainen |first4=E |last5=Vartiainen |first5=T |last6=Tuomisto |first6=J |title=Soft-tissue sarcoma and dioxin: A case-control study. |journal=International journal of cancer |date=1 March 2004 |volume=108 |issue=6 |pages=893-900 |doi=10.1002/ijc.11635 |pmid=14712494}}</ref><ref name=Tuomisto16>{{cite journal |last1=Tuomisto |first1=J |last2=Airaksinen |first2=R |last3=Kiviranta |first3=H |last4=Tukiainen |first4=E |last5=Pekkanen |first5=J |last6=Tuomisto |first6=JT |title=A pharmacokinetic analysis and dietary information are necessary to confirm or reject the hypothesis on persistent organic pollutants causing type 2 diabetes. |journal=Toxicology letters |date=2 November 2016 |volume=261 |pages=41-48 |doi=10.1016/j.toxlet.2016.08.024 |pmid=27575567}}</ref> For this reason concentrations (e.g. between population groups in epidemiological studies) cannot be compared without information on age and the year of sampling. {{Fig | number = 6 | image = Dioxin concentration by age.png | caption = Dioxin concentrations (in adipose tissue) are high in older generations for two reasons: dioxins accumulate over years, because their elimination is slow and half-lives are long, and the intake was much higher in the past than presently (cf. Fig. 7).<ref name=TuomistoSTS /> | attribution = courtesy Jouni T. Tuomisto }} Dioxin concentrations (but not all PCBs) in humans have been decreasing for over 30 years, in line with decreasing environmental levels.<ref>{{cite journal |last1=Consonni |first1=D |last2=Sindaco |first2=R |last3=Bertazzi |first3=PA |title=Blood levels of dioxins, furans, dioxin-like PCBs, and TEQs in general populations: a review, 1989-2010. |journal=Environment international |date=September 2012 |volume=44 |pages=151-62 |doi=10.1016/j.envint.2012.01.004 |pmid=22364893}}</ref> The World Health Organization has organized dioxin follow-up measurements in breast milk since 1987. In more recent surveys also PCBs and some other persistent chlorinated compounds have been measured.<ref name=Berg17b>{{cite journal |last1=van den Berg |first1=M |last2=Kypke |first2=K |last3=Kotz |first3=A |last4=Tritscher |first4=A |last5=Lee |first5=SY |last6=Magulova |first6=K |last7=Fiedler |first7=H |last8=Malisch |first8=R |title=WHO/UNEP global surveys of PCDDs, PCDFs, PCBs and DDTs in human milk and benefit-risk evaluation of breastfeeding. |journal=Archives of toxicology |date=January 2017 |volume=91 |issue=1 |pages=83-96 |doi=10.1007/s00204-016-1802-z |pmid=27438348}}</ref> Historical information is crucial, because effects on next generations are possible (see below), and if true in humans, the impact of high concentrations in 1970s would be seen during the 21^st century. Breast milk concentrations were very high in 1970s (Fig. 7), about 50 pg/g for PCDD/Fs and 50 pg/g for dl-PCBs (TEQ in fat).<ref name=Noren>{{cite journal |last1=Norén |first1=K |last2=Meironyté |first2=D |title=Certain organochlorine and organobromine contaminants in Swedish human milk in perspective of past 20-30 years. |journal=Chemosphere |date=NaN |volume=40 |issue=9-11 |pages=1111-23 |pmid=10739053|doi=10.1016/S0045-6535(99)00360-4}}</ref> During the first systematic round of breast milk measurements in 1987, PCDD/F concentrations in many countries were between 30 and 40 pg/g TEQ in milk fat<ref>WHO. Levels of PCBs, PCDDs, and PCDFs in breast milk. ''World Health Organisation, Environmental Health Series 34'' ; 1989.</ref> and during the last round in 2005–2010 between 5 and 10 pg/g in many European countries (generally below 10 pg/g<ref name=EFSAPanel18/>), and low in many African countries, but still high in e.g. India, Egypt and the Netherlands (over 20 pg/g).<ref name=Berg17b/> Thus the concentrations have decreased by 80–90 % in many but not all countries. {{Fig | number = 7 | image = Decrease of dioxins in milk.jpg | caption = Decrease of dioxin concentrations in breast milk in Sweden and Finland (Sweden, early data from Norén and Meironyté, 2000, others from van den Berg et al, 2017 and WHO database of the Institute for Health and Welfare, Finland, Hannu Kiviranta).<ref name=Noren /><ref name=Berg17b/> | attribution = }} == Toxic effects in humans == === Accidents, contamination episodes and occupational risks === A few dramatic accidental or deliberate cases of acute poisoning have taken place. Two women were poisoned in Vienna, Austria, in 1998 by huge doses of TCDD. Dioxin concentration in one of them was 144,000 pg/g in serum fat, the highest ever measured in humans.<ref name=Geusau01>{{cite journal |last1=Geusau |first1=A |last2=Abraham |first2=K |last3=Geissler |first3=K |last4=Sator |first4=MO |last5=Stingl |first5=G |last6=Tschachler |first6=E |title=Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: clinical and laboratory effects. |journal=Environmental health perspectives |date=August 2001 |volume=109 |issue=8 |pages=865-9 |doi=10.1289/ehp.01109865 |pmid=11564625}}</ref> The dose must have been about 25 µg/kg. For comparison, contemporary concentrations in young people are 5–10 pg TEQ/g fat, and in older people 50 pg TEQ/g fat or more (Fig. 6), and daily intake is 1–2 pg TEQ/kg body weight. This victim survived despite the extraordinarily high levels of TCDD in her serum, but had severe chloracne lasting for years and weight loss. There were few other symptoms or laboratory findings: gastrointestinal symptoms and amenorrhea.<ref name=Geusau01/> Victor Yushchenko, then presidential candidate of Ukraine, was deliberately poisoned in 2004 with a large dose of TCDD; the concentration in fat was 108,000 pg/g. He suffered from severe gastrointestinal symptoms, indicating pancreatitis and hepatitis, and then developed severe chloracne, but survived.<ref name=Sorg09/><ref name=Saurat12>{{cite journal |last1=Saurat |first1=JH |last2=Kaya |first2=G |last3=Saxer-Sekulic |first3=N |last4=Pardo |first4=B |last5=Becker |first5=M |last6=Fontao |first6=L |last7=Mottu |first7=F |last8=Carraux |first8=P |last9=Pham |first9=XC |last10=Barde |first10=C |last11=Fontao |first11=F |last12=Zennegg |first12=M |last13=Schmid |first13=P |last14=Schaad |first14=O |last15=Descombes |first15=P |last16=Sorg |first16=O |title=The cutaneous lesions of dioxin exposure: lessons from the poisoning of Victor Yushchenko. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=January 2012 |volume=125 |issue=1 |pages=310-7 |doi=10.1093/toxsci/kfr223 |pmid=21998131}}</ref> In both the Vienna poisoning and the Yushchenko poisoning the details of TCDD intake are unknown. Perhaps the best known dioxin accident took place in Seveso, Italy in 1976.<ref name=Mocarelli91>{{cite journal |last1=Mocarelli |first1=P |last2=Needham |first2=LL |last3=Marocchi |first3=A |last4=Patterson DG |first4=Jr |last5=Brambilla |first5=P |last6=Gerthoux |first6=PM |last7=Meazza |first7=L |last8=Carreri |first8=V |title=Serum concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin and test results from selected residents of Seveso, Italy. |journal=Journal of toxicology and environmental health |date=April 1991 |volume=32 |issue=4 |pages=357-66 |doi=10.1080/15287399109531490 |pmid=1826746}}</ref><ref>{{cite journal |last1=Eskenazi |first1=B |last2=Warner |first2=M |last3=Brambilla |first3=P |last4=Signorini |first4=S |last5=Ames |first5=J |last6=Mocarelli |first6=P |title=The Seveso accident: A look at 40 years of health research and beyond. |journal=Environment international |date=December 2018 |volume=121 |issue=Pt 1 |pages=71-84 |doi=10.1016/j.envint.2018.08.051 |pmid=30179766}}</ref> The town was contaminated by TCDD, after a tank containing 2,4,5-trichlorophenol released its contents to air. The highest levels (up to 56,000 pg/g in serum lipid) were found in children who ate local food and played outdoors. About 200 cases of chloracne occurred; other detectable human effects were few, although a number of animals such as rabbits died.<ref name=Mocarelli91/> Cancer studies have suggested a slightly increased number of hematopoietic and lymphatic tissue malignancies.<ref>{{cite journal |last1=Consonni |first1=D |last2=Pesatori |first2=AC |last3=Zocchetti |first3=C |last4=Sindaco |first4=R |last5=D'Oro |first5=LC |last6=Rubagotti |first6=M |last7=Bertazzi |first7=PA |title=Mortality in a population exposed to dioxin after the Seveso, Italy, accident in 1976: 25 years of follow-up. |journal=American journal of epidemiology |date=1 April 2008 |volume=167 |issue=7 |pages=847-58 |doi=10.1093/aje/kwm371 |pmid=18192277}}</ref><ref>{{cite journal |last1=Pesatori |first1=AC |last2=Consonni |first2=D |last3=Rubagotti |first3=M |last4=Grillo |first4=P |last5=Bertazzi |first5=PA |title=Cancer incidence in the population exposed to dioxin after the "Seveso accident": twenty years of follow-up. |journal=Environmental health : a global access science source |date=15 September 2009 |volume=8 |pages=39 |doi=10.1186/1476-069X-8-39 |pmid=19754930}}</ref> In a cohort of women with measured individual TCDD levels a slightly increased risk of all cancers was found (1.8 fold risk vs. tenfold increase in TCDD concentration) as well as a non-significant increased risk of breast cancer.<ref>{{cite journal |last1=Warner |first1=M |last2=Mocarelli |first2=P |last3=Samuels |first3=S |last4=Needham |first4=L |last5=Brambilla |first5=P |last6=Eskenazi |first6=B |title=Dioxin exposure and cancer risk in the Seveso Women's Health Study. |journal=Environmental health perspectives |date=December 2011 |volume=119 |issue=12 |pages=1700-5 |doi=10.1289/ehp.1103720 |pmid=21810551}}</ref> Several developmental consequences were detected after the Seveso incident. Dental aberrations associated with TCDD levels were found 25 years after the accident in persons who had been less than five years old at the time of the accident.<ref name=Alaluusua04>{{cite journal |last1=Alaluusua |first1=S |last2=Calderara |first2=P |last3=Gerthoux |first3=PM |last4=Lukinmaa |first4=PL |last5=Kovero |first5=O |last6=Needham |first6=L |last7=Patterson DG |first7=Jr |last8=Tuomisto |first8=J |last9=Mocarelli |first9=P |title=Developmental dental aberrations after the dioxin accident in Seveso. |journal=Environmental health perspectives |date=September 2004 |volume=112 |issue=13 |pages=1313-8 |doi=10.1289/ehp.6920 |pmid=15345345}}</ref> Lowered male/female sex ratios were found in the offspring of males exposed to high concentrations of TCDD.<ref name=Mocarelli00>{{cite journal |last1=Mocarelli |first1=P |last2=Gerthoux |first2=PM |last3=Ferrari |first3=E |last4=Patterson DG |first4=Jr |last5=Kieszak |first5=SM |last6=Brambilla |first6=P |last7=Vincoli |first7=N |last8=Signorini |first8=S |last9=Tramacere |first9=P |last10=Carreri |first10=V |last11=Sampson |first11=EJ |last12=Turner |first12=WE |last13=Needham |first13=LL |title=Paternal concentrations of dioxin and sex ratio of offspring. |journal=Lancet (London, England) |date=27 May 2000 |volume=355 |issue=9218 |pages=1858-63 |doi=10.1016/S0140-6736(00)02290-X |pmid=10866441}}</ref> Decreased sperm quality was observed in young men exposed to TCDD in utero and during lactation or during infancy or prepuberty.<ref>{{cite journal |last1=Mocarelli |first1=P |last2=Gerthoux |first2=PM |last3=Patterson DG |first3=Jr |last4=Milani |first4=S |last5=Limonta |first5=G |last6=Bertona |first6=M |last7=Signorini |first7=S |last8=Tramacere |first8=P |last9=Colombo |first9=L |last10=Crespi |first10=C |last11=Brambilla |first11=P |last12=Sarto |first12=C |last13=Carreri |first13=V |last14=Sampson |first14=EJ |last15=Turner |first15=WE |last16=Needham |first16=LL |title=Dioxin exposure, from infancy through puberty, produces endocrine disruption and affects human semen quality. |journal=Environmental health perspectives |date=January 2008 |volume=116 |issue=1 |pages=70-7 |doi=10.1289/ehp.10399 |pmid=18197302}}</ref><ref name=Mocarelli11>{{cite journal |last1=Mocarelli |first1=P |last2=Gerthoux |first2=PM |last3=Needham |first3=LL |last4=Patterson DG |first4=Jr |last5=Limonta |first5=G |last6=Falbo |first6=R |last7=Signorini |first7=S |last8=Bertona |first8=M |last9=Crespi |first9=C |last10=Sarto |first10=C |last11=Scott |first11=PK |last12=Turner |first12=WE |last13=Brambilla |first13=P |title=Perinatal exposure to low doses of dioxin can permanently impair human semen quality. |journal=Environmental health perspectives |date=May 2011 |volume=119 |issue=5 |pages=713-8 |doi=10.1289/ehp.1002134 |pmid=21262597}}</ref> Slightly increased risk of endometriosis<ref>{{cite journal |last1=Eskenazi |first1=B |last2=Mocarelli |first2=P |last3=Warner |first3=M |last4=Samuels |first4=S |last5=Vercellini |first5=P |last6=Olive |first6=D |last7=Needham |first7=LL |last8=Patterson DG |first8=Jr |last9=Brambilla |first9=P |last10=Gavoni |first10=N |last11=Casalini |first11=S |last12=Panazza |first12=S |last13=Turner |first13=W |last14=Gerthoux |first14=PM |title=Serum dioxin concentrations and endometriosis: a cohort study in Seveso, Italy. |journal=Environmental health perspectives |date=July 2002 |volume=110 |issue=7 |pages=629-34 |doi=10.1289/ehp.02110629 |pmid=12117638}}</ref> as well as a dose-dependently increased time to pregnancy and infertility were found among the most heavily exposed women.<ref>{{cite journal |last1=Eskenazi |first1=B |last2=Warner |first2=M |last3=Marks |first3=AR |last4=Samuels |first4=S |last5=Needham |first5=L |last6=Brambilla |first6=P |last7=Mocarelli |first7=P |title=Serum dioxin concentrations and time to pregnancy. |journal=Epidemiology (Cambridge, Mass.) |date=March 2010 |volume=21 |issue=2 |pages=224-31 |doi=10.1097/EDE.0b013e3181cb8b95 |pmid=20124903}}</ref> However, in 30 years’ follow-up no association between TCDD exposure and adverse pregnancy outcomes were detected except for a non-significant decrease in birthweight.<ref>{{cite journal |last1=Wesselink |first1=A |last2=Warner |first2=M |last3=Samuels |first3=S |last4=Parigi |first4=A |last5=Brambilla |first5=P |last6=Mocarelli |first6=P |last7=Eskenazi |first7=B |title=Maternal dioxin exposure and pregnancy outcomes over 30 years of follow-up in Seveso. |journal=Environment international |date=February 2014 |volume=63 |pages=143-8 |doi=10.1016/j.envint.2013.11.005 |pmid=24291766}}</ref> Some metabolic and endocrine effects were seen for a limited time period.<ref>{{cite journal |last1=Sweeney |first1=MH |last2=Mocarelli |first2=P |title=Human health effects after exposure to 2,3,7,8-TCDD. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=303-16 |doi=10.1080/026520300283379 |pmid=10912244}}</ref> Neonatal thyroid stimulating hormone levels were increased in newborns of mothers with high body burdens of TCDD.<ref>{{cite journal |last1=Baccarelli |first1=A |last2=Giacomini |first2=SM |last3=Corbetta |first3=C |last4=Landi |first4=MT |last5=Bonzini |first5=M |last6=Consonni |first6=D |last7=Grillo |first7=P |last8=Patterson |first8=DG |last9=Pesatori |first9=AC |last10=Bertazzi |first10=PA |title=Neonatal thyroid function in Seveso 25 years after maternal exposure to dioxin. |journal=PLoS medicine |date=29 July 2008 |volume=5 |issue=7 |pages=e161 |doi=10.1371/journal.pmed.0050161 |pmid=18666825}}</ref> There have also been several cases of food contamination. In Japan (Yusho incident, 1968) and in Taiwan (Yu-cheng incident, 1979) PCB oil used in heat exchangers leaked to rice bran oil. Consumption of contaminated oil caused over 2000<ref>{{cite journal |last1=Kashima |first1=S |last2=Yorifuji |first2=T |last3=Tsuda |first3=T |last4=Eboshida |first4=A |title=Cancer and non-cancer excess mortality resulting from mixed exposure to polychlorinated biphenyls and polychlorinated dibenzofurans from contaminated rice oil: "Yusho". |journal=International archives of occupational and environmental health |date=May 2015 |volume=88 |issue=4 |pages=419-30 |doi=10.1007/s00420-014-0966-1 |pmid=25091711}}</ref> and about 2000<ref name=Tsai07>{{cite journal |last1=Tsai |first1=PC |last2=Ko |first2=YC |last3=Huang |first3=W |last4=Liu |first4=HS |last5=Guo |first5=YL |title=Increased liver and lupus mortalities in 24-year follow-up of the Taiwanese people highly exposed to polychlorinated biphenyls and dibenzofurans. |journal=The Science of the total environment |date=15 March 2007 |volume=374 |issue=2-3 |pages=216-22 |doi=10.1016/j.scitotenv.2006.12.024 |pmid=17257654}}</ref> cases of poisoning, respectively. Most of the toxic effects have been attributed to PCDFs and dl-PCBs. The most dramatic health effects were caused by developmental toxicity during pregnancy. The average daily intake was calculated to have been 154,000 pg I-TEQ/kg in the Yusho incident,<ref>{{cite journal |last1=Masuda |first1=Y |title=Approach to risk assessment of chlorinated dioxins from Yusho PCB poisoning. |journal=Chemosphere |date=February 1996 |volume=32 |issue=3 |pages=583-94 |pmid=8907236|doi=10.1016/0045-6535(95)00314-2}}</ref> 100,000 fold higher than average background intake at present. The Yu-cheng incident was roughly similar, and the concentrations were still over 1300 pg I-TEQ/g fat about 15 years later.<ref>{{cite journal |last1=Hsu |first1=JF |last2=Guo |first2=YL |last3=Yang |first3=SY |last4=Liao |first4=PC |title=Congener profiles of PCBs and PCDD/Fs in Yucheng victims fifteen years after exposure to toxic rice-bran oils and their implications for epidemiologic studies. |journal=Chemosphere |date=December 2005 |volume=61 |issue=9 |pages=1231-43 |doi=10.1016/j.chemosphere.2005.03.081 |pmid=15893794}}</ref> There were many skin problems such as hypersecretion of Meibomian glands in the eyes, swelling of eyelids, abnormal pigmentation of skin, hyperkeratosis and chloracne. Babies born to Yusho and Yu-cheng mothers were smaller than normal. They had dark brown pigmentation, gingival hyperplasia, and sometimes dentition at birth or other tooth deformities. Foetal deaths and miscarriages were common.<ref name=Mitoma15/> Cancer studies initially gave inconsistent results in spite of the heavy exposure.<ref>{{cite journal |last1=Onozuka |first1=D |last2=Yoshimura |first2=T |last3=Kaneko |first3=S |last4=Furue |first4=M |title=Mortality after exposure to polychlorinated biphenyls and polychlorinated dibenzofurans: a 40-year follow-up study of Yusho patients. |journal=American journal of epidemiology |date=1 January 2009 |volume=169 |issue=1 |pages=86-95 |doi=10.1093/aje/kwn295 |pmid=18974082}}</ref><ref name=Tsai07/> Later, a combined analysis of both episodes indicated increased mortality from all causes, all cancers, lung cancer, and heart disease in men, and liver cancer in women.<ref>{{cite journal |last1=Li |first1=MC |last2=Chen |first2=PC |last3=Tsai |first3=PC |last4=Furue |first4=M |last5=Onozuka |first5=D |last6=Hagihara |first6=A |last7=Uchi |first7=H |last8=Yoshimura |first8=T |last9=Guo |first9=YL |title=Mortality after exposure to polychlorinated biphenyls and polychlorinated dibenzofurans: a meta-analysis of two highly exposed cohorts. |journal=International journal of cancer |date=15 September 2015 |volume=137 |issue=6 |pages=1427-32 |doi=10.1002/ijc.29504 |pmid=25754105}}</ref> Several feed and food contamination episodes with dioxin-like compounds have occurred also in Europe and elsewhere.<ref name=Malisch14>{{cite journal |last1=Malisch |first1=R |last2=Kotz |first2=A |title=Dioxins and PCBs in feed and food--review from European perspective. |journal=The Science of the total environment |date=1 September 2014 |volume=491-492 |pages=2-10 |doi=10.1016/j.scitotenv.2014.03.022 |pmid=24804623}}</ref><ref name=Hoogenboom15/> A tank of recycled fats was contaminated with at least 160 kg PCB oil in 1999 in Belgium, and used for animal feed. Low fertility of chickens and deformed chicks were noted. About 1 g of dioxins and 2 g dl-PCBs (TEQ) were involved.<ref name=Debacker07>{{cite journal |last1=Debacker |first1=N |last2=Sasse |first2=A |last3=van Wouwe |first3=N |last4=Goeyens |first4=L |last5=Sartor |first5=F |last6=van Oyen |first6=H |title=PCDD/F levels in plasma of a belgian population before and after the 1999 belgian PCB/DIOXIN incident. |journal=Chemosphere |date=April 2007 |volume=67 |issue=9 |pages=S217-23 |doi=10.1016/j.chemosphere.2006.05.101 |pmid=17208274}}</ref> This caused a major dioxin alarm, and European Union set very strict limits for dioxins in food and feed. Due to fairly rapid intervention, total dioxin concentrations in the population did not increase even in Belgium: 23.1 versus 22.9 pg TEQ/g fat.<ref name=Debacker07/> No health effects have been noted. Similar conclusions were drawn after a food contamination incident in Ireland: a short term exceedance of limit values is not likely to lead to health effects.<ref>{{Cite journal|last=Tlustos|first=C.|last2=Anderson|first2=W.|last3=Flynn|first3=A.|last4=Pratt|first4=I.|date=2014-05-04|title=Additional exposure of the Irish adult population to dioxins and PCBs from the diet as a consequence of the 2008 Irish dioxin food contamination incident|url=http://www.tandfonline.com/doi/abs/10.1080/19440049.2014.893399|journal=Food Additives & Contaminants: Part A|language=en|volume=31|issue=5|pages=889–904|doi=10.1080/19440049.2014.893399|issn=1944-0049}}</ref> The incidences show that careful food controls are necessary, but no individual health measures (e.g. abortions) are rational in case of short moderately increased intake, because human dioxin body burden (accumulated during the whole lifetime) is large compared with short-term additional exposures, and therefore levels increase very slowly. Phenoxy acid herbicides (Agent Orange and others, contaminated by dioxins, especially TCDD) were used in large quantities during the Vietnam War. The veterans have been thoroughly studied, but variable levels complicate assessments. There is some evidence for increased cancer, diabetes,<ref>{{cite journal |last1=Michalek |first1=JE |last2=Pavuk |first2=M |title=Diabetes and cancer in veterans of Operation Ranch Hand after adjustment for calendar period, days of spraying, and time spent in Southeast Asia. |journal=Journal of occupational and environmental medicine |date=March 2008 |volume=50 |issue=3 |pages=330-40 |doi=10.1097/JOM.0b013e31815f889b |pmid=18332783}}</ref> and hypertension<ref>{{cite journal |last1=Cypel |first1=YS |last2=Kress |first2=AM |last3=Eber |first3=SM |last4=Schneiderman |first4=AI |last5=Davey |first5=VJ |title=Herbicide Exposure, Vietnam Service, and Hypertension Risk in Army Chemical Corps Veterans. |journal=Journal of occupational and environmental medicine |date=November 2016 |volume=58 |issue=11 |pages=1127-1136 |doi=10.1097/JOM.0000000000000876 |pmid=27820763}}</ref> in the most highly exposed groups. However, causal relationship has been difficult to prove, and e.g. in case of diabetes a reverse causality has been suggested,<ref>{{Cite journal|last=Kerger|first=Brent D.|last2=Scott|first2=Paul K.|last3=Pavuk|first3=Marian|last4=Gough|first4=Michael|last5=Paustenbach|first5=Dennis J.|date=2012-06-21|title=Re-analysis of Ranch Hand study supports reverse causation hypothesis between dioxin and diabetes|url=http://dx.doi.org/10.3109/10408444.2012.694095|journal=Critical Reviews in Toxicology|volume=42|issue=8|pages=669–687|doi=10.3109/10408444.2012.694095|issn=1040-8444}}</ref> and dose-responses do not support causality.<ref>{{Cite journal|last=Steenland|first=K|date=2001-10-01|title=Dioxin and diabetes mellitus: an analysis of the combined NIOSH and Ranch Hand data|url=http://dx.doi.org/10.1136/oem.58.10.641|journal=Occupational and Environmental Medicine|volume=58|issue=10|pages=641–648|doi=10.1136/oem.58.10.641|issn=1351-0711}}</ref><ref name=Jaacks>{{Cite journal|last=Jaacks|first=Lindsay M.|last2=Staimez|first2=Lisa R.|date=2015-03|title=Association of persistent organic pollutants and non-persistent pesticides with diabetes and diabetes-related health outcomes in Asia: A systematic review|url=http://dx.doi.org/10.1016/j.envint.2014.12.001|journal=Environment International|volume=76|pages=57–70|doi=10.1016/j.envint.2014.12.001|issn=0160-4120}}</ref><ref name=Tuomisto16/> Effects on local population in Vietnam have been less scrutinized.<ref>{{cite journal |last1=Young |first1=Alvin |title=A Review of Public Health in Vietnam: 50 Years after Agent Orange was Sprayed |journal=Health Education and Public Health |date=2019 |volume=2 |issue=2 |pages=170-180 |doi=10.31488 /heph.119 |url=https://www.academia.edu/39168589/A_Review_of_Public_Health_in_Vietnam_50_Years_after_Agent_Orange_was_Sprayed |language=en}}</ref> Tooth enamel defects were found to be more common in dioxin-affected regions,<ref name=Pham19>{{cite journal |last1=Pham |first1=NT |last2=Nishijo |first2=M |last3=Pham |first3=TT |last4=Tran |first4=NN |last5=Le |first5=VQ |last6=Tran |first6=HA |last7=Phan |first7=HAV |last8=Nishino |first8=Y |last9=Nishijo |first9=H |title=Perinatal dioxin exposure and neurodevelopment of 2-year-old Vietnamese children in the most contaminated area from Agent Orange in Vietnam. |journal=The Science of the total environment |date=15 August 2019 |volume=678 |pages=217-226 |doi=10.1016/j.scitotenv.2019.04.425 |pmid=31075589}}</ref> as well as borderline impaired neurodevelopment<ref>{{cite journal |last1=Tran |first1=NN |last2=Pham |first2=TT |last3=Ozawa |first3=K |last4=Nishijo |first4=M |last5=Nguyen |first5=AT |last6=Tran |first6=TQ |last7=Hoang |first7=LV |last8=Tran |first8=AH |last9=Phan |first9=VH |last10=Nakai |first10=A |last11=Nishino |first11=Y |last12=Nishijo |first12=H |title=Impacts of Perinatal Dioxin Exposure on Motor Coordination and Higher Cognitive Development in Vietnamese Preschool Children: A Five-Year Follow-Up. |journal=PloS one |date=2016 |volume=11 |issue=1 |pages=e0147655 |doi=10.1371/journal.pone.0147655 |pmid=26824471}}</ref><ref name=Pham19/> and eating disorders.<ref>{{cite journal |last1=Nguyen |first1=Anh Thi Nguyet |last2=Nishijo |first2=Muneko |last3=Pham |first3=Tai The |last4=Tran |first4=Nghi Ngoc |last5=Tran |first5=Anh Hai |last6=Hoang |first6=Luong Van |last7=Boda |first7=Hitomi |last8=Morikawa |first8=Yuko |last9=Nishino |first9=Yoshikazu |last10=Nishijo |first10=Hisao |title=Sex-specific effects of perinatal dioxin exposure on eating behavior in 3-year-old Vietnamese children |journal=BMC Pediatrics |date=5 July 2018 |volume=18 |issue=1 |pages=213 |doi=10.1186/s12887-018-1171-2 |url=https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-018-1171-2 |issn=1471-2431}}</ref> Both modelling and monitoring results suggest that although somewhat higher than normal, highly elevated exposures to TCDD are not common in local people occasionally exposed to spraying.<ref>{{cite journal |last1=Armitage |first1=JM |last2=Ginevan |first2=ME |last3=Hewitt |first3=A |last4=Ross |first4=JH |last5=Watkins |first5=DK |last6=Solomon |first6=KR |title=Environmental fate and dietary exposures of humans to TCDD as a result of the spraying of Agent Orange in upland forests of Vietnam. |journal=The Science of the total environment |date=15 February 2015 |volume=506-507 |pages=621-30 |doi=10.1016/j.scitotenv.2014.11.026 |pmid=25433383}}</ref> However, there are remarkable differences in PCDD/F levels in breast milk in different locations, and hot spots exist.<ref>{{cite journal |last1=Hue |first1=NT |last2=Nam |first2=VD |last3=Thuong |first3=NV |last4=Huyen |first4=NT |last5=Phuong |first5=NT |last6=Hung |first6=NX |last7=Tuan |first7=NH |last8=Son |first8=LK |last9=Minh |first9=NH |title=Determination of PCDD/Fs in breast milk of women living in the vicinities of Da Nang Agent Orange hot spot (Vietnam) and estimation of the infant's daily intake. |journal=The Science of the total environment |date=1 September 2014 |volume=491-492 |pages=212-8 |doi=10.1016/j.scitotenv.2014.02.054 |pmid=24613651}}</ref> Several industrial settings have caused high exposures to dioxins when synthesizing chlorophenols or phenoxy acid herbicides.<ref>{{cite journal |last1=Flesch-Janys |first1=D |last2=Berger |first2=J |last3=Gurn |first3=P |last4=Manz |first4=A |last5=Nagel |first5=S |last6=Waltsgott |first6=H |last7=Dwyer |first7=JH |title=Exposure to polychlorinated dioxins and furans (PCDD/F) and mortality in a cohort of workers from a herbicide-producing plant in Hamburg, Federal Republic of Germany. |journal=American journal of epidemiology |date=1 December 1995 |volume=142 |issue=11 |pages=1165-75 |doi=10.1093/oxfordjournals.aje.a117575 |pmid=7485063}}</ref><ref>{{cite journal |last1=Ott |first1=MG |last2=Zober |first2=A |title=Cause specific mortality and cancer incidence among employees exposed to 2,3,7,8-TCDD after a 1953 reactor accident. |journal=Occupational and environmental medicine |date=September 1996 |volume=53 |issue=9 |pages=606-12 |doi=10.1136/oem.53.9.606 |pmid=8882118}}</ref><ref>{{cite journal |last1=Steenland |first1=K |last2=Piacitelli |first2=L |last3=Deddens |first3=J |last4=Fingerhut |first4=M |last5=Chang |first5=LI |title=Cancer, heart disease, and diabetes in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. |journal=Journal of the National Cancer Institute |date=5 May 1999 |volume=91 |issue=9 |pages=779-86 |doi=10.1093/jnci/91.9.779 |pmid=10328108}}</ref><ref>{{cite journal |last1=Boers |first1=D |last2=Portengen |first2=L |last3=Bueno-de-Mesquita |first3=HB |last4=Heederik |first4=D |last5=Vermeulen |first5=R |title=Cause-specific mortality of Dutch chlorophenoxy herbicide manufacturing workers. |journal=Occupational and environmental medicine |date=January 2010 |volume=67 |issue=1 |pages=24-31 |doi=10.1136/oem.2008.044222 |pmid=19736176}}</ref> Some of these main chemicals are carcinogenic which makes pinpointing the risk to a specific chemical problematic.<ref name=IARC16>{{Cite book|url=https://publications.iarc.fr/Book-And-Report-Series/Iarc-Monographs-On-The-Identification-Of-Carcinogenic-Hazards-To-Humans/Pentachlorophenol-And-Some-Related-Compounds-2019|date=2016|chapter=Pentachlorophenol and Some Related Compounds|title=IARC Monographs on the Evaluation of Carcinogenic Risks to Humans|publisher=IARC|volume=117|pages=33-168|isbn=978-92-832-0155-7|language=en}}</ref><ref name=Tuomisto12b/> Chloracne is a hallmark characteristic at the higher end of exposure levels. Occupational cancer studies have been pooled in a large international combined cohort, suggesting an increased risk of all cancers and of soft-tissue sarcoma.<ref name=Kogevinas97>{{cite journal |last1=Kogevinas |first1=M |last2=Becher |first2=H |last3=Benn |first3=T |last4=et al. |title=Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins |journal=Am J Epidemiol |date=1997 |volume=145 |pages=1061-1075 |doi=10.1093/oxfordjournals.aje.a009069 |pmid=9199536}}</ref> The difficulty in interpreting the effects is that exposure levels were not measured directly and appear to be highly variable, i.e. very high industrial levels and marginally increased levels in workers spraying phenoxy herbicides.<ref name=Tuomisto12b/> The study<ref name=Kogevinas97/> was crucial for IARC evaluations,<ref name=IARC97/><ref name="IARC12">{{Cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK304398/|title=2,3,7,8-tetrachlorodibenzopara-dioxin, 2,3,4,7,8-pentachlorodibenzofuran, and 3,3',4,4',5-pentachlorobiphenyl|last=IARC Working Group on the Evaluation of Carcinogenic Risk to Humans|first=|date=2012|publisher=International Agency for Research on Cancer|year=|isbn=|volume=100F|location=|pages=339-378|language=en}}</ref> which have also been criticized.<ref name=Yamaguchi99>{{Cite journal|last=Yamaguchi|first=N|date=1999-12|title=Uncertainty in Risk Characterization of Weak Carcinogens|url=http://dx.doi.org/10.1111/j.1749-6632.1999.tb08094.x|journal=Annals of the New York Academy of Sciences|volume=895|issue=1 UNCERTAINTY I|pages=338–347|doi=10.1111/j.1749-6632.1999.tb08094.x|issn=0077-8923}}</ref><ref name=Cole02/><ref name=Boffetta11>{{Cite journal|last=Boffetta|first=Paolo|last2=Mundt|first2=Kenneth A.|last3=Adami|first3=Hans-Olov|last4=Cole|first4=Philip|last5=Mandel|first5=Jack S.|date=2011-07|title=TCDD and cancer: A critical review of epidemiologic studies|url=http://dx.doi.org/10.3109/10408444.2011.560141|journal=Critical Reviews in Toxicology|volume=41|issue=7|pages=622–636|doi=10.3109/10408444.2011.560141|issn=1040-8444}}</ref> Especially the evidence on soft-tissue sarcoma is weak and based on very few cases,<ref name=Tuomisto12b>{{cite journal |last1=Tuomisto |first1=J |last2=Tuomisto |first2=JT |title=Is the fear of dioxin cancer more harmful than dioxin? |journal=Toxicology letters |date=5 May 2012 |volume=210 |issue=3 |pages=338-44 |doi=10.1016/j.toxlet.2012.02.007 |pmid=22387160}}</ref> but a slight increase of all cancers is likely to be real considering recent new evidence on Yusho, Yu-cheng and Seveso accidents. An increase in lung cancer risk would be logical among smokers due to promotion. A recent meta-analysis concluded that there is an association between dioxins and increased all cancer incidence and mortality and non-Hodgkin's lymphoma mortality.<ref name=Xu2017>{{Cite journal|last=Xu|first=Jinming|last2=Ye|first2=Yao|last3=Huang|first3=Fang|last4=Chen|first4=Hanwen|last5=Wu|first5=Han|last6=Huang|first6=Jian|last7=Hu|first7=Jian|last8=Xia|first8=Dajing|last9=Wu|first9=Yihua|date=2016-11-29|title=Association between dioxin and cancer incidence and mortality: a meta-analysis|url=http://dx.doi.org/10.1038/srep38012|journal=Scientific Reports|volume=6|issue=1|doi=10.1038/srep38012|issn=2045-2322}}</ref> The association was non-linear.<ref name=Xu2017/> A review of high-exposure studies suggests that dioxin exposure is associated with increased mortality from cardiovascular disease and, especially, ischemic heart disease.<ref>{{cite journal |last1=Humblet |first1=O |last2=Birnbaum |first2=L |last3=Rimm |first3=E |last4=Mittleman |first4=MA |last5=Hauser |first5=R |title=Dioxins and cardiovascular disease mortality. |journal=Environmental health perspectives |date=November 2008 |volume=116 |issue=11 |pages=1443-8 |doi=10.1289/ehp.11579 |pmid=19057694}}</ref> High industrial male dioxin levels were associated with lowered male/female ratio of offspring agreeing with the Seveso results.<ref>{{cite journal |last1=Ryan |first1=JJ |last2=Amirova |first2=Z |last3=Carrier |first3=G |title=Sex ratios of children of Russian pesticide producers exposed to dioxin. |journal=Environmental health perspectives |date=November 2002 |volume=110 |issue=11 |pages=A699-701 |doi=10.1289/ehp.021100699 |pmid=12417498}}</ref> === Risks connected with low exposures of general population === Tooth deformities have been considered a plausible developmental effect in a general population after a long breast-feeding with relatively high dioxin concentrations in breast milk (range 7.7–258) pg/g TEQ in fat.<ref name=Alaluusua96>{{cite journal |last1=Alaluusua |first1=S |last2=Lukinmaa |first2=PL |last3=Vartiainen |first3=T |last4=Partanen |first4=M |last5=Torppa |first5=J |last6=Tuomisto |first6=J |title=Polychlorinated dibenzo-p-dioxins and dibenzofurans via mother's milk may cause developmental defects in the child's teeth. |journal=Environmental toxicology and pharmacology |date=15 May 1996 |volume=1 |issue=3 |pages=193-7 |pmid=21781681|doi=10.1016/1382-6689(96)00007-5}}</ref><ref>{{cite journal |last1=Alaluusua |first1=S |last2=Lukinmaa |first2=PL |last3=Torppa |first3=J |last4=Tuomisto |first4=J |last5=Vartiainen |first5=T |title=Developing teeth as biomarker of dioxin exposure. |journal=Lancet (London, England) |date=16 January 1999 |volume=353 |issue=9148 |pages=206 |doi=10.1016/S0140-6736(05)77214-7 |pmid=9923879}}</ref> The effects were no longer seen when dioxin levels in milk decreased over the years. Cryptorchidism did not associate with placental levels of dioxins and PCBs,<ref name=Virtanen12/> but adipose tissue levels at the time of operation may support an association.<ref>{{cite journal |last1=Koskenniemi |first1=JJ |last2=Virtanen |first2=HE |last3=Kiviranta |first3=H |last4=Damgaard |first4=IN |last5=Matomäki |first5=J |last6=Thorup |first6=JM |last7=Hurme |first7=T |last8=Skakkebaek |first8=NE |last9=Main |first9=KM |last10=Toppari |first10=J |title=Association between levels of persistent organic pollutants in adipose tissue and cryptorchidism in early childhood: a case-control study. |journal=Environmental health : a global access science source |date=24 September 2015 |volume=14 |pages=78 |doi=10.1186/s12940-015-0065-0 |pmid=26403566}}</ref> Sperm counts at age 18–19 years were inversely associated with dioxin levels at age 8–9 years in a cohort of Russian boys.<ref name=MínguezAlarcon17>{{cite journal |last1=Mínguez-Alarcón |first1=L |last2=Sergeyev |first2=O |last3=Burns |first3=JS |last4=Williams |first4=PL |last5=Lee |first5=MM |last6=Korrick |first6=SA |last7=Smigulina |first7=L |last8=Revich |first8=B |last9=Hauser |first9=R |title=A Longitudinal Study of Peripubertal Serum Organochlorine Concentrations and Semen Parameters in Young Men: The Russian Children's Study. |journal=Environmental health perspectives |date=March 2017 |volume=125 |issue=3 |pages=460-466 |doi=10.1289/EHP25 |pmid=27713107}}</ref> The range of PCDD/F+PCB TEQ was 4.88–107 pg/g lipid, or relatively high for age due to local industrial emissions. Maternal levels of dioxins were 5 to 173 pg TEQ/g fat, but the levels in babies are not known.<ref>{{cite journal |last1=Humblet |first1=O |last2=Williams |first2=PL |last3=Korrick |first3=SA |last4=Sergeyev |first4=O |last5=Emond |first5=C |last6=Birnbaum |first6=LS |last7=Burns |first7=JS |last8=Altshul |first8=L |last9=Patterson |first9=DG |last10=Turner |first10=WE |last11=Lee |first11=MM |last12=Revich |first12=B |last13=Hauser |first13=R |title=Predictors of serum dioxin, furan, and PCB concentrations among women from Chapaevsk, Russia. |journal=Environmental science & technology |date=15 July 2010 |volume=44 |issue=14 |pages=5633-40 |doi=10.1021/es100976j |pmid=20578718}}</ref> Several endpoints in male sexual development including those in the Russian Children study have been reviewed and the most sensitive endpoint was interpreted to be sperm count due to epididymal factors.<ref name=Pilsner17>{{cite journal |last1=Pilsner |first1=JR |last2=Parker |first2=M |last3=Sergeyev |first3=O |last4=Suvorov |first4=A |title=Spermatogenesis disruption by dioxins: Epigenetic reprograming and windows of susceptibility. |journal=Reproductive toxicology (Elmsford, N.Y.) |date=April 2017 |volume=69 |pages=221-229 |doi=10.1016/j.reprotox.2017.03.002 |pmid=28286111}}</ref> It was hypothesized that the mechanism is associated with sperm DNA methylation in young adults.<ref>{{cite journal |last1=Pilsner |first1=JR |last2=Shershebnev |first2=A |last3=Medvedeva |first3=YA |last4=et al. |title=Peripubertal serum dioxin concentrations and subsequent sperm methylome profiles of young Russian adults. |journal=Reproductive toxicology (Elmsford, N.Y.) |date=June 2018 |volume=78 |pages=40-49 |doi=10.1016/j.reprotox.2018.03.007 |pmid=29550351}}</ref> Recently a number of cross-sectional studies have shown associations between type 2 diabetes and several POP compounds including dioxins (reviewed by Magliano et al.).<ref name=Magliano14>{{cite journal |last1=Magliano |first1=DJ |last2=Loh |first2=VH |last3=Harding |first3=JL |last4=Botton |first4=J |last5=Shaw |first5=JE |title=Persistent organic pollutants and diabetes: a review of the epidemiological evidence. |journal=Diabetes & metabolism |date=February 2014 |volume=40 |issue=1 |pages=1-14 |doi=10.1016/j.diabet.2013.09.006 |pmid=24262435}}</ref> Their significance remains uncertain, however, because ecological observational studies cannot prove causality, and prospective studies have been inconsistent.<ref name=Magliano14/><ref name=Tornevi19>{{cite journal |last1=Tornevi |first1=A |last2=Sommar |first2=J |last3=Rantakokko |first3=P |last4=Åkesson |first4=A |last5=Donat-Vargas |first5=C |last6=Kiviranta |first6=H |last7=Rolandsson |first7=O |last8=Rylander |first8=L |last9=Wennberg |first9=M |last10=Bergdahl |first10=IA |title=Chlorinated persistent organic pollutants and type 2 diabetes - A population-based study with pre- and post- diagnostic plasma samples. |journal=Environmental research |date=July 2019 |volume=174 |pages=35-45 |doi=10.1016/j.envres.2019.04.017 |pmid=31029940}}</ref> One of the problems is that similar results have been obtained with a large variety of chlorinated pesticides, non-dioxin-like PCBs, dl-PCBs, PCDDs and PCDFs. These compounds have different mechanisms of action, and the only common denominator is long half-life leading to unpredictable toxicokinetics. This suggests that the results may be confounded by diet and obesity which are by far the most important risk factors of type 2 diabetes.<ref name=Magliano14/><ref name=Tuomisto16/><ref name=Tornevi19/> Well-planned controlled studies are clearly needed.<ref name=Jaacks/> An international panel met in 1998, organized by the World Health Organization and International Programme on Chemical Safety, to give guidance for assessing tolerable daily intake (TDI) values.<ref>{{cite journal |editor1-last=Van Leeuwen |editor1-first=F.X.R. |editor2-last=Younes, |editor2-first=M.M. |title=Assessment of the health risk of dioxins: re-evaluation of the tolerable daily intake (TDI). Geneva, Switzerland, 25-29 May 1998. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=223-369 |pmid=10960271|doi=10.1080/713810655}}</ref> Critical body burdens were compared in humans and animals, and the respective estimated human intake was calculated. The most relevant effects were found to be sperm count, immune suppression, genital malformations, and neurobehavioural effects in offspring and endometriosis in adults.<ref name=WHO00>{{cite journal |last1=WHO temporary advisor group |title=Consultation on assessment of the health risk of dioxins; re-evaluation of the tolerable daily intake (TDI): executive summary. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=223-40 |doi=10.1080/713810655 |pmid=10912238}}</ref> Thus the safety margins for different developmental effects were considered lowest. The TDI recommendation was 1-4 pg/kg TEQ, with an ultimate goal to reduce it to 1 pg/kg. This recommendation was based on the intake of dioxins by women in fertile age subsequently delivering dioxins during pregnancy and breast feeding to the child. Dioxin concentration in breast milk fat is about the same as in mother's adipose tissue. Therefore a baby is exposed to higher daily amounts of dioxins during breastfeeding than at any later stage of life. Considering the amount of fat transported from mother to child during a long breast feeding period, this was considered the most vulnerable situation. Therefore the TDI does not directly guide intake in any other population group, including older children.<ref name=WHO00/> It should be noted that the body burden of dioxins at steady state is about 5000 daily doses meaning that only long-term intake is important.<ref name=TuomistoSynopsis/> The Joint FAO/WHO Expert Committee on Food Additives (JECFA) derived in 2001 a provisional tolerable monthly intake (PTMI) of 70 pg TEQ/kg body weight.<ref name=Malisch14/> The Scientific Committee on Food (SCI) of the European Commission applied a tolerable weekly intake (TWI) of 14 pg TEQ/kg, which is very close to the JECFA PTMI.<ref>{{Cite web|url=https://ec.europa.eu/food/sites/food/files/safety/docs/cs_contaminants_catalogue_dioxins_out90_en.pdf|title=Opinion of the scientific committee on food on the risk assessment of dioxins and dioxin-like PCBs in food (S/CNTM/DIOXIN/20 final)|publisher=European Commission|date=2001|website=hero.epa.gov|language=en|access-date=2019-12-17}}</ref> (Table 3) The U.S. Environmental Protection Agency (U.S. EPA) established an oral reference dose (RfD) of 0.7 pg/kg b.w. per day for TCDD.<ref>{{Cite web|url=https://cfpub.epa.gov/ncea/risk/recordisplay.cfm?deid=222203|title=EPA's Reanalysis of Key Issues Related to Dioxin Toxicity and Response to NAS Comments (External Review Draft)|publisher=US EPA National Center for Environmental Assessment,Cincinnati Oh|last=Rice|first=Glenn|website=cfpub.epa.gov|language=en|access-date=2019-12-16}}</ref> The differences are based on two factors, EPA assessment is based on human data and tenfold uncertainty factor, the others on animal data and a threefold safety factor. In view of different approaches European Food Safety Authority (EFSA) recommended a new comprehensive risk assessment,<ref name=EFSA15b>{{cite journal |last1=EFSA (European Food Safety Authority) |title=Scientific statement on the health‐based guidance values for dioxins and dioxin‐like PCBs |journal=EFSA Journal |date=May 2015 |volume=13 |issue=5 |doi=10.2903/j.efsa.2015.4124}}</ref> and recently EFSA Panel on Contaminants in the Food Chain (CONTAM) recommended a TWI of 2 pg TEQ/kg which is pending.<ref name=EFSAPanel18/> (Table 3) '''Table 3 {{!}}''' Tolerable intake estimates by different agencies in Europe and the United States. {| class="wikitable sortable" !Agency !class="unsortable"|Tolerable dose !Tolerable dose expressed as TDI |- |WHO 2000 | |1-4 pg TEQ/kg |- |SCF 2001 |14 pg TEQ/kg weekly |2 pg TEQ/kg |- |JECFA 2001 |70 pg TEQ/kg monthly |2.3 pg TEQ/kg |- |USEPA 2012 |0.7 pg TCDD/kg daily (reference dose) | |- |EFSA CONTAM Panel 2018 |2 pg TEQ/kg weekly |0.29 TEQ/kg |} The CONTAM panel of EFSA recommended a TWI of 2 pg/kg based heavily on the Russian Children Study.<ref name=EFSAPanel18/> There is an uncertainty in that we do not know the sensitive time period, and if it is e.g. two first years of life associated with breast feeding, we do not know the concentrations that may have been higher than at 8–9 years. Modelling is limited by the lack of exact information on kinetics in small children. Decreasing sperm counts in many countries while the concentrations of dioxins have been decreasing, do not support a causal role of present dioxin intake. If multigenerational mechanisms are involved, it would be more important to evaluate the concentrations some decades back, and contemporary restrictions no longer help. Setting strict arbitrary limits may fire back, and changes in diet, e.g. avoiding fish consumption could lead to harmful health effects.<ref>{{Cite journal|last=Olsen|first=Sjúrđur Fróđi|last2=Secher|first2=Niels Jørgen|date=2002-10|title=Low Consumption of Seafood in Early Pregnancy as a Risk Factor for Preterm Delivery: Prospective Cohort Study|url=http://dx.doi.org/10.1097/00006254-200210000-00004|journal=Obstetrical & Gynecological Survey|volume=57|issue=10|pages=651–652|doi=10.1097/00006254-200210000-00004|issn=0029-7828}}</ref><ref name=Cohen2005>{{Cite journal|last=Cohen|first=Joshua T.|last2=Bellinger|first2=David C.|last3=Connor|first3=William E.|last4=Kris-Etherton|first4=Penny M.|last5=Lawrence|first5=Robert S.|last6=Savitz|first6=David A.|last7=Shaywitz|first7=Bennett A.|last8=Teutsch|first8=Steven M.|last9=Gray|first9=George M.|date=2005-11-01|title=A Quantitative Risk–Benefit Analysis of Changes in Population Fish Consumption|url=https://www.ajpmonline.org/article/S0749-3797(05)00253-9/abstract|journal=American Journal of Preventive Medicine|language=English|volume=29|issue=4|pages=325–334.e6|doi=10.1016/j.amepre.2005.07.003|issn=0749-3797}}</ref><ref>{{Cite journal|last=Mozaffarian|first=Dariush|last2=Rimm|first2=Eric B.|date=2006-10-18|title=Fish Intake, Contaminants, and Human Health|url=http://dx.doi.org/10.1001/jama.296.15.1885|journal=JAMA|volume=296|issue=15|pages=1885|doi=10.1001/jama.296.15.1885|issn=0098-7484}}</ref><ref name=Starling>{{Cite journal|last=Starling|first=Phoebe|last2=Charlton|first2=Karen|last3=McMahon|first3=Anne|last4=Lucas|first4=Catherine|date=2015-03-18|title=Fish Intake during Pregnancy and Foetal Neurodevelopment—A Systematic Review of the Evidence|url=http://dx.doi.org/10.3390/nu7032001|journal=Nutrients|volume=7|issue=3|pages=2001–2014|doi=10.3390/nu7032001|issn=2072-6643}}</ref><ref name="Tuomisto19">{{Cite journal|last=Tuomisto|first=Jouni T.|last2=Asikainen|first2=Arja|last3=Meriläinen|first3=Päivi|last4=Haapasaari|first4=Päivi|date=2020-01-15|title=Health effects of nutrients and environmental pollutants in Baltic herring and salmon: a quantitative benefit-risk assessment|url=https://doi.org/10.1186/s12889-019-8094-1|journal=BMC Public Health|volume=20|issue=1|pages=64|doi=10.1186/s12889-019-8094-1|issn=1471-2458|pmc=PMC6964011|pmid=31941472}}</ref> It is also a problem that potentially harmful intake may only concern certain age categories (esp. young women before their first pregnancy affecting the child), and otherwise fish consumption unquestionably means a health benefit.<ref name=Cohen2005/><ref name=Tuomisto19/> Cancer risk from dioxin exposures has been hotly debated. IARC<ref name="IARC97">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK409980/|title=Polychlorinated Dibenzo-para-dioxins and Polychlorinated Dibenzofurans|last1=IARC Working Group on the Evaluation of Carcinogenic Risk to Humans|first1=|date=1997|publisher=International Agency for Research on Cancer|year=|isbn=|volume=69|location=|pages=1-636}}</ref><ref name=IARC12/> has deemed TCDD and 2,3,4,7,8-TCDF as carcinogenic to humans (class 1). However, the assessments are based on animal experiments and high accidental or occupational exposures.<ref name=Schrenk12/> IARC only assesses the certainty of evidence regardless of the dose, and it remains unclear what is the risk for the general population. The high-exposure populations<ref>{{cite journal |last1=Kogevinas |first1=M |title=Studies of cancer in humans. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=317-24 |doi=10.1080/026520300283388 |pmid=10912245}}</ref> were exposed to 100–1000 or more times higher levels than the general population. Thus both animal studies and epidemiological studies refer to high doses and require extrapolation to low population levels. The assessment has been challenged in several papers on various grounds.<ref name=Yamaguchi99/><ref>{{Cite journal|last=Kayajanian|first=Gary Michael|date=2002-01|title=The J-Shaped Dioxin Dose Response Curve|url=http://dx.doi.org/10.1006/eesa.2001.2115|journal=Ecotoxicology and Environmental Safety|volume=51|issue=1|pages=1–4|doi=10.1006/eesa.2001.2115|issn=0147-6513}}</ref><ref name=Cole02>{{cite journal |last1=Cole |first1=P |last2=Trichopoulos |first2=D |last3=Pastides |first3=H |last4=Starr |first4=T |last5=Mandel |first5=JS |title=Dioxin and cancer: a critical review. |journal=Regulatory toxicology and pharmacology : RTP |date=December 2003 |volume=38 |issue=3 |pages=378-88 |pmid=14623487|doi=10.1016/j.yrtph.2003.08.002}}</ref><ref name=Boffetta11/><ref name=Tuomisto12b/> It may be concluded that dioxins are carcinogenic in animals and probably carcinogenic at high dose levels in humans. However, there is no good evidence that there would be any significant increase in cancer risk at the present levels detected in the general population. The WHO consultation group<ref name=WHO00/> concluded that the potential cancer risk is taken care of, if TDI is determined on the basis of developmental effects. A population risk in humans is unlikely on several grounds. Dioxins do not cause carcinogenic mutations of DNA.<ref name=IARC12/> Therefore linear extrapolation is not likely to be valid,<ref name=Xu2017/> and safety margins can be applied as in other forms of toxicity. The important physiological role of the AH receptor means that an appropriate receptor activation is beneficial. Only inappropriate stimulation is harmful, which is the case with other receptors such as steroid and thyroid receptors.<ref name=Tuomisto12b/> Cancer interpretation based on case-control studies relying on exposure assessment by questionnaires after diagnosing cancer is problematic because of recall bias.<ref>{{cite journal |last1=Tuomisto |first1=J |last2=Airaksinen |first2=R |last3=Pekkanen |first3=J |last4=Tukiainen |first4=E |last5=Kiviranta |first5=H |last6=Tuomisto |first6=JT |title=Comparison of questionnaire data and analyzed dioxin concentrations as a measure of exposure in soft-tissue sarcoma studies. |journal=Toxicology letters |date=15 March 2017 |volume=270 |pages=8-11 |doi=10.1016/j.toxlet.2017.02.011 |pmid=28189645}}</ref> Cohort studies have given equivocal results.<ref name=Tuomisto12b/> A specific cancer that many studies associate with dioxins is soft tissue sarcoma. In a large case-control study with individual measured concentration data, no positive associations were found between soft-tissue sarcoma and TEQs or individual dioxins or PCBs.<ref name=TuomistoSTS/> Rather there was a trend of decreasing risk at higher exposure groups suggesting a hormetic effect.<ref>{{cite journal |last1=Tuomisto |first1=J |last2=Pekkanen |first2=J |last3=Kiviranta |first3=H |last4=Tukiainen |first4=E |last5=Vartiainen |first5=T |last6=Viluksela |first6=M |last7=Tuomisto |first7=JT |title=Dioxin cancer risk--example of hormesis? |journal=Dose-response : a publication of International Hormesis Society |date=1 May 2006 |volume=3 |issue=3 |pages=332-41 |doi=10.2203/dose-response.003.03.004 |pmid=18648613}}</ref> Other side of the coin may even be that AH receptor agonists could be used in search for drugs in treating cancer.<ref name=Kolluri17/> Recently a few among a large number of POPs analysed were found to correlate with breast cancer metastasis.<ref>{{Cite journal|last=Koual|first=Meriem|last2=Cano-Sancho|first2=German|last3=Bats|first3=Anne-Sophie|last4=Tomkiewicz|first4=Céline|last5=Kaddouch-Amar|first5=Yael|last6=Douay-Hauser|first6=Nathalie|last7=Ngo|first7=Charlotte|last8=Bonsang|first8=Hélène|last9=Deloménie|first9=Myriam|date=2019-11|title=Associations between persistent organic pollutants and risk of breast cancer metastasis|url=http://dx.doi.org/10.1016/j.envint.2019.105028|journal=Environment International|volume=132|pages=105028|doi=10.1016/j.envint.2019.105028|issn=0160-4120}}</ref> In addition to chance effects there is a problem of causality: what is primary and what is secondary.<ref name=Tuomisto16/> In conclusion the safety margins seem to be lowest for developmental effects. Sex ratio changes were seen at concentrations about 20 times the present levels,<ref name=Mocarelli00/> and for enamel defects in teeth and the sperm quality the margin may be slightly lower.<ref name=Alaluusua96/><ref name=Alaluusua04/><ref name=MínguezAlarcon17/><ref name=Pilsner17/> These are in line with the assessment by the WHO panel.<ref name=WHO00/> The WHO panel based their assessment in the exposure of child-bearing women who excrete much of their body burden to the child during pregnancy and lactation. In other population groups the risks are low. The panel concluded that even if the safety margin concerning the child is fairly narrow, the benefits of breast feeding clearly exceed the risks. Similarly, the health benefits of fish consumption clearly exceed the risks of dioxins or other persistent organic compounds.<ref name=Starling/><ref>{{cite journal |last1=Tuomisto |first1=JT |last2=Tuomisto |first2=J |last3=Tainio |first3=M |last4=Niittynen |first4=M |last5=Verkasalo |first5=P |last6=Vartiainen |first6=T |last7=Kiviranta |first7=H |last8=Pekkanen |first8=J |title=Risk-benefit analysis of eating farmed salmon. |journal=Science (New York, N.Y.) |date=23 July 2004 |volume=305 |issue=5683 |pages=476-7; author reply 476-7 |doi=10.1126/science.305.5683.476 |pmid=15273377}}</ref><ref name=Tuomisto19/> In case of competing risks (e.g. cardiovascular disease) the application of precautionary principle may be dangerous. This means that while acknowledging the modest safety margins concerning food, it is more relevant to emphasize the importance of decreasing dioxin emissions to the environment and reducing environmental levels.<ref name=Assefa/><ref name=White09/> == Effects in laboratory animals and their relevance in risk assessment == Effects of dioxins in animals can be broadly divided to clearly toxic effects (such as lethality, wasting syndrome, liver injury, developmental toxicity), and metabolic effects that often can be classified as adaptive responses (such as induction of enzymes metabolizing xenobiotic chemicals).<ref name=WHO00/> Highly detailed descriptions on dioxin toxicity in animals can be found in several reviews.<ref name=Poland82/><ref name=Pohjanvirta94/><ref name=Birnbaum00>{{cite journal |last1=Birnbaum |first1=LS |last2=Tuomisto |first2=J |title=Non-carcinogenic effects of TCDD in animals. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=275-88 |doi=10.1080/026520300283351 |pmid=10912242}}</ref><ref name=TuomistoDeich>{{cite journal |last1=Tuomisto |first1=J |title=Does mechanistic understanding help in risk assessment--the example of dioxins. |journal=Toxicology and applied pharmacology |date=1 September 2005 |volume=207 |issue=2 Suppl |pages=2-10 |doi=10.1016/j.taap.2005.01.053 |pmid=15996698}}</ref><ref name=Okey07/><ref name=White09/><ref name=Linden10/><ref name=Pohjanvirta12/> === The most conspicuous acute toxic effects in adult animals === Acute toxicity of dioxins differs highly among species (Table 4). Guinea pig is considered to be the most sensitive mammal; the LD50 of TCDD is about 1-2 µg/kg. Hamsters tolerate more than a thousand fold dose. The differences between and within species are sometimes based on different ligand binding affinities (e.g. C57BL/6 mice and ten times more resistant DBA2/2J mice), sometimes to the structure of the transactivation domain of the receptor (such as a thousand fold difference between Long-Evans and Han/Wistar/Kuo rats, and possibly between guinea pig and hamster). These differences have complicated risk assessment on the basis of animal studies. It is typical that even after a high single dose the animals do not die immediately, but following a reduced feed intake and wasting (so called wasting syndrome) in two to three weeks.<ref name=Pohjanvirta94/> The syndrome is associated with decreased appetite and food intake, but the exact mechanism is not clear.<ref name=Linden10/> A wasting-syndrome-like poisoning has never been seen in humans even after huge doses (see above).<ref name=Geusau01/><ref name=Saurat12/> At very low doses there is a clear aversion response to novel foods which may not be related to the fatal wasting syndrome, but is rather an adaptive safety response preventing consumption of toxic food items.<ref name=Lensu17>{{cite journal |last1=Lensu |first1=S |last2=Tuomisto |first2=JT |last3=Tuomisto |first3=J |last4=Pohjanvirta |first4=R |title=Characterization of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-provoked strong and rapid aversion to unfamiliar foodstuffs in rats. |journal=Toxicology |date=10 May 2011 |volume=283 |issue=2-3 |pages=140-50 |doi=10.1016/j.tox.2011.03.007 |pmid=21435369}}</ref><ref name=Lensu2011>{{cite journal |last1=Lensu |first1=S |last2=Tuomisto |first2=JT |last3=Tuomisto |first3=J |last4=Viluksela |first4=M |last5=Niittynen |first5=M |last6=Pohjanvirta |first6=R |title=Immediate and highly sensitive aversion response to a novel food item linked to AH receptor stimulation. |journal=Toxicology letters |date=24 June 2011 |volume=203 |issue=3 |pages=252-7 |doi=10.1016/j.toxlet.2011.03.025 |pmid=21458548}}</ref> '''Table 4 {{!}}''' Lethal dose in some animal species<ref name=Pohjanvirta94/> {| class="wikitable" !Species !LD50 (μg/kg body weight) |- |Guinea pig |2 |- |Rat |10-60 |- |Rhesus monkey |~70 |- |Rabbit |115 |- |Mouse |100-300 |- |Dog |>300 |- |Bullfrog |>500 |- |Hamster |~3,000 |- |Han/Wistar(Kuopio) rat |>10,000 |} Some changes in the transactivation domain of AH receptor influence drastically the wasting syndrome and lethality whereas biochemical effects such as CYP1A1 enzyme induction are unaffected as well as AHR binding.<ref>{{cite journal |last1=Pohjanvirta |first1=R |last2=Wong |first2=JM |last3=Li |first3=W |last4=Harper |first4=PA |last5=Tuomisto |first5=J |last6=Okey |first6=AB |title=Point mutation in intron sequence causes altered carboxyl-terminal structure in the aryl hydrocarbon receptor of the most 2,3,7,8-tetrachlorodibenzo-p-dioxin-resistant rat strain. |journal=Molecular pharmacology |date=July 1998 |volume=54 |issue=1 |pages=86-93 |doi=10.1124/mol.54.1.86 |pmid=9658193}}</ref> Therefore two types of dioxin effects have been proposed (Table 5). Type I responses include developmental effects, aversion to novel foods, and the typical induction of CYP1A1 and other oxidative enzymes which occur at the same dose levels regardless of the structure of the AHR. Type II responses with great variation between species and strains include several high-dose effects such as wasting syndrome, lethality, and liver toxicity.<ref>{{cite journal |last1=Tuomisto |first1=JT |last2=Viluksela |first2=M |last3=Pohjanvirta |first3=R |last4=Tuomisto |first4=J |title=The AH receptor and a novel gene determine acute toxic responses to TCDD: segregation of the resistant alleles to different rat lines. |journal=Toxicology and applied pharmacology |date=15 February 1999 |volume=155 |issue=1 |pages=71-81 |doi=10.1006/taap.1998.8564 |pmid=10036220}}</ref><ref>{{cite journal |last1=Simanainen |first1=U |last2=Tuomisto |first2=JT |last3=Tuomisto |first3=J |last4=Viluksela |first4=M |title=Dose-response analysis of short-term effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in three differentially susceptible rat lines. |journal=Toxicology and applied pharmacology |date=1 March 2003 |volume=187 |issue=2 |pages=128-36 |doi=10.1016/s0041-008x(02)00068-6 |pmid=12649045}}</ref> There is some evidence that tumour promotion might belong to type II responses.<ref name="Viluksela00">{{cite journal |last1=Viluksela |first1=M |last2=Bager |first2=Y |last3=Tuomisto |first3=JT |last4=Scheu |first4=G |last5=Unkila |first5=M |last6=Pohjanvirta |first6=R |last7=Flodström |first7=S |last8=Kosma |first8=VM |last9=Mäki-Paakkanen |first9=J |last10=Vartiainen |first10=T |last11=Klimm |first11=C |last12=Schramm |first12=KW |last13=Wärngård |first13=L |last14=Tuomisto |first14=J |title=Liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive and TCDD-resistant rat strains. |journal=Cancer research |date=15 December 2000 |volume=60 |issue=24 |pages=6911-20 |pmid=11156390}}</ref> '''Table 5 {{!}}''' Examples of toxic and adaptive responses to TCDD in very differently sensitive rat lines, the resistant Han/Wistar Kuopio and the sensitive Long-Evans strains<ref name=TuomistoDeich/> (novel food aversion, resistant line A and sensitive line C developed from H/W and L-E strains<ref name=Lensu2011/>). {| class="wikitable" !Response !H/W or line A !L-E or line C |- | colspan="3" |'''The most sensitive toxic effects and adaptive responses (type I)''' |- |Enzyme induction |0.1-1 μg/kg |0.1-1 μg/kg |- |Aversion to novel foods<ref name=Lensu17/><ref name=Lensu2011/> |0.1-0.6 μg/kg |0.2-0.4 μg/kg |- |Developmental effects (teeth)<ref name=Kattainen01/><ref name=Miettinen2006>{{cite journal |last1=Miettinen |first1=HM |last2=Sorvari |first2=R |last3=Alaluusua |first3=S |last4=Murtomaa |first4=M |last5=Tuukkanen |first5=J |last6=Viluksela |first6=M |title=The effect of perinatal TCDD exposure on caries susceptibility in rats. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=June 2006 |volume=91 |issue=2 |pages=568-75 |doi=10.1093/toxsci/kfj158 |pmid=16543294}}</ref> |0.1-1 μg/kg (dam) |0.1-1 μg/kg (dam) |- | colspan="3" |'''Robust toxic outcomes (type II)''' |- |Lethality |> 10,000 μg/kg |10 μg/kg |- |Liver damage |mild |severe |- |Severe anorexia and wasting syndrome |transient |to lethality |- |Tumour promotion |>100 μg/kg |>1 μg/kg |- | colspan="3" |'''Other''' |- |AH receptor binding |23 fmol/mg |20 fmol/mg |} Thus type I effects are relatively similar among species or strains (see also<ref name=WHO00/><ref name=Birnbaum00/><ref>{{Cite journal|last=Kransler|first=Kevin M.|last2=McGarrigle|first2=Barbara P.|last3=Olson|first3=James R.|date=2007-01|title=Comparative developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the hamster, rat and guinea pig|url=http://dx.doi.org/10.1016/j.tox.2006.10.019|journal=Toxicology|volume=229|issue=3|pages=214–225|doi=10.1016/j.tox.2006.10.019|issn=0300-483X}}</ref>), but type II effects cannot be reliably predicted over species. It is of interest that many of the type I responses can be interpreted as defence mechanisms toward noxious chemicals via the AH receptor (induction of metabolism, aversion of toxic foods) and can therefore be considered adaptive and protective. Dioxins cause various pleiotropic effects. There may be both proliferative responses and atrophic responses. Thymic atrophy and some immunological effects are consistent findings in multiple laboratory species. Liver toxicity is variable, it is typical in rabbits, but some effects are seen in other species, e.g. disturbances of porphyrin metabolism, oxidative damage, and fatty infiltration. There are also multiple high-dose effects on the nervous system, such as tryptophan metabolism or neuropathies.<ref>{{cite journal |last1=Unkila |first1=M |last2=Pohjanvirta |first2=R |last3=Tuomisto |first3=J |title=Dioxin-induced perturbations in tryptophan homeostasis in laboratory animals. |journal=Advances in experimental medicine and biology |date=1999 |volume=467 |pages=433-42 |doi=10.1007/978-1-4615-4709-9_55 |pmid=10721086}}</ref> Generally speaking, adverse effects at low doses in adult animals are few.<ref name=Poland82/><ref name=Pohjanvirta94/> === Developmental effects === Developmental effects have been found to be the most sensitive adverse effects of TCDD in several animal species. Transfer of dioxins through placenta varies by compound and animal species,<ref name=Hamm01>{{cite journal |last1=Chen |first1=CY |last2=Hamm |first2=JT |last3=Hass |first3=JR |last4=Birnbaum |first4=LS |title=Disposition of polychlorinated dibenzo-p-dioxins, dibenzofurans, and non-ortho polychlorinated biphenyls in pregnant long evans rats and the transfer to offspring. |journal=Toxicology and applied pharmacology |date=1 June 2001 |volume=173 |issue=2 |pages=65-88 |doi=10.1006/taap.2001.9143 |pmid=11384209}}</ref> and the amount transferred by lactation in rodents seems to be more than placental transfer.<ref>{{cite journal |last1=Li |first1=X |last2=Weber |first2=LW |last3=Rozman |first3=KK |title=Toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Sprague-Dawley rats including placental and lactational transfer to fetuses and neonates. |journal=Fundamental and applied toxicology: Official journal of the Society of Toxicology |date=August 1995 |volume=27 |issue=1 |pages=70-6 |pmid=7589930|doi=10.1006/faat.1995.1109}}</ref><ref name=Hamm01/> Comparison of single-dose studies to continuous daily intake studies resulting in a similar body burden is problematic, because distribution of dioxins during the peak concentration in the dam is different from long-term distribution.<ref name=Bell10>{{cite journal |last1=Bell |first1=DR |last2=Clode |first2=S |last3=Fan |first3=MQ |last4=Fernandes |first4=A |last5=Foster |first5=PM |last6=Jiang |first6=T |last7=Loizou |first7=G |last8=MacNicoll |first8=A |last9=Miller |first9=BG |last10=Rose |first10=M |last11=Tran |first11=L |last12=White |first12=S |title=Interpretation of studies on the developmental reproductive toxicology of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male offspring. |journal=Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association |date=June 2010 |volume=48 |issue=6 |pages=1439-47 |doi=10.1016/j.fct.2010.04.005 |pmid=20388530}}</ref> Some of the effects are observed at exposure levels indicating relatively small safety margins to the human background exposure.<ref name=Birnbaum00/><ref name=Viluksela19/> The sensitive targets include developing male and female reproductive system, immune system, nervous system, and teeth and bone. Clear teratogenic effects such as cleft palate and hydronephrosis were detected early after relatively high doses in mice.<ref name=Birnbaum95>{{cite journal |last1=Birnbaum |first1=LS |title=Developmental effects of dioxins. |journal=Environmental health perspectives |date=October 1995 |volume=103 Suppl 7 |pages=89-94 |doi=10.1289/ehp.95103s789 |pmid=8593882}}</ref><ref name=Yoshioka19/> Some developmental effects may be caused by indirect mechanisms, e.g. enzyme induction may lead to accelerated metabolism of thyroid hormones resulting in decreased hormone levels. Thyroid hormones are essential for normal development, notably the development of the nervous system. In many other cases the mechanisms seem to involve local growth factors, and the phenomenon cannot be described as endocrine disruption in strict sense. Development of teeth and the skeleton are highly sensitive targets of dioxin toxicity in several vertebrate species.<ref name=Viluksela12>{{cite book |last1=Viluksela |first1=M |last2=Miettinen |first2=HM |last3=Korkalainen |first3=M |editor1-last=Pohjanvirta |editor1-first=Raimo |title=The AH receptor in biology and toxicology |date=2012 |publisher=Wiley |isbn=9780470601822 |pages=285-297 |chapter=Effects of dioxins on teeth and bone: The role of AHR|doi=10.1002/9781118140574.ch20}}</ref> Teeth are useful indicators of developmental toxicity, because they do not undergo continuous remodelling after mineralization like bone, where remodelling may repair mineralization defects. Developmental defects of teeth can therefore be detected later in life, as in the case of the Seveso accident, when dental defects were observed 25 years after the accident.<ref name=Alaluusua04/> In utero and lactational exposure to TCDD was shown to result in wide range of alterations in rats and mice at doses below 1 μg/kg to the dam. They included smaller molar size, delayed eruption, increased susceptibility to caries, altered mineral composition of enamel, increased fluctuating asymmetry of molars and complete arrest of development of the third molars.<ref name=Kattainen01/><ref>{{cite journal |last1=Miettinen |first1=HM |last2=Alaluusua |first2=S |last3=Tuomisto |first3=J |last4=Viluksela |first4=M |title=Effect of in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on rat molar development: the role of exposure time. |journal=Toxicology and applied pharmacology |date=1 October 2002 |volume=184 |issue=1 |pages=57-66 |pmid=12392969|doi=10.1006/taap.2002.9490}}</ref><ref name=Miettinen2006/><ref>{{cite journal |last1=Keller |first1=JM |last2=Allen |first2=DE |last3=Davis |first3=CR |last4=Leamy |first4=LJ |title=2,3,7,8-Tetrachlorodibenzo-p-dioxin affects fluctuating asymmetry of molar shape in mice, and an epistatic interaction of two genes for molar size. |journal=Heredity |date=May 2007 |volume=98 |issue=5 |pages=259-67 |doi=10.1038/sj.hdy.6800928 |pmid=17213866}}</ref><ref>{{cite journal |last1=Keller |first1=JM |last2=Huet-Hudson |first2=YM |last3=Leamy |first3=LJ |title=Qualitative effects of dioxin on molars vary among inbred mouse strains. |journal=Archives of oral biology |date=May 2007 |volume=52 |issue=5 |pages=450-4 |doi=10.1016/j.archoralbio.2006.10.017 |pmid=17141729}}</ref> Sensitivity of tooth development to TCDD was also shown in rhesus monkeys, minks, rainbow trout and zebrafish.<ref>{{cite journal |last1=Yasuda |first1=I |last2=Yasuda |first2=M |last3=Sumida |first3=H |last4=Tsusaki |first4=H |last5=Arima |first5=A |last6=Ihara |first6=T |last7=Kubota |first7=S |last8=Asaoka |first8=K |last9=Tsuga |first9=K |last10=Akagawa |first10=Y |title=In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects tooth development in rhesus monkeys. |journal=Reproductive toxicology (Elmsford, N.Y.) |date=NaN |volume=20 |issue=1 |pages=21-30 |doi=10.1016/j.reprotox.2004.12.016 |pmid=15808782}}</ref><ref>{{cite journal |last1=Render |first1=JA |last2=Bursian |first2=SJ |last3=Rosenstein |first3=DS |last4=Aulerich |first4=RJ |title=Squamous epithelial proliferation in the jaws of mink fed diets containing 3,3',4,4',5-pentachlorobiphenyl (PCB 126) or 2,3,7,8-tetrachlorodibenzo-P-dioxin (TCDD). |journal=Veterinary and human toxicology |date=February 2001 |volume=43 |issue=1 |pages=22-6 |pmid=11205072}}</ref><ref>{{cite journal |last1=Hornung |first1=MW |last2=Spitsbergen |first2=JM |last3=Peterson |first3=RE |title=2,3,7,8-Tetrachlorodibenzo-p-dioxin alters cardiovascular and craniofacial development and function in sac fry of rainbow trout (Oncorhynchus mykiss). |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=January 1999 |volume=47 |issue=1 |pages=40-51 |doi=10.1093/toxsci/47.1.40 |pmid=10048152}}</ref><ref>{{cite journal |last1=Planchart |first1=A |last2=Mattingly |first2=CJ |title=2,3,7,8-Tetrachlorodibenzo-p-dioxin upregulates FoxQ1b in zebrafish jaw primordium. |journal=Chemical research in toxicology |date=15 March 2010 |volume=23 |issue=3 |pages=480-7 |doi=10.1021/tx9003165 |pmid=20055451}}</ref> In tooth development (as well as in the development of several other organs), the target of toxicity seems to be the developing epithelium. Developmental defects are the consequence of impaired epithelial-mesenchymal signalling, and AHR, epidermal growth factor (EGF), transforming growth factor α (TGFα) and perhaps Jun kinases are involved in mediating the effects.<ref>{{cite journal |last1=Partanen |first1=AM |last2=Alaluusua |first2=S |last3=Miettinen |first3=PJ |last4=Thesleff |first4=I |last5=Tuomisto |first5=J |last6=Pohjanvirta |first6=R |last7=Lukinmaa |first7=PL |title=Epidermal growth factor receptor as a mediator of developmental toxicity of dioxin in mouse embryonic teeth. |journal=Laboratory investigation; a journal of technical methods and pathology |date=December 1998 |volume=78 |issue=12 |pages=1473-81 |pmid=9881947}}</ref><ref>{{cite journal |last1=Abbott |first1=BD |last2=Buckalew |first2=AR |last3=DeVito |first3=MJ |last4=Ross |first4=D |last5=Bryant |first5=PL |last6=Schmid |first6=JE |title=EGF and TGF-alpha expression influence the developmental toxicity of TCDD: dose response and AhR phenotype in EGF, TGF-alpha, and EGF + TGF-alpha knockout mice. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=January 2003 |volume=71 |issue=1 |pages=84-95 |doi=10.1093/toxsci/71.1.84 |pmid=12520078}}</ref><ref>{{cite journal |last1=Alaluusua |first1=S |last2=Lukinmaa |first2=PL |title=Developmental dental toxicity of dioxin and related compounds--a review. |journal=International dental journal |date=December 2006 |volume=56 |issue=6 |pages=323-31 |pmid=17243464|doi=10.1111/j.1875-595X.2006.tb00336.x}}</ref><ref name=Viluksela12/><ref>{{Cite journal|last=Diry|first=M|last2=Tomkiewicz|first2=C|last3=Koehle|first3=C|last4=Coumoul|first4=X|last5=Bock|first5=K Walter|last6=Barouki|first6=R|last7=Transy|first7=C|date=2006-04-17|title=Activation of the dioxin/aryl hydrocarbon receptor (AhR) modulates cell plasticity through a JNK-dependent mechanism|url=http://dx.doi.org/10.1038/sj.onc.1209553|journal=Oncogene|volume=25|issue=40|pages=5570–5574|doi=10.1038/sj.onc.1209553|issn=0950-9232}}</ref> Cleft palate is the best-known skeletal effect of dioxins at relatively high maternal doses.<ref name=Birnbaum95/><ref name=Yoshioka19>{{cite journal |last1=Yoshioka |first1=W |last2=Tohyama |first2=C |title=Mechanisms of Developmental Toxicity of Dioxins and Related Compounds. |journal=International journal of molecular sciences |date=31 January 2019 |volume=20 |issue=3 |doi=10.3390/ijms20030617 |pmid=30708991}}</ref> In utero and lactational exposure to lower doses of TCDD was shown to affect long bones of rats, mice and rhesus monkeys by inducing altered bone geometry, decreased bone mineral density and biomechanical strength and retardation of bone matrix maturation.<ref>{{cite journal |last1=Miettinen |first1=HM |last2=Pulkkinen |first2=P |last3=Jämsä |first3=T |last4=Koistinen |first4=J |last5=Simanainen |first5=U |last6=Tuomisto |first6=J |last7=Tuukkanen |first7=J |last8=Viluksela |first8=M |title=Effects of in utero and lactational TCDD exposure on bone development in differentially sensitive rat lines. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=June 2005 |volume=85 |issue=2 |pages=1003-12 |doi=10.1093/toxsci/kfi136 |pmid=15746008}}</ref><ref>{{cite journal |last1=Hermsen |first1=SA |last2=Larsson |first2=S |last3=Arima |first3=A |last4=Muneoka |first4=A |last5=Ihara |first5=T |last6=Sumida |first6=H |last7=Fukusato |first7=T |last8=Kubota |first8=S |last9=Yasuda |first9=M |last10=Lind |first10=PM |title=In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects bone tissue in rhesus monkeys. |journal=Toxicology |date=20 November 2008 |volume=253 |issue=1-3 |pages=147-52 |doi=10.1016/j.tox.2008.09.005 |pmid=18835322}}</ref><ref>{{cite journal |last1=Nishimura |first1=N |last2=Nishimura |first2=H |last3=Ito |first3=T |last4=Miyata |first4=C |last5=Izumi |first5=K |last6=Fujimaki |first6=H |last7=Matsumura |first7=F |title=Dioxin-induced up-regulation of the active form of vitamin D is the main cause for its inhibitory action on osteoblast activities, leading to developmental bone toxicity. |journal=Toxicology and applied pharmacology |date=1 May 2009 |volume=236 |issue=3 |pages=301-9 |doi=10.1016/j.taap.2009.01.025 |pmid=19367694}}</ref><ref>{{cite journal |last1=Finnilä |first1=MA |last2=Zioupos |first2=P |last3=Herlin |first3=M |last4=Miettinen |first4=HM |last5=Simanainen |first5=U |last6=Håkansson |first6=H |last7=Tuukkanen |first7=J |last8=Viluksela |first8=M |last9=Jämsä |first9=T |title=Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on bone material properties. |journal=Journal of biomechanics |date=19 April 2010 |volume=43 |issue=6 |pages=1097-103 |doi=10.1016/j.jbiomech.2009.12.011 |pmid=20132933}}</ref> Further studies indicated that differentiation of bone marrow stem cells to bone forming osteoblasts and bone resorbing osteoclasts is disrupted by TCDD in AHR-dependent manner.<ref>{{cite journal |last1=Korkalainen |first1=M |last2=Kallio |first2=E |last3=Olkku |first3=A |last4=Nelo |first4=K |last5=Ilvesaro |first5=J |last6=Tuukkanen |first6=J |last7=Mahonen |first7=A |last8=Viluksela |first8=M |title=Dioxins interfere with differentiation of osteoblasts and osteoclasts. |journal=Bone |date=June 2009 |volume=44 |issue=6 |pages=1134-42 |doi=10.1016/j.bone.2009.02.019 |pmid=19264158}}</ref> Several studies from different laboratories have indicated a variety of adverse effects on the male reproductive system after in utero or lactational exposure of rats to low doses of TCDD. These include reduction of cauda epididymal sperm counts, daily sperm production, weight of accessory sex organs as well as increased proportion of abnormal sperm and delayed puberty (reviewed by Bell ''et al''.).<ref name=Bell10/> There is remarkable variability among different studies, but the delay in developmental milestones for male reproductive endpoints seems to be the most consistent and sensitive finding. Also decreased male/female sex ratios were reported in the offspring of male mice exposed to TCDD for 12 weeks prior to mating.<ref>{{cite journal |last1=Ishihara |first1=K |last2=Warita |first2=K |last3=Tanida |first3=T |last4=Sugawara |first4=T |last5=Kitagawa |first5=H |last6=Hoshi |first6=N |title=Does paternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affect the sex ratio of offspring? |journal=The Journal of veterinary medical science |date=April 2007 |volume=69 |issue=4 |pages=347-52 |doi=10.1292/jvms.69.347 |pmid=17485921}}</ref> However, maternal exposure did not affect the sex ratio of rat offspring.<ref>{{cite journal |last1=Bell |first1=DR |last2=Clode |first2=S |last3=Fan |first3=MQ |last4=Fernandes |first4=A |last5=Foster |first5=PM |last6=Jiang |first6=T |last7=Loizou |first7=G |last8=MacNicoll |first8=A |last9=Miller |first9=BG |last10=Rose |first10=M |last11=Tran |first11=L |last12=White |first12=S |title=Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the developing male Wistar(Han) rat. II: Chronic dosing causes developmental delay. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=September 2007 |volume=99 |issue=1 |pages=224-33 |doi=10.1093/toxsci/kfm141 |pmid=17545211}}</ref> The mechanism has been suggested to be reduced fertility of Y-bearing sperm.<ref name=Viluksela19/> === Multigenerational and transgenerational effects === Understanding possible effects on next generations is essential for risk assessment, because dioxin concentrations in the environment and human intake have decreased, but effects initiated several decades ago might still linger with us. This was illustrated by the Seveso studies (see above).<ref name=Mocarelli00/><ref name=Mocarelli11/> Epigenetically mediated multigenerational or transgenerational effects of TCDD have been found in rats and mice (reviewed by Viluksela and Pohjanvirta).<ref name=Viluksela19/> Some of them were paternally mediated or resulted in adult onset disease states. Toxic effects are considered transgenerational if neither the parent nor the offspring is directly exposed (i.e. F3 generation is the first generation without direct exposure). TCDD has been shown to cause typical epigenetic modifications (e.g. methylation, histone acetylation) in a number of studies.<ref name=Viluksela19/> When these occur in gametes they may affect the future generations. When pregnant rats were exposed to low doses of TCDD several endpoints of toxicity were found in F1-F3 (or F4) generations: primordial follicle loss, polycystic ovaries and early onset of puberty were observed in female F1 and F3 offspring, and histopathological alterations of testis and kidney abnormalities in male F1 and F3 offspring.<ref>{{cite journal |last1=Manikkam |first1=Mohan |last2=Tracey |first2=Rebecca |last3=Guerrero-Bosagna |first3=Carlos |last4=Skinner |first4=Michael K. |last5=Shioda |first5=Toshi |title=Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations |journal=PLoS ONE |date=26 September 2012 |volume=7 |issue=9 |pages=e46249 |doi=10.1371/journal.pone.0046249 |pmid=23049995}}</ref> These changes were associated with differentially methylated DNA regions in F3 generation sperm epigenome. Relatively high doses of TCDD (10 μg/kg) in female mice indicated robust transgenerational changes in pregnancy outcomes and progesterone receptor density. In the offspring of exposed mice reduced fertility, increased incidence of premature birth and increased uterine sensitivity to inflammation were found in F1-F4 generations.<ref>{{cite journal |last1=Bruner-Tran |first1=KL |last2=Osteen |first2=KG |title=Developmental exposure to TCDD reduces fertility and negatively affects pregnancy outcomes across multiple generations. |journal=Reproductive toxicology (Elmsford, N.Y.) |date=April 2011 |volume=31 |issue=3 |pages=344-50 |doi=10.1016/j.reprotox.2010.10.003 |pmid=20955784}}</ref><ref>{{cite journal |last1=Bruner-Tran |first1=KL |last2=Gnecco |first2=J |last3=Ding |first3=T |last4=Glore |first4=DR |last5=Pensabene |first5=V |last6=Osteen |first6=KG |title=Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: Translating lessons from murine models. |journal=Reproductive toxicology (Elmsford, N.Y.) |date=March 2017 |volume=68 |pages=59-71 |doi=10.1016/j.reprotox.2016.07.007 |pmid=27423904}}</ref> Interestingly, infertility and increased incidence of premature birth was also found in unexposed female mice mated with males exposed to TCDD in utero.<ref>{{cite journal |last1=Ding |first1=T |last2=McConaha |first2=M |last3=Boyd |first3=KL |last4=Osteen |first4=KG |last5=Bruner-Tran |first5=KL |title=Developmental dioxin exposure of either parent is associated with an increased risk of preterm birth in adult mice. |journal=Reproductive toxicology (Elmsford, N.Y.) |date=April 2011 |volume=31 |issue=3 |pages=351-8 |doi=10.1016/j.reprotox.2010.11.003 |pmid=21093581}}</ref> Premature birth was associated with reduced progesterone receptor expression and inflammation of placenta. In male mice infertility and increased premature births in unexposed mating partners that persisted to F2 and F3 generations were associated with testicular inflammation and apoptosis of developing spermatocytes.<ref>{{cite journal |last1=Bruner-Tran |first1=KL |last2=Ding |first2=T |last3=Yeoman |first3=KB |last4=Archibong |first4=A |last5=Arosh |first5=JA |last6=Osteen |first6=KG |title=Developmental exposure of mice to dioxin promotes transgenerational testicular inflammation and an increased risk of preterm birth in unexposed mating partners. |journal=PloS one |date=2014 |volume=9 |issue=8 |pages=e105084 |doi=10.1371/journal.pone.0105084 |pmid=25127480}}</ref> The role of paternal exposure was also studied in male rat offspring (F1) exposed in utero and lactationally to low doses of TCDD and mated with unexposed females to obtain the F2 generation and further the F3 generation.<ref>{{cite journal |last1=Sanabria |first1=M |last2=Cucielo |first2=MS |last3=Guerra |first3=MT |last4=Dos Santos Borges |first4=C |last5=Banzato |first5=TP |last6=Perobelli |first6=JE |last7=Leite |first7=GA |last8=Anselmo-Franci |first8=JA |last9=De Grava Kempinas |first9=W |title=Sperm quality and fertility in rats after prenatal exposure to low doses of TCDD: A three-generation study. |journal=Reproductive toxicology (Elmsford, N.Y.) |date=October 2016 |volume=65 |pages=29-38 |doi=10.1016/j.reprotox.2016.06.019 |pmid=27352640}}</ref> The proportion of implantations per corpus luteum was significantly decreased in all three generations. Thus both maternal and paternal changes can lead to effects in offspring. Small zebra fish have been extensively used to study the mechanisms of toxicity in fish in the laboratory, especially cardiovascular toxicity, craniofacial malformations, and reproductive toxicity (reviewed by King-Heiden ''et al''.).<ref name=KingHeiden12/> Apart from rats and mice, transgenerationally inherited dioxin-induced effects have also been studied in the zebrafish model.<ref>{{cite journal |last1=Baker |first1=TR |last2=King-Heiden |first2=TC |last3=Peterson |first3=RE |last4=Heideman |first4=W |title=Dioxin induction of transgenerational inheritance of disease in zebrafish. |journal=Molecular and cellular endocrinology |date=December 2014 |volume=398 |issue=1-2 |pages=36-41 |doi=10.1016/j.mce.2014.08.011 |pmid=25194296}}</ref><ref>{{cite journal |last1=Baker |first1=TR |last2=Peterson |first2=RE |last3=Heideman |first3=W |title=Using zebrafish as a model system for studying the transgenerational effects of dioxin. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=April 2014 |volume=138 |issue=2 |pages=403-11 |doi=10.1093/toxsci/kfu006 |pmid=24470537}}</ref><ref>{{cite journal |last1=Meyer |first1=DN |last2=Baker |first2=BB |last3=Baker |first3=TR |title=Ancestral TCDD Exposure Induces Multigenerational Histologic and Transcriptomic Alterations in Gonads of Male Zebrafish. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=1 August 2018 |volume=164 |issue=2 |pages=603-612 |doi=10.1093/toxsci/kfy115 |pmid=29788325}}</ref> In zebrafish, TCDD-induced transgenerational and partly paternally-mediated effects include reproductive dysfunction, reduced fertility, skeletal malformations and lowered male/female sex ratio. These effects seem to be phenotypically very similar across these vertebrate classes. === Cancer in laboratory animals === Dioxins are clear multisite carcinogens in animal studies, but are not genotoxic as indicated both by mutagenicity assays and tumour promotion studies. Also the ability of TCDD to inhibit apoptosis and enhance proliferation supports a nongenotoxic mechanism of carcinogenicity. Much of the cancer risk assessment has been based on an early rat study,<ref>{{cite journal |last1=Kociba |first1=RJ |last2=Keyes |first2=DG |last3=Beyer |first3=JE |last4=Carreon |first4=RM |last5=Wade |first5=CE |last6=Dittenber |first6=DA |last7=Kalnins |first7=RP |last8=Frauson |first8=LE |last9=Park |first9=CN |last10=Barnard |first10=SD |last11=Hummel |first11=RA |last12=Humiston |first12=CG |title=Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. |journal=Toxicology and applied pharmacology |date=November 1978 |volume=46 |issue=2 |pages=279-303 |doi=10.1016/0041-008x(78)90075-3 |pmid=734660}}</ref> demonstrating liver tumours in female rats at low doses (10 ng/kg/day TCDD for 2 years). Other studies have confirmed multisite carcinogenicity in several species, but the doses have usually been higher. Toxic hepatitis has also been found in animals with tumours. Nongenotoxic or promoting mechanisms are favoured, especially inhibition of apoptosis of cancer precursor cells.<ref>{{cite journal |last1=Dragan |first1=YP |last2=Schrenk |first2=D |title=Animal studies addressing the carcinogenicity of TCDD (or related compounds) with an emphasis on tumour promotion. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=289-302 |doi=10.1080/026520300283360 |pmid=10912243}}</ref><ref name=Schrenk12>{{cite book |last1=Schrenk |first1=D |last2=Chopra |first2=M |editor1-last=Pohjanvirta |editor1-first=R |title=The AH receptor in biology and toxicology |publisher=Wiley |isbn=9780470601822 |chapter=Dioxin activated AHR and cancer in laboratory animals}}</ref> When differently sensitive Long-Evans (Turku/AB) (L-E) and H/W (Kuopio) rat substrains were compared in a 3-month tumour promotion study, there was a difference in effective dose of almost two orders of magnitude, and in both strains tumour promotion was associated with signs of liver toxicity.<ref name=Viluksela00/> Such findings suggest that carcinogenicity may be secondary to organ toxicity. It has been speculated that induction of oxidative enzymes such as CYP1A1 would produce excessive reactive carcinogenic intermediates, and dioxins would thus indirectly increase cancer risk. Oxidation combined with subsequent conjugating reactions is, however, essentially a protective mechanism, and conjugation enzymes are induced simultaneously.<ref>{{Cite journal|last=Nebert|first=Daniel W.|last2=Dalton|first2=Timothy P.|last3=Okey|first3=Allan B.|last4=Gonzalez|first4=Frank J.|date=2004-03-17|title=Role of Aryl Hydrocarbon Receptor-mediated Induction of the CYP1 Enzymes in Environmental Toxicity and Cancer|url=http://dx.doi.org/10.1074/jbc.r400004200|journal=Journal of Biological Chemistry|volume=279|issue=23|pages=23847–23850|doi=10.1074/jbc.r400004200|issn=0021-9258}}</ref> Thus, while plausible, this mechanism would require disproportionate induction of oxidation over conjugation and be likely only at relatively high doses. In tumour promotion studies with two rat strains enzyme induction did not correlate with tumour promoting activity.<ref name=Viluksela00/> == Interactions of dioxins with microbes and the immune system == Microbiomes related to the gut, skin and respiratory tract are in frontline of encountering xenobiotics. The microbiome of our intestinal system metabolizes many chemicals in our food, and on the other hand the chemicals may influence the microbes. There are complex interrelationships between chemicals, microbes and our immune systems. The host and microbiome together can even be seen as a “superorganism”.<ref>{{cite journal |last1=Dietert |first1=RR |last2=Silbergeld |first2=EK |title=Biomarkers for the 21st century: listening to the microbiome. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=April 2015 |volume=144 |issue=2 |pages=208-16 |doi=10.1093/toxsci/kfv013 |pmid=25795652}}</ref> AH receptors and therefore dioxins are deeply involved in these interactions. Active research has started to meet the challenge of understanding these phenomena during the last few years, but obviously only the tip of the iceberg has been revealed as yet, and there is limited information about specific microorganisms, enzymes and genes involved.<ref name=Atashgani18/> The simplest part of these interactions is the effects of the microbiome on chemicals. Intestinal microbes can metabolize xenobiotics before they are absorbed into the body. This may increase or decrease physicochemical properties and toxicity. As to dioxins, not much is known; dehalogenation is possible,<ref name=Atashgani18/> but obviously not very effective. On the other hand, several bacteria are able to metabolize polycyclic aromatic hydrocarbons also binding to AH receptors such as benzo''(a)''pyrene to carcinogenic metabolites prior to absorption.<ref>{{cite journal |last1=Sowada |first1=J |last2=Schmalenberger |first2=A |last3=Ebner |first3=I |last4=Luch |first4=A |last5=Tralau |first5=T |title=Degradation of benzo[a]pyrene by bacterial isolates from human skin. |journal=FEMS microbiology ecology |date=April 2014 |volume=88 |issue=1 |pages=129-39 |doi=10.1111/1574-6941.12276 |pmid=24372170}}</ref> As to the effect of dioxins on microbes, relatively high doses have been shown to cause remarkable changes in the overall population, and e.g. somewhat ambiguous changes in the ''Firmicutes'' vs. ''Bacteroides'' ratio in mice and increases in ''Lactobacillaceae'' and ''Desulfovibrionaceae'' have been noticed.<ref>{{cite journal |last1=Zhang |first1=L |last2=Nichols |first2=RG |last3=Correll |first3=J |last4=Murray |first4=IA |last5=Tanaka |first5=N |last6=Smith |first6=PB |last7=Hubbard |first7=TD |last8=Sebastian |first8=A |last9=Albert |first9=I |last10=Hatzakis |first10=E |last11=Gonzalez |first11=FJ |last12=Perdew |first12=GH |last13=Patterson |first13=AD |title=Persistent Organic Pollutants Modify Gut Microbiota-Host Metabolic Homeostasis in Mice Through Aryl Hydrocarbon Receptor Activation. |journal=Environmental health perspectives |date=July 2015 |volume=123 |issue=7 |pages=679-88 |doi=10.1289/ehp.1409055 |pmid=25768209}}</ref><ref>{{cite journal |last1=Lefever |first1=DE |last2=Xu |first2=J |last3=Chen |first3=Y |last4=Huang |first4=G |last5=Tamas |first5=N |last6=Guo |first6=TL |title=TCDD modulation of gut microbiome correlated with liver and immune toxicity in streptozotocin (STZ)-induced hyperglycemic mice. |journal=Toxicology and applied pharmacology |date=1 August 2016 |volume=304 |pages=48-58 |doi=10.1016/j.taap.2016.05.016 |pmid=27221631}}</ref> These changes might be in part involved in the toxic effects, e.g. liver toxicity. AH receptors seem to sense microbial toxins and stimulate their neutralization by enzyme induction as well as regulating cytokine and chemokine production and leukocyte activation.<ref name=MouraAlves14>{{cite journal |last1=Moura-Alves |first1=P |last2=Faé |first2=K |last3=Houthuys |first3=E |last4=Dorhoi |first4=A |last5=Kreuchwig |first5=A |last6=Furkert |first6=J |last7=Barison |first7=N |last8=Diehl |first8=A |last9=Munder |first9=A |last10=Constant |first10=P |last11=Skrahina |first11=T |last12=Guhlich-Bornhof |first12=U |last13=Klemm |first13=M |last14=Koehler |first14=AB |last15=Bandermann |first15=S |last16=Goosmann |first16=C |last17=Mollenkopf |first17=HJ |last18=Hurwitz |first18=R |last19=Brinkmann |first19=V |last20=Fillatreau |first20=S |last21=Daffe |first21=M |last22=Tümmler |first22=B |last23=Kolbe |first23=M |last24=Oschkinat |first24=H |last25=Krause |first25=G |last26=Kaufmann |first26=SH |title=AhR sensing of bacterial pigments regulates antibacterial defence. |journal=Nature |date=28 August 2014 |volume=512 |issue=7515 |pages=387-92 |doi=10.1038/nature13684 |pmid=25119038}}</ref> An interesting field in these interactions is the highly complex influence of chemicals via the AH receptors on the immune systems.<ref>{{cite journal |last1=Hao |first1=N |last2=Whitelaw |first2=ML |title=The emerging roles of AhR in physiology and immunity. |journal=Biochemical pharmacology |date=1 September 2013 |volume=86 |issue=5 |pages=561-70 |doi=10.1016/j.bcp.2013.07.004 |pmid=23856287}}</ref><ref name=Boule18/><ref name=Rothhammer19/> This is mostly outside the scope of this review, and only dealt with briefly. Interested readers are encouraged to read the thorough recent review of Rothhammer and Quintana.<ref name=Rothhammer19/> AHR activation seems to be crucial in maintaining intraepithelial lymphocytes in the intestines and skin as a first line of defence against microorganisms.<ref>{{cite journal |last1=Li |first1=Y |last2=Innocentin |first2=S |last3=Withers |first3=DR |last4=Roberts |first4=NA |last5=Gallagher |first5=AR |last6=Grigorieva |first6=EF |last7=Wilhelm |first7=C |last8=Veldhoen |first8=M |title=Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. |journal=Cell |date=28 October 2011 |volume=147 |issue=3 |pages=629-40 |doi=10.1016/j.cell.2011.09.025 |pmid=21999944}}</ref> By using several genetically modified mouse models it was shown that high constitutive activity of CYP1A1 depletes natural AHR ligands in the gut and this leads to similar deficiencies in immune defence mechanisms and increased susceptibility to infections as seen in AHR knockout animals. Interestingly this deficiency can be counteracted by increased supply of natural AHR ligands such as 6-formylindolo[3,2-b]carbazole (FICZ) many of which are present e.g. in vegetables.<ref name=Schiering17/> This implies that CYP enzymes act as feedback controls metabolizing more or less of the AHR ligand supply to keep the receptor activity at an optimal level. In fact AHR activity in intestinal epithelial cells, intraepithelial lymphocytes and innate lymphoid cells seems important for tissue homeostasis at the structural and functional level.<ref name=Rothhammer19/> Respiratory system is the other important pathway for environmental noxious agents to the body, especially viral infections, and the AHR seems to be intrinsically involved in defence mechanisms.<ref name=Boule18/><ref>{{cite journal |last1=Guerrina |first1=N |last2=Traboulsi |first2=H |last3=Eidelman |first3=DH |last4=Baglole |first4=CJ |title=The Aryl Hydrocarbon Receptor and the Maintenance of Lung Health. |journal=International journal of molecular sciences |date=5 December 2018 |volume=19 |issue=12 |doi=10.3390/ijms19123882 |pmid=30563036}}</ref> An interesting indole derivative is malassezin produced by pathogenic skin yeast ''Malassezia furfur''.<ref>{{cite journal |last1=Wille |first1=G |last2=Mayser |first2=P |last3=Thoma |first3=W |last4=Monsees |first4=T |last5=Baumgart |first5=A |last6=Schmitz |first6=HJ |last7=Schrenk |first7=D |last8=Polborn |first8=K |last9=Steglich |first9=W |title=Malassezin--A novel agonist of the arylhydrocarbon receptor from the yeast Malassezia furfur. |journal=Bioorganic & medicinal chemistry |date=April 2001 |volume=9 |issue=4 |pages=955-60 |pmid=11354679|doi=10.1016/S0968-0896(00)00319-9}}</ref> The question has been how AHR can mediate protective effects in some contexts and toxicity in others. This is partially an open question, but it may simply include the impact of time and dose. FICZ and other similar ligands are metabolized rapidly, and so their concentrations will never increase very high and persistent. Therefore their toxicity is not apparent. Microglia are specialized macrophages in the central nervous system, and as such important for immune surveillance, debris removal and defence against microorganisms as well as for the development of immune functions and synapse maturation.<ref name=Rothhammer19/> AHR expression is upregulated in the CNS traumatic or autoimmune injury, and may control the inflammatory activities. Here AHR ligands produced by microbes may be important and deficits of AHR agonists have been reported in multiple conditions.<ref name=Rothhammer19/> Thus there may be option of therapeutic development of AHR ligands in autoimmune, neoplastic and degenerative diseases. Although the AHR signalling may be fundamental in neuronal development, overactivation seems harmful.<ref>{{cite journal |last1=Kobayashi |first1=Y |last2=Hirano |first2=T |last3=Omotehara |first3=T |last4=Hashimoto |first4=R |last5=Umemura |first5=Y |last6=Yuasa |first6=H |last7=Masuda |first7=N |last8=Kubota |first8=N |last9=Minami |first9=K |last10=Yanai |first10=S |last11=Ishihara-Sugano |first11=M |last12=Mantani |first12=Y |last13=Yokoyama |first13=T |last14=Kitagawa |first14=H |last15=Hoshi |first15=N |title=Immunohistochemical analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity on the developmental dentate gyrus and hippocampal fimbria in fetal mice. |journal=The Journal of veterinary medical science |date=November 2015 |volume=77 |issue=11 |pages=1355-61 |doi=10.1292/jvms.15-0238 |pmid=26096965}}</ref><ref>{{cite journal |last1=Kimura |first1=E |last2=Kubo |first2=KI |last3=Endo |first3=T |last4=Ling |first4=W |last5=Nakajima |first5=K |last6=Kakeyama |first6=M |last7=Tohyama |first7=C |title=Impaired dendritic growth and positioning of cortical pyramidal neurons by activation of aryl hydrocarbon receptor signaling in the developing mouse. |journal=PloS one |date=2017 |volume=12 |issue=8 |pages=e0183497 |doi=10.1371/journal.pone.0183497 |pmid=28820910}}</ref> Thus the current understanding is limited and active research is needed. == Conclusions == Dioxins are a group of related persistent, bioaccumulating environmental poisons that act via the AH receptor, an intracellular receptor which also serves to regulate multiple physiological functions. Hence a certain level of AH receptor activity is important in normal biology, but inappropriate activation leads to a number of deleterious effects. The most sensitive adverse effects of dioxins are developmental consequences in different structures, from teeth and bones to sexual organs. This concerns specifically women in child-bearing age, because a child is exposed prenatally during pregnancy as well as postnatally via breast milk. The exposure is higher than in other population groups. The safety margins between the current environmental exposure levels and the levels required for sensitive adverse effects are presently about an order of magnitude, but the safe level was probably exceeded in the 1970s and 1980s. Transgenerational effects of these historical high exposures (causing milk dioxin levels of 50 to 100 pg TEQ per g fat, tenfold to contemporary levels) are of concern, but are so far poorly known. Carcinogenicity has caused confusion, because it probably occurs at high industrial or accidental exposure levels, but dioxins are not genotoxic, and there is neither good evidence nor logical reason to assume that dioxins would cause cancer at levels below those causing developmental effects. It is essential to understand dioxins as one risk factor among others rather than as a sole causative agent. This means that dose-responses should be appreciated in regulations as with any other chemical, and benefit-risk aspects should be carefully taken into account. Otherwise unwise remedy may turn out to be worse than the disease. It is risk management and political issue to decide how large safety margins are necessary. In conclusion, strict environmental controls of dioxin emissions are still important and they should be the first priority. Limitations of important food items are problematic, and it is important to avoid measures that would increase competing risks. This danger is obvious when overregulating the levels in food. The benefits of e.g. breast feeding are estimated clearly greater than possible risks of contaminants, and the nutritional benefits of fish consumption also outweigh toxic effects, if any. == Additional information == === Acknowledgements === I appreciate the comments of several colleagues screening through the manuscript: Prof. Allan B. Okey, Toronto, Prof. Dieter Schrenk, Kaiserslautern, Prof. Robert Barouki, Paris, Prof. Xavier Coumoul, Paris, Prof. Raimo Pohjanvirta, Helsinki, Prof. Matti Viluksela, Kuopio, Dr. Jouni T. Tuomisto, Kuopio, and Dr. Hanna Miettinen, Kuopio. I also want to thank expert rewiewers Prof. Helmut Greim, Munich, Dr. Martin Rose, Manchester, and Prof. Helen Håkansson, Stockholm, for their constructive comments. === Competing interests === It is acknowledged that after writing a textbook chapter on the same topic, it was not possible to avoid some repetition of both style and details (Tuomisto and Viluksela).<ref>{{Cite book|url=https://www.worldcat.org/oclc/1085638074|last1=Tuomisto|first1=J|last2=Viluksela |first2=M|editor-last=D’Mello|editor-first=J. P. F.|chapter=Dioxins II. human exposure and health risks|title=A handbook of environmental toxicology : human disorders and ecotoxicology|isbn=978-1-78639-467-5|location=Wallingford, Oxfordshire, UK|oclc=1085638074}}</ref> Otherwise there are no conflicts of interests. There was no funding for writing this article. == References == {{reflist|35em}} g5sfv9lmz3bz6u001hyldga6wjez25n 2408051 2408050 2022-07-19T22:23:56Z Bobamnertiopsis 24451 tidy ref wikitext text/x-wiki {{Article info | first1 = Jouko | last1 = Tuomisto | orcid1 = 0000-0003-1710-0377 | affiliation1 = National Institute for Health and Welfare, Kuopio, Finland | correspondence1 = j.tuomisto@dnainternet.net | journal = WikiJournal of Medicine | keywords = dioxins; TCDD; polychlorinated dibenzo-p-dioxins; AH receptor; developmental toxicity; cancer | submitted = 2019-08-05 | accepted = 2019-12-12 | doi = 10.15347/wjm/2019.008 | abstract = '''Dioxins and dioxin-like compounds''' comprise a group of chemicals including polychlorinated dibenzo''-p-''dioxins (PCDD) and polychlorinated dibenzofurans (PCDF), as well as certain dioxin-like polychlorinated biphenyls (dl-PCB), and potentially others. They act via a common mechanism, stimulation of aryl hydrocarbon receptor (AH receptor, AHR), a vital transcription factor in cells. There are very high differences in potency among these compounds, i.e. in the ability to stimulate the receptor. This leads to ten thousand fold or higher differences in doses causing similar toxic effects. Most of these compounds are eliminated very slowly in the environment, animals, or humans, which makes them persistent. They are much more soluble in fat than in water, and therefore they tend to accumulate in lipid or fatty tissues, and concentrate along the food web (bioaccumulation and biomagnification). PCDD/PCDFs are formed mostly as side products in burning processes, but PCBs were oils manufactured for many purposes. Because of toxicity and persistence, dioxin-like compounds have been regulated strictly since 1980s, and their levels in the environment and animals have decreased by an order of magnitude or more. Therefore the effects on wildlife have clearly decreased, and even populations at the top of the food web such as fish-eating birds or seals have recovered after serious effects on their reproductive capacity and developmental effects in their young especially in 1970s and 1980s. This does not exclude the possibility of some remaining effects. In humans the intake is mostly from food of animal sources, but because our diet is much more diverse than that of such hallmark animals as white-tailed eagles or seals, the concentrations never increased to similar levels. However, during 1970s and 1980s effects were probably also seen in humans, including developmental effects in teeth, sexual organs, and the development of immune systems. Both scientists and administrative bodies debate at the moment about the importance of remaining risks. This is very important, because the AH receptors seem to be physiologically important regulators of growth and development of organs, immunological development, food intake and hunger, and in addition regulate enzymes protecting us from many chemicals. Thus a certain level of activation is needed, although inappropriate stimulation of the receptor is harmful. This dualism emphasizes the importance of benefit versus risk analysis. As a whole, regulating the emissions to the environment is still highly important, but one should be very cautious in limiting consumption of important and otherwise healthy food items and e.g. breast feeding. Distinct toxic effects of high doses of dioxins in humans have been clearly demonstrated by frank poisonings and the highest occupational exposures. Hallmark effects have been skin lesions called chloracne, various developmental effects of children, and a slightly increased risk of total cancer rate. The highest dioxin levels have been ten thousand fold higher than those seen in the general population today. |note= '''Note:''' This review is based on original studies and scientific reviews, independently of existing Wikipedia articles, and as interpreted by author's 35 year experience in dioxin research. However, pieces of similar information can be found in Wikipedia articles [[w:Dioxins and dioxin-like compounds|Dioxins and dioxin-like compounds]], [[w:2,3,7,8-Tetrachlorodibenzodioxin|2,3,7,8-tetrachlorodibenzodioxin]], [[w:Polychlorinated dibenzodioxins|Polychlorinated dibenzodioxins]], [[w:Polychlorinated dibenzofurans|Polychlorinated dibenzofurans]], [[w:Polychlorinated biphenyl|Polychlorinated biphenyl]], and [[w:Persistent organic pollutant|Persistent organic pollutant]]. }} == General introduction == “Dioxins” is an imprecise term including structurally related groups of chemicals such as polychlorinated dibenzo-''p''-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). Certain polychlorinated biphenyls (dl-PCBs) and many other chemicals<ref name=Poland82>{{cite journal |last1=Poland |first1=A |last2=Knutson |first2=JC |title=2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. |journal=Annual review of pharmacology and toxicology |date=1982 |volume=22 |pages=517-54 |doi=10.1146/annurev.pa.22.040182.002505 |pmid=6282188}}</ref><ref name=Pohjanvirta94>{{cite journal |last1=Pohjanvirta |first1=R |last2=Tuomisto |first2=J |title=Short-term toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in laboratory animals: effects, mechanisms, and animal models. |journal=Pharmacological reviews |date=December 1994 |volume=46 |issue=4 |pages=483-549 |pmid=7899475}}</ref><ref name=Denison03>{{cite journal |last1=Denison |first1=MS |last2=Nagy |first2=SR |title=Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. |journal=Annual review of pharmacology and toxicology |date=2003 |volume=43 |pages=309-34 |doi=10.1146/annurev.pharmtox.43.100901.135828 |pmid=12540743}}</ref><ref name=TuomistoSynopsis>{{Cite report|last=Tuomisto|first=Jouko|last2=Vartiainen|first2=Terttu|last3=Tuomisto|first3=Jouni T.|date=2011|title=Synopsis on dioxins and PCBs|url=https://www.julkari.fi/bitstream/handle/10024/80313/81322e2c-e9b6-4003-bb13-995dcd1b68cb.pdf?sequence=1&isAllowed=y|issn=1798-0089|publisher=National Institute for Health and Welfare|language=en}}</ref> have dioxin-like properties. The term “dioxin-like” is used because these chemicals have a common mechanism of action, i.e. inappropriate stimulation of aryl hydrocarbon receptor (AH receptor, AHR, “dioxin receptor”).<ref name=Poland82/><ref name=Pohjanvirta94/><ref>{{cite journal |last1=Denison |first1=MS |last2=Faber |first2=SC |title=And Now for Something Completely Different: Diversity in Ligand-Dependent Activation of Ah Receptor Responses. |journal=Current opinion in toxicology |date=February 2017 |volume=2 |pages=124-131 |doi=10.1016/j.cotox.2017.01.006 |pmid=28845473}}</ref><ref name=Rothhammer19>{{cite journal |last1=Rothhammer |first1=V |last2=Quintana |first2=FJ |title=The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. |journal=Nature reviews. Immunology |date=March 2019 |volume=19 |issue=3 |pages=184-197 |doi=10.1038/s41577-019-0125-8 |pmid=30718831}}</ref> Among compounds binding to the AH receptor, the higher the binding affinity, the higher will be the toxicity. High toxicity means that even low doses or low exposure levels are sufficient to produce toxic responses. Compounds with lower affinity for the AH receptor require higher doses to elicit similar toxic effects. Low-affinity compounds (e.g. some PCBs, usually at relatively high doses) can elicit toxic effects that are different from those of characteristic dioxin-like effects of chemicals such as 2,3,7,8-tetrachlorodibenzo-''p''-dioxin (TCDD). Dioxins are a puzzling group of chemicals that have widely diverse effects in different cell-types, tissues and animal species. Many lay people consider them only dreaded environmental “superpoisons”. But they are also highly interesting tools for studying the mechanisms of intracellular receptors, gene expression, growth and development of organs, metabolism of chemicals in the body, carcinogenesis, food intake and hunger, as well as interactions of chemicals, microbes and immunological systems. The AH receptor, the mediator of dioxin toxicity seems to be an important physiological actor in the body, a ligand-activated transcription factor functionally similar but structurally unrelated to intracellular receptors such as steroid or thyroid receptors. This reminds us of the ultimate principle of Paracelsus: all things are poisons, only the dose makes that a thing is not a poison. AH receptors are necessary for many normal biological functions,<ref>{{Cite journal|last=Barouki|first=Robert|last2=Coumoul|first2=Xavier|last3=Fernandez-Salguero|first3=Pedro M.|date=2007-03-30|title=The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein|url=http://dx.doi.org/10.1016/j.febslet.2007.03.046|journal=FEBS Letters|volume=581|issue=19|pages=3608–3615|doi=10.1016/j.febslet.2007.03.046|issn=0014-5793}}</ref><ref name=Rothhammer19/> and their physiological activation regulates our wellbeing, but their inappropriate activation leads to multiple forms of toxicity. The best studied compound is the most toxic 2,3,7,8-tetrachlorodibenzo''-p-''dioxin (TCDD). The toxicity of other compounds is compared with this prototype. TCDD is assigned a toxicity equivalence factor (TEF) of 1. The potency and toxicokinetics of other compounds vary over orders of magnitude, and therefore each compound is assigned its own TEF that may range from 1 to 0.000 03 (or lower for fish, see below). The TEF for each compound forms the basis for defining toxic equivalency (TEQ) when assessing the toxicity of mixtures. The metabolism and excretion of dioxins in mammals is generally very slow. Dioxins are also persistent and accumulate in the biosphere. Due to slow accumulation to animals and humans, delayed toxicity is the typical mode of harmful effects and the delay between exposure and effect complicates the assessment of risk from dioxins. Developmental adverse effects are seen at the lowest doses. A few dramatic cases of accidental or deliberate acute poisoning are known. Two women were poisoned in Vienna, Austria, in 1998 by large doses of TCDD. In 2004 Victor Yushchenko, then presidential candidate of Ukraine, was deliberately poisoned with a huge dose of TCDD. A widely known dioxin accident took place in Seveso, Italy in 1976. These and similar high-dose incidents have delineated the acute effects on humans. As described in detail later in this article it is more difficult to ascertain, precisely, what are the human health effects of chronic low-dose exposures to dioxin-like compounds. This remains a contentious issue of importance to regulatory agencies as well as to the general public. For a short account of historical legacies of dioxins see Weber et al.<ref name=Weber08>{{cite journal |last1=Weber |first1=R |last2=Tysklind |first2=M |last3=Gaus |first3=C |title=Dioxin--contemporary and future challenges of historical legacies. Dedicated to Prof. Dr. Otto Hutzinger, the founder of the DIOXIN Conference Series. |journal=Environmental science and pollution research international |date=March 2008 |volume=15 |issue=2 |pages=96-100 |pmid=18380226|doi=10.1065/espr2008.01.473}}</ref> Due to intensive research efforts dioxin toxicity is known and understood better than that of most environmental toxic agents. On the other hand, it is beguilingly complicated. == Chemistry == There are 75 possible congeners of polychlorinated dibenzo-''p-''dioxins (PCDD) and 135 possible congeners of polychlorinated dibenzofurans (PCDF). So-called lateral chlorine substitutions at the positions 2,3,7, and 8 (Fig. 1) allow the dioxins to bind to the AH receptor with high affinity. They also prevent enzymatic attacks on the molecule causing persistence both in human body and in the environment. Such compounds are particularly toxic and constitute the prototype for dioxin-like toxicity. TEF values have been assigned to 17 congeners (seven dibenzo''-p-''dioxins and ten dibenzofurans) having four to eight chlorine substitutions. Chlorines in excess of the four (2,3,7 and 8) decrease the potency, but the type of toxic effects remains mainly the same.<ref name=Berg06>{{cite journal |last1=Van den Berg |first1=M |last2=Birnbaum |first2=LS |last3=Denison |first3=M |last4=De Vito |first4=M |last5=Farland |first5=W |last6=Feeley |first6=M |last7=Fiedler |first7=H |last8=Hakansson |first8=H |last9=Hanberg |first9=A |last10=Haws |first10=L |last11=Rose |first11=M |last12=Safe |first12=S |last13=Schrenk |first13=D |last14=Tohyama |first14=C |last15=Tritscher |first15=A |last16=Tuomisto |first16=J |last17=Tysklind |first17=M |last18=Walker |first18=N |last19=Peterson |first19=RE |title=The 2005 World Health Organization reevaluation of human and Mammalian toxic equivalency factors for dioxins and dioxin-like compounds. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=October 2006 |volume=93 |issue=2 |pages=223-41 |doi=10.1093/toxsci/kfl055 |pmid=16829543}}</ref> {{Fig | number = 1 | width = 400px | image = Structures of dibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,3,4,7,8-pentachlorodibenzofurane.jpg | caption = Structures of dibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,3,4,7,8-pentachlorodibenzofurane | attribution = }} There are 209 PCB-compounds. Four non-ortho compounds that have no chlorine substitution in any o-position to the inter-ring C-C-bridge (2, 2’, 6 or 6’) have the greatest dioxin-like potency (Fig. 2). The toxicity of 3,3’,4,4’,5-penta-CB (PCB126) is comparable to those dioxins assigned the TEF value<ref name=Berg06/> although high toxicity in humans has been challenged.<ref name=Larsson15>{{cite journal |last1=Larsson |first1=M |last2=van den Berg |first2=M |last3=Brenerová |first3=P |last4=van Duursen |first4=MB |last5=van Ede |first5=KI |last6=Lohr |first6=C |last7=Luecke-Johansson |first7=S |last8=Machala |first8=M |last9=Neser |first9=S |last10=Pěnčíková |first10=K |last11=Poellinger |first11=L |last12=Schrenk |first12=D |last13=Strapáčová |first13=S |last14=Vondráček |first14=J |last15=Andersson |first15=PL |title=Consensus toxicity factors for polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls combining in silico models and extensive in vitro screening of AhR-mediated effects in human and rodent cells. |journal=Chemical research in toxicology |date=20 April 2015 |volume=28 |issue=4 |pages=641-50 |doi=10.1021/tx500434j |pmid=25654323}}</ref> Eight mono-ortho PCBs have very low activity. All other PCBs are devoid of noticeable dioxin-like effects. Only compounds that are able to assume a planar (flat) conformation can bind to the AH receptor. Non-ortho compounds rotate relatively freely along the C-C-bridge between the rings, but each o-chlorine causes a steric hindrance and makes it more difficult for the molecule to assume a planar conformation (Fig. 2). {{Fig | number = 2 | image = Structures of biphenyl and 3,3’,4,4’,5-pentachlorobiphenyl.jpg | caption = Structures of biphenyl and 3,3’,4,4’,5-pentachlorobiphenyl (PCB 126) }} Brominated dioxins, furans and biphenyls, as well as mixed halogenated congeners, may share the toxicity and the ability to bind to AH receptor. They probably deserve TEF values as well, but lack sufficient data.<ref name=Berg13>{{cite journal |last1=van den Berg |first1=M |last2=Denison |first2=MS |last3=Birnbaum |first3=LS |last4=Devito |first4=MJ |last5=Fiedler |first5=H |last6=Falandysz |first6=J |last7=Rose |first7=M |last8=Schrenk |first8=D |last9=Safe |first9=S |last10=Tohyama |first10=C |last11=Tritscher |first11=A |last12=Tysklind |first12=M |last13=Peterson |first13=RE |title=Polybrominated dibenzo-p-dioxins, dibenzofurans, and biphenyls: inclusion in the toxicity equivalency factor concept for dioxin-like compounds. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=June 2013 |volume=133 |issue=2 |pages=197-208 |doi=10.1093/toxsci/kft070 |pmid=23492812}}</ref> Many other compounds bind to the AH receptor, e.g. polyaromatic hydrocarbons and polychlorinated azoxy-benzenes and naphthalenes.<ref name=Poland82/> Surprisingly, many natural compounds have very high affinity to AH receptors. These include e.g. indoles, flavones, benzoflavones, imidazoles and pyridines (for review, see Denison and Nagy<ref name=Denison03/>; DeGroot et al.<ref>{{cite book |last1=DeGroot |first1=Danica |last2=He |first2=Guochun |last3=Fraccalvieri |first3=Domenico |last4=Bonati |first4=Laura |last5=Pandini |first5=Allesandro |last6=Denison |first6=Michael S. |title=The AH Receptor in Biology and Toxicology |date=2011 |publisher=John Wiley & Sons, Ltd |isbn=9781118140574 |pages=63–79 |url=https://onlinelibrary.wiley.com/doi/10.1002/9781118140574.ch4 |language=en |chapter=AHR Ligands: Promiscuity in Binding and Diversity in Response|doi=10.1002/9781118140574.ch4}}</ref>). They are usually metabolized rapidly, but due to continuous intake from food, especially vegetables, they may cause receptor activation at the same level as or higher than the present background concentrations of contaminant dioxins.<ref>{{cite journal |last1=Connor |first1=KT |last2=Harris |first2=MA |last3=Edwards |first3=MR |last4=Budinsky |first4=RA |last5=Clark |first5=GC |last6=Chu |first6=AC |last7=Finley |first7=BL |last8=Rowlands |first8=JC |title=AH receptor agonist activity in human blood measured with a cell-based bioassay: evidence for naturally occurring AH receptor ligands in vivo. |journal=Journal of exposure science & environmental epidemiology |date=July 2008 |volume=18 |issue=4 |pages=369-80 |doi=10.1038/sj.jes.7500607 |pmid=17912254}}</ref> Short-acting stimulations of the receptor may, however, be qualitatively different from the persistent stimulation of dioxins.<ref>{{Cite journal|last=Gouedard|first=C.|last2=Barouki|first2=R.|last3=Morel|first3=Y.|date=2004-05-28|title=Dietary Polyphenols Increase Paraoxonase 1 Gene Expression by an Aryl Hydrocarbon Receptor-Dependent Mechanism|url=http://dx.doi.org/10.1128/mcb.24.12.5209-5222.2004|journal=Molecular and Cellular Biology|volume=24|issue=12|pages=5209–5222|doi=10.1128/mcb.24.12.5209-5222.2004|issn=0270-7306}}</ref><ref>{{Cite journal|last=Mahiout|first=Selma|last2=Lindén|first2=Jere|last3=Esteban|first3=Javier|last4=Sánchez-Pérez|first4=Ismael|last5=Sankari|first5=Satu|last6=Pettersson|first6=Lars|last7=Håkansson|first7=Helen|last8=Pohjanvirta|first8=Raimo|date=2017-07|title=Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats|url=http://dx.doi.org/10.1016/j.taap.2017.04.020|journal=Toxicology and Applied Pharmacology|volume=326|pages=54–65|doi=10.1016/j.taap.2017.04.020|issn=0041-008X}}</ref> Intriguingly many of these vegetables are considered very healthy. == Sources == Sources of different dioxin-like chemicals are different depending upon the chemical class. PCDD/F compounds are unwanted side products in burning processes or are impurities in the synthesis of PCBs, chlorophenol fungicides and phenoxy acid herbicides.<ref name=Kanan>{{cite journal |last1=Kanan |first1=Sofian |last2=Samara |first2=Fatin |title=Dioxins and furans: A review from chemical and environmental perspectives |journal=Trends in Environmental Analytical Chemistry |date=January 2018 |volume=17 |pages=1–13 |doi=10.1016/j.teac.2017.12.001}}</ref> Due to control measures, main sources are very different today than they were 30 or 40 years ago. The decrease in environmental levels was clearly demonstrated in sea bottom sediment core studies: the peak concentrations are in sediments layered in about 1980s.<ref name=Assefa>{{Cite journal|last=Assefa|first=Anteneh T.|last2=Sobek|first2=Anna|last3=Sundqvist|first3=Kristina L.|last4=Cato|first4=Ingemar|last5=Jonsson|first5=Per|last6=Tysklind|first6=Mats|last7=Wiberg|first7=Karin|date=2013-12-24|title=Temporal Trends of PCDD/Fs in Baltic Sea Sediment Cores Covering the 20th Century|url=http://dx.doi.org/10.1021/es404599z|journal=Environmental Science & Technology|volume=48|issue=2|pages=947–953|doi=10.1021/es404599z|issn=0013-936X}}</ref><ref>{{cite journal |last1=Sobek |first1=A |last2=Sundqvist |first2=KL |last3=Assefa |first3=AT |last4=Wiberg |first4=K |title=Baltic Sea sediment records: unlikely near-future declines in PCBs and HCB. |journal=The Science of the total environment |date=15 June 2015 |volume=518-519 |pages=8-15 |doi=10.1016/j.scitotenv.2015.02.093 |pmid=25747358}}</ref> However, further reduction especially of air emissions is needed.<ref name=Assefa/> Any burning will produce PCDD/Fs if chlorine (particularly along with metal catalysts) is available, even burning wood<ref>{{Cite journal|last=Northcross|first=Amanda L.|last2=Katharine Hammond|first2=S.|last3=Canuz|first3=Eduardo|last4=Smith|first4=Kirk R.|date=2012-03|title=Dioxin inhalation doses from wood combustion in indoor cookfires|url=http://dx.doi.org/10.1016/j.atmosenv.2011.11.054|journal=Atmospheric Environment|volume=49|pages=415–418|doi=10.1016/j.atmosenv.2011.11.054|issn=1352-2310}}</ref> and burning incense.<ref>{{Cite journal|last=Hu|first=Ming-Tsan|last2=Chen|first2=Shen-Jen|last3=Huang|first3=Kuo-Lin|last4=Lin|first4=Yuan-Chung|last5=Lee|first5=Wen-Jhy|last6=Chang-Chien|first6=Guo-Ping|last7=Tsai|first7=Jen-Hsiung|last8=Lee|first8=Jia-Twu|last9=Chiu|first9=Chuen-Huey|date=2009-08|title=Characteritization of, and health risks from, polychlorinated dibenzo-p-dioxins/dibenzofurans from incense burned in a temple|url=https://linkinghub.elsevier.com/retrieve/pii/S0048969709005026|journal=Science of The Total Environment|language=en|volume=407|issue=17|pages=4870–4875|doi=10.1016/j.scitotenv.2009.05.027}}</ref> Poorly controlled urban waste incineration was one of the most important sources in past. This can be technically solved by ensuring high incineration temperature (1,000 °C or higher), long burning time, and effective flue gas filtration. In modern good-quality incinerators PCDD/Fs are effectively removed.<ref name=Zhang17>{{cite journal |last1=Zhang |first1=Mengmei |last2=Buekens |first2=Alfons |last3=Li |first3=Xiaodong |title=Open burning as a source of dioxins |journal=Critical Reviews in Environmental Science and Technology |date=22 June 2017 |volume=47 |issue=8 |pages=543–620 |doi=10.1080/10643389.2017.1320154}}</ref> On the other hand, accidental dumpsite fires and backyard burning of waste are much more problematic and poorly controlled. In poor burning conditions the production of PCDD/Fs can be very high.<ref name=Dopico15>{{cite journal |last1=Dopico |first1=M |last2=Gómez |first2=A |title=Review of the current state and main sources of dioxins around the world. |journal=Journal of the Air & Waste Management Association (1995) |date=September 2015 |volume=65 |issue=9 |pages=1033-49 |doi=10.1080/10962247.2015.1058869 |pmid=26068294}}</ref><ref name=Zhang17/> Many previous sources of PCDD/Fs are presently in reasonable control (e.g. decreased chlorine bleaching of pulp, syntheses of PCBs, chlorophenols and phenoxy acids etc.). Metal industries and local burning of solid fuels remain as sources.<ref name=Zhang17/> Emissions decreased between 1985 and 2004 by about 80 % in Europe (from 14 kg per year I-TEQ{{efn|I-TEQ (international TEQ for PCDD/Fs) was used before present TEQs were agreed under the auspices of the World Health Organization. The differences are minor. The TEQs used in this text are sometimes called WHO-TEQs.}} to 2–4 kg),<ref>{{cite journal |last1=Quass |first1=U |last2=Fermann |first2=M |last3=Bröker |first3=G |title=The European dioxin air emission inventory project--final results. |journal=Chemosphere |date=March 2004 |volume=54 |issue=9 |pages=1319-27 |doi=10.1016/S0045-6535(03)00251-0 |pmid=14659425}}</ref> in the USA between 1987 and 2000 even more (from 14 kg to 1.4 kg)<ref>{{Cite web|url=https://cfpub.epa.gov/ncea/risk/recordisplay.cfm?deid=159286|title=An Inventory Of Sources And Environmental Releases Of Dioxin-Like Compounds In The U.S. For The Years 1987, 1995, And 2000 (Final, Nov 2006)|publisher=US EPA National Center for Environmental Assessment,Washington DC|website=cfpub.epa.gov|language=en|access-date=2019-12-16}}</ref> (Fig. 3). In the USA the top three current sources of dioxin emissions to air are forest fires, backyard burning of trash, and medical waste incinerators.<ref name=USEPA13>{{Cite web|url=https://cfpub.epa.gov/ncea/dioxin/recordisplay.cfm?deid=235432|title=Update to An Inventory of Sources and Environmental Releases of Dioxin-Like Compounds in the United States for the Years 1987, 1995, and 2000 (2013, External Review Draft)|publisher=US EPA National Center for Environmental Assessment, Washington DC|website=cfpub.epa.gov|language=en|access-date=2019-12-16}}</ref> The trend is not satisfactory in all countries, however.<ref>{{cite journal |last1=Momeniha |first1=F |last2=Faridi |first2=S |last3=Amini |first3=H |last4=Shamsipour |first4=M |last5=Naddafi |first5=K |last6=Yunesian |first6=M |last7=Niazi |first7=S |last8=Gohari |first8=K |last9=Farzadfar |first9=F |last10=Nabizadeh |first10=R |last11=Mokammel |first11=A |last12=Mahvi |first12=AH |last13=Mesdaghinia |first13=A |last14=Kashani |first14=H |last15=Nasseri |first15=S |last16=Gholampour |first16=A |last17=Saeedi |first17=R |last18=Hassanvand |first18=MS |title=Estimating national dioxins and furans emissions, major sources, intake doses, and temporal trends in Iran from 1990-2010. |journal=Journal of environmental health science & engineering |date=2017 |volume=15 |pages=20 |doi=10.1186/s40201-017-0283-1 |pmid=29051819}}</ref><ref name=Kanan/> Electronic waste recycling in poorly-controlled conditions is a recent additional concern as a source of dioxin-like compounds.<ref>{{cite journal |last1=Zhang |first1=J |last2=Jiang |first2=Y |last3=Zhou |first3=J |last4=Wu |first4=B |last5=Liang |first5=Y |last6=Peng |first6=Z |last7=Fang |first7=D |last8=Liu |first8=B |last9=Huang |first9=H |last10=He |first10=C |last11=Wang |first11=C |last12=Lu |first12=F |title=Elevated body burdens of PBDEs, dioxins, and PCBs on thyroid hormone homeostasis at an electronic waste recycling site in China. |journal=Environmental science & technology |date=15 May 2010 |volume=44 |issue=10 |pages=3956-62 |doi=10.1021/es902883a |pmid=20408536}}</ref><ref>{{cite journal |last1=Hu |first1=Jianfang |last2=Xiao |first2=Xiao |last3=Peng |first3=Ping'an |last4=Huang |first4=Weilin |last5=Chen |first5=Deyi |last6=Cai |first6=Ying |title=Spatial distribution of polychlorinated dibenzo-p-dioxins and dibenzo-furans (PCDDs/Fs) in dust, soil, sediment and health risk assessment from an intensive electronic waste recycling site in Southern China |journal=Environmental Science: Processes & Impacts |date=2013 |volume=15 |issue=10 |pages=1889 |doi=10.1039/c3em00319a |pmid=23955158}}</ref> It should be noted that there are also natural sources of PCDD/Fs such as kaolinic clay and volcanic eruptions.<ref name=Hoogenboom15>{{cite journal |last1=Hoogenboom |first1=Ron |last2=Traag |first2=Wim |last3=Fernandes |first3=Alwyn |last4=Rose |first4=Martin |title=European developments following incidents with dioxins and PCBs in the food and feed chain |journal=Food Control |date=April 2015 |volume=50 |pages=670–683 |doi=10.1016/j.foodcont.2014.10.010}}</ref><ref>{{cite journal |last1=Jin |first1=LJ |last2=Chen |first2=BL |title=Natural origins, concentration levels, and formation mechanisms of organohalogens in the environment |journal=Progr Chemistry |date=2017 |volume=29 |pages=1093-1114 |doi=10.7536/PC170563 |url=http://manu56.magtech.com.cn/progchem/EN/abstract/abstract11961.shtml}}</ref><ref name=Rathna18>{{cite journal |last1=Rathna |first1=R |last2=Varjani |first2=S |last3=Nakkeeran |first3=E |title=Recent developments and prospects of dioxins and furans remediation. |journal=Journal of environmental management |date=1 October 2018 |volume=223 |pages=797-806 |doi=10.1016/j.jenvman.2018.06.095 |pmid=29986327}}</ref> {{Fig | number = 3 | width = 400px | image = Decrease of dioxins in ambient air over 20 years.jpg | caption = Decrease of dioxins in ambient air in different regions | attribution = (redrawn from Dopico and Gomez, 2015).<ref name=Dopico15/> }} PCB compounds were in wide use from 1930s to 1980s for multiple purposes because they are technically excellent oils, resistant to pressure, chemically resistant, non-flammable, and do not conduct electricity. Although their production was discontinued in most countries in the 1980s, these compounds still linger in many products such as electrical transformers and plastic materials. Some of it ends up to the general environment. Only a minor portion of PCBs in mixtures are dioxin-like, depending on the matrix, for example non-ortho congeners are of the order of 0.1 % and mono-ortho congeners 10 % of the total amount of PCBs.<ref>{{cite journal |last1=Kiviranta |first1=H |last2=Ovaskainen |first2=ML |last3=Vartiainen |first3=T |title=Market basket study on dietary intake of PCDD/Fs, PCBs, and PBDEs in Finland. |journal=Environment international |date=September 2004 |volume=30 |issue=7 |pages=923-32 |doi=10.1016/j.envint.2004.03.002 |pmid=15196840}}</ref> {{notelist}} == Environmental fate == Dioxins tend to accumulate in the environment, because they are persistent and not easily degraded by environmental microbes. Because dioxins are much more soluble in lipids than in water, they tend to accumulate in e.g. plankton (bioaccumulation). The concentration tends to magnify at each trophic level (biomagnification), which leads to high concentrations at the highest trophic levels, e.g. seals and predatory birds. Human concentrations are not nearly as high as in the most endangered wild species, because human diet is quite diverse. However, there have been concerns regarding the safety of wild and farmed fish in our diet (see below). TCDD has been long known to be sensitive to photochemical dechlorination. If exposed to direct sunlight or UV-radiation, it will decompose in a matter of hours.<ref>{{Cite journal|last=Crosby|first=D.|last2=Wong|first2=A.|date=1977-03-25|title=Environmental degradation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)|url=http://dx.doi.org/10.1126/science.841331|journal=Science|volume=195|issue=4284|pages=1337–1338|doi=10.1126/science.841331|issn=0036-8075}}</ref> Photocatalysis and other methods have also been tested in attempts to remove dioxins in soils and other environments.<ref name=Kanan/><ref name=Rathna18/> Because dioxins adsorb tightly to soil particles, and microbial degradation (mostly via dehalogenation) of dioxins is very slow, researchers have actively tried to search for mechanisms to increase degradation<ref>{{Cite journal|last=Isosaari|first=Pirjo|last2=Tuhkanen|first2=Tuula|last3=Vartiainen|first3=Terttu|date=2004-05|title=Photodegradation of polychlorinated dibenzo-p-dioxins and dibenzofurans in soil with vegetable oil|url=http://dx.doi.org/10.1007/bf02979673|journal=Environmental Science and Pollution Research|volume=11|issue=3|pages=181–185|doi=10.1007/bf02979673|issn=0944-1344}}</ref> or to find especially active microbial species for the purposes of bioremediation.<ref>{{cite journal |last1=Smidt |first1=H |last2=de Vos |first2=WM |title=Anaerobic microbial dehalogenation. |journal=Annual review of microbiology |date=2004 |volume=58 |pages=43-73 |doi=10.1146/annurev.micro.58.030603.123600 |pmid=15487929}}</ref><ref name=Kanan/><ref name=Rathna18/> By and large, this has not been very successful. Also interactions with the microbiome in the intestines are poorly known.<ref name=Atashgani18>{{cite journal |last1=Atashgahi |first1=S |last2=Shetty |first2=SA |last3=Smidt |first3=H |last4=de Vos |first4=WM |title=Flux, Impact, and Fate of Halogenated Xenobiotic Compounds in the Gut. |journal=Frontiers in physiology |date=2018 |volume=9 |pages=888 |doi=10.3389/fphys.2018.00888 |pmid=30042695}}</ref> {| class="wikitable" |Dioxin literature is confusing to many readers, because units used may be less known and they are sometimes used in a confusing manner. Some dioxins are very potent and therefore the amounts of our concern are very small, usually measured as picograms or nanograms. Picogram is 0.000 000 000 001 g. Concentrations in animal or human tissues are usually expressed as pg/g lipid or ng/kg lipid. Some authors use non-standard expression ppt (parts per trillion). This is confusing and should be avoided, since trillion may mean 10¹² or 10¹⁸ in different countries depending on the use of [[w:Long and short scales|short scale or long scale]] system, resp. To make it clear, weight units are g (gram), mg (milligram, 10^-3 g), μg (microgram, 10^-6 g), ng (nanogram, 10^-9 g), pg (picogram, 10^-12 g), fg (femtogram, 10^-15 g). |} == Toxicokinetics: absorption, distribution and elimination == The main source of dioxins in animals and humans is food.<ref name=Liem00>{{cite journal |last1=Liem |first1=AK |last2=Fürst |first2=P |last3=Rappe |first3=C |title=Exposure of populations to dioxins and related compounds. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=241-59 |doi=10.1080/026520300283324 |pmid=10912239}}</ref><ref>{{cite journal |last1=Fernández-González |first1=R |last2=Yebra-Pimentel |first2=I |last3=Martínez-Carballo |first3=E |last4=Simal-Gándara |first4=J |title=A Critical Review about Human Exposure to Polychlorinated Dibenzo-p-Dioxins (PCDDs), Polychlorinated Dibenzofurans (PCDFs) and Polychlorinated Biphenyls (PCBs) through Foods. |journal=Critical reviews in food science and nutrition |date=2015 |volume=55 |issue=11 |pages=1590-617 |doi=10.1080/10408398.2012.710279 |pmid=24279584}}</ref> Oral absorption of dioxins depends on the carrier. Dioxins in the fat of fish or meat are well absorbed, but those in e.g. soils poorly. Also dermal absorption depends on the carrier.<ref name=Pohjanvirta94/> After absorption they are distributed mostly to adipose tissue and to the liver.<ref name=Pohjanvirta94/><ref>{{cite journal |last1=Warenik-Bany |first1=M |last2=Strucinski |first2=P |last3=Piskorska-Pliszczynska |first3=J |title=Dioxins and PCBs in game animals: Interspecies comparison and related consumer exposure. |journal=Environment international |date=NaN |volume=89-90 |pages=21-9 |doi=10.1016/j.envint.2016.01.007 |pmid=26826359}}</ref><ref>{{Cite journal|last=La Merrill|first=Michele|last2=Emond|first2=Claude|last3=Kim|first3=Min Ji|last4=Antignac|first4=Jean-Philippe|last5=Le Bizec|first5=Bruno|last6=Clément|first6=Karine|last7=Birnbaum|first7=Linda S.|last8=Barouki|first8=Robert|date=2013-02|title=Toxicological Function of Adipose Tissue: Focus on Persistent Organic Pollutants|url=http://dx.doi.org/10.1289/ehp.1205485|journal=Environmental Health Perspectives|volume=121|issue=2|pages=162–169|doi=10.1289/ehp.1205485|issn=0091-6765}}</ref> Liver sequestration increases at high dose levels due to induction of CYP1A2 binding dioxins.<ref>{{cite journal |last1=van Birgelen |first1=AP |last2=van den Berg |first2=M |title=Toxicokinetics. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=267-73 |doi=10.1080/026520300283342 |pmid=10912241}}</ref> Elimination of dioxins is slow, because they are not easily metabolized and urinary excretion is negligible. Elimination is mainly via faeces after slow metabolism in the liver, followed by biliary excretion into the gut. Variation between species is large, e.g. the half-life of TCDD in rats is about 3 weeks, in man about 7 years.<ref name=Pohjanvirta94/> Elimination half-lives of various congeners in people may vary tenfold (Table 1). There may be high individual variation.<ref name=Mitoma15>{{cite journal |last1=Mitoma |first1=C |last2=Uchi |first2=H |last3=Tsukimori |first3=K |last4=Yamada |first4=H |last5=Akahane |first5=M |last6=Imamura |first6=T |last7=Utani |first7=A |last8=Furue |first8=M |title=Yusho and its latest findings-A review in studies conducted by the Yusho Group. |journal=Environment international |date=September 2015 |volume=82 |pages=41-8 |doi=10.1016/j.envint.2015.05.004 |pmid=26010306}}</ref> Very high concentrations seem to induce metabolizing enzymes and shorten the half-lives.<ref>{{cite journal |last1=Aylward |first1=LL |last2=Brunet |first2=RC |last3=Carrier |first3=G |last4=Hays |first4=SM |last5=Cushing |first5=CA |last6=Needham |first6=LL |last7=Patterson DG |first7=Jr |last8=Gerthoux |first8=PM |last9=Brambilla |first9=P |last10=Mocarelli |first10=P |title=Concentration-dependent TCDD elimination kinetics in humans: toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort. |journal=Journal of exposure analysis and environmental epidemiology |date=January 2005 |volume=15 |issue=1 |pages=51-65 |doi=10.1038/sj.jea.7500370 |pmid=15083163}}</ref><ref name=Sorg09>{{cite journal |last1=Sorg |first1=O |last2=Zennegg |first2=M |last3=Schmid |first3=P |last4=Fedosyuk |first4=R |last5=Valikhnovskyi |first5=R |last6=Gaide |first6=O |last7=Kniazevych |first7=V |last8=Saurat |first8=JH |title=2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites. |journal=Lancet (London, England) |date=3 October 2009 |volume=374 |issue=9696 |pages=1179-85 |doi=10.1016/S0140-6736(09)60912-0 |pmid=19660807}}</ref> '''Table 1 {{!}}''' Elimination half-lives in humans of some PCDD/Fs.<ref>{{cite journal |last1=Milbrath |first1=MO |last2=Wenger |first2=Y |last3=Chang |first3=CW |last4=Emond |first4=C |last5=Garabrant |first5=D |last6=Gillespie |first6=BW |last7=Jolliet |first7=O |title=Apparent half-lives of dioxins, furans, and polychlorinated biphenyls as a function of age, body fat, smoking status, and breast-feeding. |journal=Environmental health perspectives |date=March 2009 |volume=117 |issue=3 |pages=417-25 |doi=10.1289/ehp.11781 |pmid=19337517}}</ref> {| class="wikitable sortable" !Congener !Half-life, years |- |2,3,7,8-TCDD |7.2 |- |1,2,3,7,8-PeCDD |11.2 |- |1,2,3,4,7,8-HxCDD |9.8 |- |1,2,3,6,7,8-HxCDD |13.1 |- |1,2,3,7,8,9-HxCDD |5.1 |- |1,2,3,4,6,7,8-HpCDD |4.9 |- |OCDD |6.7 |- |2,3,7,8-TCDF |2.1 |- |1,2,3,7,8-PeCDF |3.5 |- |2,3,4,7,8-PeCDF |7.0 |- |1,2,3,4,7,8-HxCDF |6.4 |- |1,2,3,6,7,8-HxCDF |7.2 |- |1,2,3,7,8,9-HxCDF |7.2 |- |2,3,4,6,7,8-HxCDF |2.8 |- |1,2,3,4,6,7,8-HpCDF |3.1 |- |1,2,3,4,7,8,9-HpCDF |4.6 |- |OCDF |1.4 |} Nursing mothers excrete dioxins in milk fat at approximately the same concentrations as their own level in body fat. This means that maternal dioxin levels decrease during the lactation period (even by 20%).<ref>{{cite journal |last1=Vartiainen |first1=T |last2=Jaakkola |first2=JJ |last3=Saarikoski |first3=S |last4=Tuomisto |first4=J |title=Birth weight and sex of children and the correlation to the body burden of PCDDs/PCDFs and PCBs of the mother. |journal=Environmental health perspectives |date=February 1998 |volume=106 |issue=2 |pages=61-6 |doi=10.1289/ehp.9810661 |pmid=9432971}}</ref> Also placental PCDD/F concentrations are in the same range as in maternal body or breast milk (as pg/g fat)<ref name=Virtanen12>{{cite journal |last1=Virtanen |first1=HE |last2=Koskenniemi |first2=JJ |last3=Sundqvist |first3=E |last4=Main |first4=KM |last5=Kiviranta |first5=H |last6=Tuomisto |first6=JT |last7=Tuomisto |first7=J |last8=Viluksela |first8=M |last9=Vartiainen |first9=T |last10=Skakkebaek |first10=NE |last11=Toppari |first11=J |title=Associations between congenital cryptorchidism in newborn boys and levels of dioxins and PCBs in placenta. |journal=International journal of andrology |date=June 2012 |volume=35 |issue=3 |pages=283-93 |doi=10.1111/j.1365-2605.2011.01233.x |pmid=22150420}}</ref> and placental transfer to the foetus occurs.<ref>{{cite journal |last1=Feeley |first1=M |last2=Brouwer |first2=A |title=Health risks to infants from exposure to PCBs, PCDDs and PCDFs. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=325-33 |doi=10.1080/026520300283397 |pmid=10912246}}</ref> Each delivery and lactation decreases the mother's body burden by 25–30%. In children elimination is faster than in adults, initially with a half-life of months rather than years,<ref>{{cite journal |last1=Kreuzer |first1=PE |last2=Csanády |first2=GA |last3=Baur |first3=C |last4=Kessler |first4=W |last5=Päpke |first5=O |last6=Greim |first6=H |last7=Filser |first7=JG |title=2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition. |journal=Archives of toxicology |date=1997 |volume=71 |issue=6 |pages=383-400 |pmid=9195020|doi=10.1007/s002040050402}}</ref><ref>{{cite journal |last1=Kerger |first1=BD |last2=Leung |first2=HW |last3=Scott |first3=P |last4=Paustenbach |first4=DJ |last5=Needham |first5=LL |last6=Patterson DG |first6=Jr |last7=Gerthoux |first7=PM |last8=Mocarelli |first8=P |title=Age- and concentration-dependent elimination half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso children. |journal=Environmental health perspectives |date=October 2006 |volume=114 |issue=10 |pages=1596-602 |doi=10.1289/ehp.8884 |pmid=17035149}}</ref><ref>{{cite journal |last1=Leung |first1=HW |last2=Kerger |first2=BD |last3=Paustenbach |first3=DJ |last4=Ryan |first4=JJ |last5=Masuda |first5=Y |title=Concentration and age-dependent elimination kinetics of polychlorinated dibenzofurans in Yucheng and Yusho patients. |journal=Toxicology and industrial health |date=September 2007 |volume=23 |issue=8 |pages=493-501 |doi=10.1177/0748233708089024 |pmid=18669171}}</ref> probably due to several factors, faster rate of faecal lipid excretion, and increased metabolism.<ref>{{cite journal |last1=Kerger |first1=BD |last2=Leung |first2=HW |last3=Scott |first3=PK |last4=Paustenbach |first4=DJ |title=Refinements on the age-dependent half-life model for estimating child body burdens of polychlorodibenzodioxins and dibenzofurans. |journal=Chemosphere |date=April 2007 |volume=67 |issue=9 |pages=S272-8 |doi=10.1016/j.chemosphere.2006.05.108 |pmid=17207842}}</ref> Rapid growth and dilution decrease the concentrations as well, even if the body burden does not change to the same extent. == Mechanism of action: the Aryl Hydrocarbon Receptor == Most biological actions of dioxins, including their toxicity, are mediated by the AHR (Fig. 4). The AHR is an evolutionarily ancient receptor, an over 600-million-year old protein occurring in all vertebrates. Homologs of the AHR have also been discovered in invertebrates and insects. These primitive AHR-homologs do not bind dioxins or other external ligands. They seem to play important developmental roles in neuronal differentiation and regulation of feeding-related aggregation behaviour or in regulation of normal morphogenesis.<ref name=Linden10>{{cite journal |last1=Lindén |first1=J |last2=Lensu |first2=S |last3=Tuomisto |first3=J |last4=Pohjanvirta |first4=R |title=Dioxins, the aryl hydrocarbon receptor and the central regulation of energy balance. |journal=Frontiers in neuroendocrinology |date=October 2010 |volume=31 |issue=4 |pages=452-78 |doi=10.1016/j.yfrne.2010.07.002 |pmid=20624415}}</ref><ref>{{cite book |last1=Hahn |first1=Mark E. |last2=Karchner |first2=Sibel I. |title=The AH Receptor in Biology and Toxicology |date=2011 |publisher=John Wiley & Sons, Ltd |isbn=9781118140574 |pages=387–403 |url=https://onlinelibrary.wiley.com/doi/10.1002/9781118140574.ch27 |language=en|doi=10.1002/9781118140574.ch27 |chapter=Structural and Functional Diversification of AHRs during Metazoan Evolution}}</ref><ref>{{cite book |last1=Powell‐Coffman |first1=Jo Anne |last2=Qin |first2=Hongtao |title=The AH Receptor in Biology and Toxicology |date=2011 |publisher=John Wiley & Sons, Ltd |isbn=9781118140574 |pages=405–411 |url=https://onlinelibrary.wiley.com/doi/abs/10.1002/9781118140574.ch28|doi=10.1002/9781118140574.ch28 |language=en |chapter=Invertebrate AHR Homologs: Ancestral Functions in Sensory Systems}}</ref><ref>{{cite journal |last1=Tian |first1=J |last2=Feng |first2=Y |last3=Fu |first3=H |last4=Xie |first4=HQ |last5=Jiang |first5=JX |last6=Zhao |first6=B |title=The Aryl Hydrocarbon Receptor: A Key Bridging Molecule of External and Internal Chemical Signals |journal=Environmental science & technology |date=18 August 2015 |volume=49 |issue=16 |pages=9518-31 |doi=10.1021/acs.est.5b00385 |pmid=26079192}}</ref><ref name=Bock17>{{cite journal |last1=Bock |first1=KW |title=Human and rodent aryl hydrocarbon receptor (AHR): from mediator of dioxin toxicity to physiologic AHR functions and therapeutic options. |journal=Biological chemistry |date=1 April 2017 |volume=398 |issue=4 |pages=455-464 |doi=10.1515/hsz-2016-0303 |pmid=27805907}}</ref> {{Fig | number = 4 | width = 400px | image = AHR functional domains.svg | caption = The structure of AHR. The approximate sites for DNA binding, ligand binding, HSP90 binding, heterodimerization, and transactivation are shown | attribution = Jeff Dahl, CC BY-SA 4.0 }} The AHR belongs to the family of basic Helix–Loop–Helix-PAS (bHLH/PAS) proteins, which have important roles in e.g. regulation of neural development, in generation and maintenance of circadian rhythms, in sensing cellular environment, and as transcriptional partners and co-activators. Although it is structurally different, the AHR acts as a transcription factor analogously to the nuclear receptors such as steroid receptors or thyroid receptors. The AHR is a ligand-activated transcription factor that integrates environmental, dietary, microbial and metabolic cues to control complex transcriptional programmes in a ligand-specific, cell-type-specific and context-specific manner.<ref name=Rothhammer19/> The AHR exists in the cytosol in a protein complex including several proteins (Fig. 5). These chaperones keep the AHR in a conformation able to bind a ligand but unable to enter the nucleus. After ligand binding, the protein complex enters into the nucleus. The AHR releases its chaperones and heterodimerizes with another bHLH/PAS protein, ARNT (AHR nuclear translocator). The AHR/ARNT dimer binds to DNA at the major groove of the DNA helix at specific sites, AHR response elements (also known as dioxin response elements, DREs, or xenobiotic response elements XREs). {{Fig | number = 5 | width = 400px | image = AHR pathways in cell.jpg | caption = A schematic diagram of some AHR signaling pathways. The canonical pathway is depicted with solid black arrows, alternative pathways with dashed arrows, and an intersection of these two with a solid red arrow. The green bars represent the AHR, red bars ARNT, yellow bars ARA9 (AIP, Xap2), blue bars HSP90 and the blue ovals p23. Dioxin binding to the AHR (1.) leads to its translocation into the nucleus by importin-β, (2.) heterodimerization with ARNT and binding to the DNA at DREs, (3.) modulating expression levels of target genes (green arrows). One of the gene products elevated by this mechanism is AHRR, a repressor protein which forms a feedback loop that inhibits AHR action. The AHR is finally degraded by the ubiquitin–proteasome system (4.). AHR activation can also rapidly increase intracellular Ca2+ concentration (5.) which in turn may ultimately result in augmented Cox2 gene expression. Elevation of Ca2+ activates CaMKs, which appear to have a critical role in the translocation of the AHR. Another example of effects mediated by the AHR via non-canonical pathways is suppression of acute-phase proteins (6.) which does not involve DNA binding. | attribution = (simplified and modified from Lindén et al.).<ref name=Linden10/>, Jouko Tuomisto }} In addition to this canonical pathway, some actions of dioxins and AHR are mediated via non-canonical pathways. These may be involved e.g. in interactions with other receptors, such as estrogen receptor, other transcription factors such as NFκB signalling complex, different kinases, and various epigenetic mechanisms.<ref name=Linden10/><ref name=Brunnberg2012>{{Cite book|url=http://dx.doi.org/10.1002/9781118140574.ch9|title=The AH Receptor in Biology and Toxicology|last=Brunnberg|first=Sara|last2=Swedenborg|first2=Elin|last3=Gustafsson|first3=Jan-Åke|date=2011-11-10|editor-first=R|editor-last=Pohjanvirta|publisher=John Wiley & Sons, Inc.|isbn=978-1-118-14057-4|location=Hoboken, NJ, USA|pages=127–141|doi=10.1002/9781118140574.ch9|chapter=Functional Interactions of AHR with other Receptors}}</ref><ref name=Ko2012>{{Cite book|url=http://dx.doi.org/10.1002/9781118140574.ch11|chapter=Epigenetic mechanisms in AHR function|doi=10.1002/9781118140574.ch11|title=The AH Receptor in Biology and Toxicology|last=Ko|first=Chia-I|last2=Puga|first2=Alvaro|editor-first=R|editor-last=Pohjanvirta|date=2011-11-10|publisher=John Wiley & Sons, Inc.|isbn=978-1-118-14057-4|location=Hoboken, NJ, USA|pages=157–178}}</ref><ref>{{cite journal |last1=Patrizi |first1=B |last2=Siciliani de Cumis |first2=M |title=TCDD Toxicity Mediated by Epigenetic Mechanisms |journal=International journal of molecular sciences |date=18 December 2018 |volume=19 |issue=12 |doi=10.3390/ijms19124101 |pmid=30567322}}</ref><ref name=Rothhammer19/><ref name=Viluksela19>{{cite journal |last1=Viluksela |first1=M |last2=Pohjanvirta |first2=R |title=Multigenerational and Transgenerational Effects of Dioxins. |journal=International journal of molecular sciences |date=17 June 2019 |volume=20 |issue=12 |doi=10.3390/ijms20122947 |pmid=31212893}}</ref><ref>{{cite book |last1=Matsumura |first1=Fumio |title=The AH Receptor in Biology and Toxicology |date=2011 |publisher=John Wiley & Sons, Ltd |isbn=9781118140574 |pages=197–215 |url=https://onlinelibrary.wiley.com/doi/10.1002/9781118140574.ch13 |language=en |chapter=Nongenomic route of action of TCDD: Identity, characteristics, and toxicological significance|doi=10.1002/9781118140574.ch13|editor-first=R|editor-last=Pohjanvirta}}</ref> Interactions with the retinoid system are especially interesting, because some effects of dioxins are similar to symptoms of vitamin A deficiency (e.g. retarded growth, problems in reproduction) and some resemble the toxic effects of vitamin A (such as developmental malformations).<ref name=Nilsson2002>{{Cite journal|last=Nilsson|first=Charlotte B.|last2=Håkansson|first2=Helen|date=2002-01|title=The Retinoid Signaling System — A Target in Dioxin Toxicity|url=http://dx.doi.org/10.1080/20024091064228|journal=Critical Reviews in Toxicology|volume=32|issue=3|pages=211–232|doi=10.1080/20024091064228|issn=1040-8444}}</ref> It seems that dioxins are involved both in metabolic steps of retinoid activation and metabolism as well as in molecular interactions of retinoid receptors and AHR in the transactivation machinery. <ref name=Nilsson2002/><ref name=Brunnberg2012/> In response to activation by dioxins, the AHR signalling pathway modifies the expression levels of numerous genes. The best characterized of these at the molecular level is the induction of the gene for a Phase I cytochrome P-450 drug-metabolizing enzyme, CYP1A1.<ref>{{cite journal |last1=Okey |first1=AB |last2=Franc |first2=MA |last3=Moffat |first3=ID |last4=Tijet |first4=N |last5=Boutros |first5=PC |last6=Korkalainen |first6=M |last7=Tuomisto |first7=J |last8=Pohjanvirta |first8=R |title=Toxicological implications of polymorphisms in receptors for xenobiotic chemicals: the case of the aryl hydrocarbon receptor. |journal=Toxicology and applied pharmacology |date=1 September 2005 |volume=207 |issue=2 Suppl |pages=43-51 |doi=10.1016/j.taap.2004.12.028 |pmid=15993909}}</ref><ref name=Okey07>{{cite journal |last1=Okey |first1=AB |title=An aryl hydrocarbon receptor odyssey to the shores of toxicology: the Deichmann Lecture, International Congress of Toxicology-XI. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=July 2007 |volume=98 |issue=1 |pages=5-38 |doi=10.1093/toxsci/kfm096 |pmid=17569696}}</ref><ref>{{cite book |last1=Ma |first1=Qiang |title=The AH Receptor in Biology and Toxicology |date=2011 |publisher=John Wiley & Sons, Ltd |isbn=9781118140574 |pages=33–45 |url=https://onlinelibrary.wiley.com/doi/10.1002/9781118140574.ch2 |language=en |chapter=Overview of AHR Functional Domains and the Classical AHR Signaling Pathway: Induction of Drug Metabolizing Enzymes|editor-first=R|editor-last=Pohjanvirta|doi=10.1002/9781118140574.ch2}}</ref> Dioxin-activated AHR induces other Phase I and II enzymes that metabolize chemicals in the liver including CYP1A2, CYP1B1, CYP2S1, CYP2A5, ALDH3, GSTA1, UGT1A1, UGT1A6, UGT1A7 and NQO1. Probably this induction system evolved as a mechanism to enhance the elimination of foreign fat-soluble chemicals. In addition to xenobiotic-metabolizing enzymes, TCDD exposure modifies the expression of a large number of other genes. For example, in adult mouse or rat liver, hundreds of genes are affected.<ref>{{cite journal |last1=Tijet |first1=N |last2=Boutros |first2=PC |last3=Moffat |first3=ID |last4=Okey |first4=AB |last5=Tuomisto |first5=J |last6=Pohjanvirta |first6=R |title=Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries. |journal=Molecular pharmacology |date=January 2006 |volume=69 |issue=1 |pages=140-53 |doi=10.1124/mol.105.018705 |pmid=16214954}}</ref><ref name=Linden10/><ref name=Rothhammer19/> It is still unclear which genes are the most important for the toxic effects such as lethality, anorexia and wasting syndrome, and various hyperplastic and atrophic tissue changes. The role of AH receptor predominantly as an inducer of metabolic enzymes to protect us from xenobiotics is rapidly changing. Mice lacking AHR (AHR knockout) have clearly demonstrated the necessity of AHR activation for normal physiology, and these animals are severely sick with e.g. cardiac hypertrophy, liver fibrosis, reproductive problems, and impaired immunology. AH receptors participate in many regulatory functions in the body (the reader is referred to recent reviews).<ref name=Linden10/><ref>{{cite journal |last1=Casado |first1=FL |last2=Singh |first2=KP |last3=Gasiewicz |first3=TA |title=The aryl hydrocarbon receptor: regulation of hematopoiesis and involvement in the progression of blood diseases. |journal=Blood cells, molecules & diseases |date=15 April 2010 |volume=44 |issue=4 |pages=199-206 |doi=10.1016/j.bcmd.2010.01.005 |pmid=20171126}}</ref><ref name=Pohjanvirta12>{{cite book |editor1-last=Pohjanvirta |editor1-first=Raimo |title=The AH Receptor in Biology and Toxicology |date=2011 |publisher=Wiley |url=https://onlinelibrary.wiley.com/doi/book/10.1002/9781118140574 |language=en|doi=10.1002/9781118140574}}</ref><ref>{{cite journal |last1=Van Voorhis |first1=M |last2=Fechner |first2=JH |last3=Zhang |first3=X |last4=Mezrich |first4=JD |title=The aryl hydrocarbon receptor: a novel target for immunomodulation in organ transplantation. |journal=Transplantation |date=27 April 2013 |volume=95 |issue=8 |pages=983-90 |doi=10.1097/TP.0b013e31827a3d1d |pmid=23263608}}</ref><ref>{{cite journal |last1=Esser |first1=C |last2=Rannug |first2=A |title=The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology. |journal=Pharmacological reviews |date=2015 |volume=67 |issue=2 |pages=259-79 |doi=10.1124/pr.114.009001 |pmid=25657351}}</ref><ref>{{cite journal |last1=Lahoti |first1=TS |last2=Boyer |first2=JA |last3=Kusnadi |first3=A |last4=Muku |first4=GE |last5=Murray |first5=IA |last6=Perdew |first6=GH |title=Aryl Hydrocarbon Receptor Activation Synergistically Induces Lipopolysaccharide-Mediated Expression of Proinflammatory Chemokine (c-c motif) Ligand 20. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=November 2015 |volume=148 |issue=1 |pages=229-40 |doi=10.1093/toxsci/kfv178 |pmid=26259605}}</ref><ref>{{cite journal |last1=Sibilano |first1=R |last2=Pucillo |first2=CE |last3=Gri |first3=G |title=Allergic responses and aryl hydrocarbon receptor novel pathway of mast cell activation. |journal=Molecular immunology |date=January 2015 |volume=63 |issue=1 |pages=69-73 |doi=10.1016/j.molimm.2014.02.015 |pmid=24656327}}</ref><ref>{{cite journal |last1=Kawajiri |first1=K |last2=Fujii-Kuriyama |first2=Y |title=The aryl hydrocarbon receptor: a multifunctional chemical sensor for host defense and homeostatic maintenance. |journal=Experimental animals |date=3 May 2017 |volume=66 |issue=2 |pages=75-89 |doi=10.1538/expanim.16-0092 |pmid=27980293}}</ref><ref name=Kolluri17>{{cite journal |last1=Kolluri |first1=SK |last2=Jin |first2=UH |last3=Safe |first3=S |title=Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target. |journal=Archives of toxicology |date=July 2017 |volume=91 |issue=7 |pages=2497-2513 |doi=10.1007/s00204-017-1981-2 |pmid=28508231}}</ref><ref name=Bock17/> An important area seems to be antibacterial and antiviral defence mechanisms<ref name=MouraAlves14/><ref name=Boule18>{{cite journal |last1=Boule |first1=Lisbeth A. |last2=Burke |first2=Catherine G. |last3=Jin |first3=Guang-Bi |last4=Lawrence |first4=B. Paige |title=Aryl hydrocarbon receptor signaling modulates antiviral immune responses: ligand metabolism rather than chemical source is the stronger predictor of outcome |journal=Scientific Reports |date=29 January 2018 |volume=8 |issue=1 |doi=10.1038/s41598-018-20197-4}}</ref> and the regulation of innate immunity.<ref name=Schiering17>{{cite journal |last1=Schiering |first1=C |last2=Wincent |first2=E |last3=Metidji |first3=A |last4=Iseppon |first4=A |last5=Li |first5=Y |last6=Potocnik |first6=AJ |last7=Omenetti |first7=S |last8=Henderson |first8=CJ |last9=Wolf |first9=CR |last10=Nebert |first10=DW |last11=Stockinger |first11=B |title=Feedback control of AHR signalling regulates intestinal immunity. |journal=Nature |date=9 February 2017 |volume=542 |issue=7640 |pages=242-245 |doi=10.1038/nature21080 |pmid=28146477}}</ref><ref>{{cite journal |last1=Gutiérrez-Vázquez |first1=C |last2=Quintana |first2=FJ |title=Regulation of the Immune Response by the Aryl Hydrocarbon Receptor. |journal=Immunity |date=16 January 2018 |volume=48 |issue=1 |pages=19-33 |doi=10.1016/j.immuni.2017.12.012 |pmid=29343438}}</ref><ref name=Rothhammer19/> AHR ligands are important at intestinal epithelial cells which serve as gatekeepers for their supply, and if AHR activation is too low, loss of important lymphoid cells and subsequent susceptibility to infections follow. == Toxicity equivalents == Dioxins and dioxin-like compounds vary in their potency and fate in the organisms. The toxicity of mixtures cannot be assessed by simply adding up the amounts or concentrations of all chemicals in the mixture. However, if the amount of a compound is standardized to the toxicologically equivalent amount of TCDD, chemicals with different potencies can be summed up and this equivalent quantity is very useful for regulatory and even some scientific purposes.<ref name=Berg06/><ref name=Tuomisto12>{{cite book |last1=Tuomisto |first1=Jouko |title=The AH Receptor in Biology and Toxicology |date=2011 |publisher=John Wiley & Sons, Ltd |isbn=9781118140574 |pages=317–330 |url=https://onlinelibrary.wiley.com/doi/10.1002/9781118140574.ch23 |language=en |chapter=The Toxic Equivalency Principle and its Application in Dioxin Risk Assessment|doi=10.1002/9781118140574.ch23|editor-first=R|editor-last=Pohjanvirta}}</ref> Several versions of TEF have been used since 1984, proposed by Ontario Ministry of Environment, U.S. Environmental Protection Agency, and the Nordic Countries, respectively. International harmonization was undertaken by NATO/CCMS, and most recently the World Health Organization organized re-evaluations of TEF values in 1998, 2005 and 2013.<ref name=Tuomisto12/><ref name=Berg13/> Brominated dioxins, furans and biphenyls, as well as mixed halogenated congeners, share many aspects of toxicity and the ability to bind to AH receptor. They probably deserve TEF values as well, but lack sufficient data. On interim basis the TEFs of respective chlorinated compounds has been recommended.<ref name=Berg13/> The toxicities can vary by a factor of 30,000, and TCDD is assigned a TEF of 1. Other chemicals are given TEF values of 1 to 0.000 03 (in fish down to <0.000 005) (Table 2). The amount of a given compound is multiplied by its TEF, resulting in the amount toxicologically equivalent to that of TCDD. These partial equivalent amounts are then added up to make the sum toxic equivalent (TEQ) of the mixture. This can be used as a proxy of the total dose of dioxin-like compounds. This is a consensus value based on several assumptions and not a strictly scientific fact.<ref name=Berg06/> Therefore they should be regularly updated to reflect new and more accurate information. This is because there are a number of uncertainties regarding kinetics, additivity, species differences, and slopes of dose-response curves.<ref name=Berg00>{{Cite journal|last=De Berg|first=Martin Vann|last2=Peterson|first2=Richard E.|last3=Schrenk|first3=Dieter|date=2000-04|title=Human risk assessment and TEFs|url=http://dx.doi.org/10.1080/026520300283414|journal=Food Additives and Contaminants|volume=17|issue=4|pages=347–358|doi=10.1080/026520300283414|issn=0265-203X}}</ref> '''Table 2 {{!}}''' Toxic equivalency factors for PCDD/Fs and PCBs. Other congeners are not assumed to have dioxin-like effects. IUPAC numbers for PCBs are given in parenthesis.<ref name=Berg98>{{cite journal |last1=Van den Berg |first1=M |last2=Birnbaum |first2=L |last3=Bosveld |first3=AT |last4=Brunström |first4=B |last5=Cook |first5=P |last6=Feeley |first6=M |last7=Giesy |first7=JP |last8=Hanberg |first8=A |last9=Hasegawa |first9=R |last10=Kennedy |first10=SW |last11=Kubiak |first11=T |last12=Larsen |first12=JC |last13=van Leeuwen |first13=FX |last14=Liem |first14=AK |last15=Nolt |first15=C |last16=Peterson |first16=RE |last17=Poellinger |first17=L |last18=Safe |first18=S |last19=Schrenk |first19=D |last20=Tillitt |first20=D |last21=Tysklind |first21=M |last22=Younes |first22=M |last23=Waern |first23=F |last24=Zacharewski |first24=T |title=Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. |journal=Environmental health perspectives |date=December 1998 |volume=106 |issue=12 |pages=775-92 |doi=10.1289/ehp.98106775 |pmid=9831538}}</ref><ref name=Berg06/> {| class="wikitable sortable" !Class !Congener !WHO-TEF 2005 !WHO-TEF fish 1998 !WHO-TEF birds 1998 |- | rowspan="7" |PCDDs |2,3,7,8-TCDD |1 |1 |1 |- |1,2,3,7,8-PeCDD |1 |1 |1 |- |1,2,3,4,7,8-HxCDD |0.1 |0.5 |0.05 |- |1,2,3,6,7,8-HxCDD |0.1 |0.01 |0.01 |- |1,2,3,7,8,9-HxCDD |0.1 |0.01 |0.1 |- |1,2,3,4,6,7,8-HpCDD |0.01 |0.0001 |<0.001 |- |OCDD |0.0003 |<0.0001 |0.0001 |- | rowspan="10" |PCDFs |2,3,7,8-TCDF |0.1 |0.05 |1 |- |1,2,3,7,8-PeCDF |0.03 |0.05 |0.1 |- |2,3,4,7,8-PeCDF |0.3 |0.5 |1 |- |1,2,3,4,7,8-HxCDF |0.1 |0.1 |0.1 |- |1,2,3,6,7,8-HxCDF |0.1 |0.1 |0.1 |- |1,2,3,7,8,9-HxCDF |0.1 |0.1 |0.1 |- |2,3,4,6,7,8-HxCDF |0.1 |0.1 |0.1 |- |1,2,3,4,6,7,8-HpCDF |0.01 |0.01 |0.01 |- |1,2,3,4,7,8,9-HpCDF |0.01 |0.01 |0.01 |- |OCDF |0.0003 |<0.0001 |0.0001 |- | rowspan="4" |Non-ortho-PCBs |3,3’,4,4’-TCB (77) |0.0001 |0.0005 |0.1 |- |3,4,4’,5-TCB (81) |0.0003 |0.0001 |0.05 |- |3,3’,4,4’,5-PeCB (126) |0.1 |0.005 |0.1 |- |3,3’,4,4’,5,5’-HxCB (169) |0.03 |0.00005 |0.001 |- | rowspan="8" |Mono-ortho-PCBs |2,3,3’,4,4’-PeCB (105) |0.00003 |<0.000005 |0.0001 |- |2,3,4,4’,5-PeCB (114) |0.00003 |<0.000005 |0.0001 |- |2,3’,4,4’,5-PeCB (118) |0.00003 |<0.000005 |0.00001 |- |2’,3,4,4’,5-PeCB (123) |0.00003 |<0.000005 |0.00001 |- |2,3,3’,4,4’,5-HxCB (156) |0.00003 |<0.000005 |0.0001 |- |2,3,3’,4,4’,5’-HxCB (157) |0.00003 |<0.000005 |0.0001 |- |2,3’,4,4’,5,5’-HxCB (167) |0.00003 |<0.000005 |0.00001 |- |2,3,3’,4,4’,5,5’-HpCB (189) |0.00003 |<0.000005 |0.00001 |} PCDD/F congeners usually seem to act additively, which justifies the use of TEFs.<ref>{{cite journal |last1=Viluksela |first1=M |last2=Stahl |first2=BU |last3=Birnbaum |first3=LS |last4=Schramm |first4=KW |last5=Kettrup |first5=A |last6=Rozman |first6=KK |title=Subchronic/chronic toxicity of a mixture of four chlorinated dibenzo-p-dioxins in rats. I. Design, general observations, hematology,and liver concentrations. |journal=Toxicology and applied pharmacology |date=July 1998 |volume=151 |issue=1 |pages=57-69 |doi=10.1006/taap.1998.8384 |pmid=9705887}}</ref> With less potent compounds, partial antagonism is possible.<ref>{{cite journal |last1=Safe |first1=SH |title=Hazard and risk assessment of chemical mixtures using the toxic equivalency factor approach. |journal=Environmental health perspectives |date=August 1998 |volume=106 Suppl 4 |pages=1051-8 |doi=10.1289/ehp.98106s41051 |pmid=9703492}}</ref><ref name=Berg00/><ref>{{cite journal |last1=Peters |first1=AK |last2=Leonards |first2=PE |last3=Zhao |first3=B |last4=Bergman |first4=A |last5=Denison |first5=MS |last6=Van den Berg |first6=M |title=Determination of in vitro relative potency (REP) values for mono-ortho polychlorinated biphenyls after purification with active charcoal. |journal=Toxicology letters |date=10 September 2006 |volume=165 |issue=3 |pages=230-41 |doi=10.1016/j.toxlet.2006.04.005 |pmid=16750337}}</ref><ref name=Howard10>{{cite journal |last1=Howard |first1=GJ |last2=Schlezinger |first2=JJ |last3=Hahn |first3=ME |last4=Webster |first4=TF |title=Generalized concentration addition predicts joint effects of aryl hydrocarbon receptor agonists with partial agonists and competitive antagonists. |journal=Environmental health perspectives |date=May 2010 |volume=118 |issue=5 |pages=666-72 |doi=10.1289/ehp.0901312 |pmid=20435555}}</ref> This may lead to overestimation of the total toxicity.<ref name=Howard10/> In fact, some in vitro results indicate that there may be significant deviations in human sensitivity from the TEF values based mostly on rodent data.<ref name=Larsson15/> If toxicity studies, such as on lethality, immunotoxicity and reproductive toxicity, are available, TEF values are based on them. If they are lacking, it may be necessary to base the values on ''in vitro'' information. Most studies are based on oral intake, so the values correlate best with oral toxicity. Internal TEF values based on concentrations in the body would be preferable, but there is not enough data to formulate them. Different endpoints of toxicity may lead to different TEF values; hence the values are always balanced compromises and show only the order of magnitude. Slightly different TEF values have been assessed for fish and birds, in addition to those of humans and other mammals (Table 2).<ref name=Berg98/> == Wildlife: exposures and toxic effects == Toxic effects in wildlife are difficult to sort out, because usually the exposures have been to mixtures of quite different chemicals such as PCDD/Fs, dioxin-like PCBs as well as simultaneous exposure to non-dioxin-like PCBs, DDT and other chlorinated insecticides such as aldrin, dieldrin, lindane and others. Effects of individual chemicals on animals have been studied in laboratory conditions, but ecological impact is more difficult to assess. Effects on wildlife and domestic animals have been reviewed, e.g.<ref name=White09>{{cite journal |last1=White |first1=SS |last2=Birnbaum |first2=LS |title=An overview of the effects of dioxins and dioxin-like compounds on vertebrates, as documented in human and ecological epidemiology. |journal=Journal of environmental science and health. Part C, Environmental carcinogenesis & ecotoxicology reviews |date=October 2009 |volume=27 |issue=4 |pages=197-211 |doi=10.1080/10590500903310047 |pmid=19953395}}</ref> Developmental and embryotoxicity are the most sensitive effects of dioxins. Trout and other salmonids are the most sensitive species of fish. Sensitivities among fish species vary up to 120-fold.<ref>{{cite journal |last1=Elonen |first1=Gregory E. |last2=Spehar |first2=Robert L. |last3=Holcombe |first3=Gary W. |last4=Johnson |first4=Rodney D. |last5=Fernandez |first5=Joseph D. |last6=Erickson |first6=Russell J. |last7=Tietge |first7=Joseph E. |last8=Cook |first8=Philip M. |title=Comparative toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin to seven freshwater fish species during early life-stage development |journal=Environmental Toxicology and Chemistry |date=March 1998 |volume=17 |issue=3 |pages=472–483 |doi=10.1002/etc.5620170319}}</ref><ref name=KingHeiden12>{{cite journal |last1=King-Heiden |first1=TC |last2=Mehta |first2=V |last3=Xiong |first3=KM |last4=Lanham |first4=KA |last5=Antkiewicz |first5=DS |last6=Ganser |first6=A |last7=Heideman |first7=W |last8=Peterson |first8=RE |title=Reproductive and developmental toxicity of dioxin in fish. |journal=Molecular and cellular endocrinology |date=6 May 2012 |volume=354 |issue=1-2 |pages=121-38 |doi=10.1016/j.mce.2011.09.027 |pmid=21958697}}</ref> Typical findings are excess mortality, oedema, haemorrhages, and craniofacial malformations. So-called blue sac disease of early embryos is associated with high concentrations of TCDD<ref>{{cite journal |last1=Walker |first1=Mary K. |last2=Spitsbergen |first2=Jan M. |last3=Olson |first3=James R. |last4=Peterson |first4=Richard E. |title=2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Toxicity during Early Life Stage Development of Lake Trout ( ) |journal=Canadian Journal of Fisheries and Aquatic Sciences |date=May 1991 |volume=48 |issue=5 |pages=875–883 |doi=10.1139/f91-104}}</ref> and other dioxin-like compounds.<ref>{{Cite journal|last=Vuorinen|first=P|date=2002-06|title=PCDD, PCDF, PCB and thiamine in Baltic herring (Clupea harengus L.) and sprat [ Sprattus sprattus (L.)] as a background to the M74 syndrome of Baltic salmon (Salmo salar L.)|url=http://dx.doi.org/10.1006/jmsc.2002.1200|journal=ICES Journal of Marine Science|volume=59|issue=3|pages=480–496|doi=10.1006/jmsc.2002.1200|issn=1054-3139}}</ref> Adult fish are less susceptible showing wasting syndrome, fin necrosis, liver toxicity, and loss of weight at high doses, and impaired reproduction especially in females.<ref name=KingHeiden12/> Dioxins, along with overfishing, are considered a reason for the lake trout population crash in the Great Lakes in the U.S.A. and Canada in mid-twentieth century. Experimentally it is possible to pinpoint the results at a specific chemical, and the mechanisms of toxicity in fish have been studied in zebrafish, especially cardiovascular toxicity, craniofacial malformations, and reproductive toxicity (reviewed by King-Heiden ''et al''.).<ref name=KingHeiden12/> A number of bird species have also been shown to be sensitive to embryonal toxicity and problems in reproduction. High concentrations of dioxins, PCBs and DDT in fish have threatened the populations of fish-eating birds, especially eagles and ospreys with incredible total PCB levels of up to 1,000 μg/g in fat, due to the position of these birds at the top of the food chain.<ref name=Helander08>{{cite journal |last1=Helander |first1=B |last2=Bignert |first2=A |last3=Asplund |first3=L |title=Using raptors as environmental sentinels: monitoring the white-tailed sea eagle Haliaeetus albicilla in Sweden. |journal=Ambio |date=September 2008 |volume=37 |issue=6 |pages=425-31 |doi=10.1579/0044-7447(2008)37[425:uraesm]2.0.co;2 |pmid=18833795}}</ref> Marine mammals are also on top of the food chain, highest are polar bears. On the other hand, polar bears also metabolize polychlorinated compounds fairly effectively.<ref name=Braune05>{{cite journal |last1=Braune |first1=BM |last2=Outridge |first2=PM |last3=Fisk |first3=AT |last4=Muir |first4=DC |last5=Helm |first5=PA |last6=Hobbs |first6=K |last7=Hoekstra |first7=PF |last8=Kuzyk |first8=ZA |last9=Kwan |first9=M |last10=Letcher |first10=RJ |last11=Lockhart |first11=WL |last12=Norstrom |first12=RJ |last13=Stern |first13=GA |last14=Stirling |first14=I |title=Persistent organic pollutants and mercury in marine biota of the Canadian Arctic: an overview of spatial and temporal trends. |journal=The Science of the total environment |date=1 December 2005 |volume=351-352 |pages=4-56 |doi=10.1016/j.scitotenv.2004.10.034 |pmid=16109439}}</ref> PCB concentrations seem to be 2–5-fold higher than in seals, their main food source. In Canadian seals total PCB levels vary from 300 to 1,000 ng/g (wet weight in blubber), and TEQs are of the order of 0.5–0.6 pg/g.<ref name=Braune05/> In the Baltic Sea, which is the most contaminated brackish water area in the world, total PCB levels in ringed seals are presently about 5,000 ng/g (in fat) and PCDD/F levels about 40 pg/g TEQ (in fat). The levels were 8-fold and 20-fold higher, resp., in 1970s, and at that time POPs are considered having been an important reason for their poor reproductive success.<ref name=Bjurlid18>{{cite journal |last1=Bjurlid |first1=F |last2=Roos |first2=A |last3=Ericson Jogsten |first3=I |last4=Hagberg |first4=J |title=Temporal trends of PBDD/Fs, PCDD/Fs, PBDEs and PCBs in ringed seals from the Baltic Sea (Pusa hispida botnica) between 1974 and 2015. |journal=The Science of the total environment |date=March 2018 |volume=616-617 |pages=1374-1383 |doi=10.1016/j.scitotenv.2017.10.178 |pmid=29066193}}</ref> POPs are also implicated in bone deformities in seals<ref>{{cite journal |last1=Olsson |first1=Mats |last2=Karlsson |first2=Börje |last3=Ahnland |first3=Eva |title=Diseases and environmental contaminants in seals from the Baltic and the Swedish west coast |journal=Science of The Total Environment |date=September 1994 |volume=154 |issue=2-3 |pages=217–227 |doi=10.1016/0048-9697(94)90089-2}}</ref> and polar bears.<ref>{{cite journal |last1=Sonne |first1=C |last2=Dietz |first2=R |last3=Born |first3=EW |last4=Riget |first4=FF |last5=Kirkegaard |first5=M |last6=Hyldstrup |first6=L |last7=Letcher |first7=RJ |last8=Muir |first8=DC |title=Is bone mineral composition disrupted by organochlorines in east Greenland polar bears (Ursus maritimus)? |journal=Environmental health perspectives |date=December 2004 |volume=112 |issue=17 |pages=1711-6 |doi=10.1289/ehp.7293 |pmid=15579418}}</ref> In addition to marine mammals, developmental effects were shown in bank voles living in an environment contaminated by chlorophenols and their dioxin impurities: they had third molars reduced in size.<ref>{{cite journal |last1=Murtomaa |first1=M |last2=Tervaniemi |first2=OM |last3=Parviainen |first3=J |last4=Ruokojärvi |first4=P |last5=Tuukkanen |first5=J |last6=Viluksela |first6=M |title=Dioxin exposure in contaminated sawmill area: the use of molar teeth and bone of bank vole (Clethrionomys glareolus) and field vole (Microtus agrestis) as biomarkers. |journal=Chemosphere |date=June 2007 |volume=68 |issue=5 |pages=951-7 |doi=10.1016/j.chemosphere.2007.01.030 |pmid=17335869}}</ref> In laboratory rats, TCDD reduces dose-dependently the size of molars, most severely the third lower molars.<ref name=Kattainen01>{{cite journal |last1=Kattainen |first1=H |last2=Tuukkanen |first2=J |last3=Simanainen |first3=U |last4=Tuomisto |first4=JT |last5=Kovero |first5=O |last6=Lukinmaa |first6=PL |last7=Alaluusua |first7=S |last8=Tuomisto |first8=J |last9=Viluksela |first9=M |title=In utero/lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure impairs molar tooth development in rats. |journal=Toxicology and applied pharmacology |date=1 August 2001 |volume=174 |issue=3 |pages=216-24 |doi=10.1006/taap.2001.9216 |pmid=11485382}}</ref> As in humans, the concentrations of dioxins (as well as DDT and its metabolites) in wildlife have clearly decreased over the years,<ref name=Braune05/> e.g. in seals of the Baltic sea,<ref name=Bjurlid18/> in eggs of herring gulls of the Great Lakes,<ref>{{cite journal |last1=Norstrom |first1=RJ |last2=Hebert |first2=CE |title=Comprehensive re-analysis of archived herring gull eggs reconstructs historical temporal trends in chlorinated hydrocarbon contamination in Lake Ontario and Green Bay, Lake Michigan, 1971-1982. |journal=Journal of environmental monitoring : JEM |date=August 2006 |volume=8 |issue=8 |pages=835-47 |doi=10.1039/b602378a |pmid=16896467}}</ref><ref>{{cite journal |last1=de Solla |first1=Shane R.|last2=Weseloh |first2=D. V. Chip |last3=Hughes |first3=Kimberley D. |last4=Moore |first4=David J. |title=Forty-Year Decline of Organic Contaminants in Eggs of Herring Gulls ( ) from the Great Lakes, 1974 to 2013 |journal=Waterbirds |date=April 2016 |volume=39 |issue=sp1 |pages=166–179 |doi=10.1675/063.039.sp117}}</ref> in eggs around contaminated harbour sites,<ref>{{cite journal |last1=Hughes |first1=K. D. |last2=de Solla |first2=S. R. |last3=Weseloh |first3=D. V. C. |last4=Martin |first4=P. A. |title=Long-term trends in legacy contaminants in aquatic wildlife in the Hamilton Harbour Area of Concern |journal=Aquatic Ecosystem Health & Management |date=9 May 2016 |volume=19 |issue=2 |pages=171–180 |doi=10.1080/14634988.2016.1150113}}</ref> and guillemot eggs of the Baltic sea,<ref>{{cite journal |last1=Miller |first1=A |last2=Nyberg |first2=E |last3=Danielsson |first3=S |last4=Faxneld |first4=S |last5=Haglund |first5=P |last6=Bignert |first6=A |title=Comparing temporal trends of organochlorines in guillemot eggs and Baltic herring: advantages and disadvantage for selecting sentinel species for environmental monitoring. |journal=Marine environmental research |date=September 2014 |volume=100 |pages=38-47 |doi=10.1016/j.marenvres.2014.02.007 |pmid=24680644}}</ref> in white-tailed eagles in Scandinavia,<ref name=Helander08/> as well as in salmon and Baltic herring in the Baltic sea.<ref name=Airaksinen14>{{cite journal |last1=Airaksinen |first1=R |last2=Hallikainen |first2=A |last3=Rantakokko |first3=P |last4=Ruokojärvi |first4=P |last5=Vuorinen |first5=PJ |last6=Parmanne |first6=R |last7=Verta |first7=M |last8=Mannio |first8=J |last9=Kiviranta |first9=H |title=Time trends and congener profiles of PCDD/Fs, PCBs, and PBDEs in Baltic herring off the coast of Finland during 1978-2009. |journal=Chemosphere |date=November 2014 |volume=114 |pages=165-71 |doi=10.1016/j.chemosphere.2014.03.097 |pmid=25113198}}</ref><ref>{{cite journal |last1=Miller |first1=A |last2=Hedman |first2=JE |last3=Nyberg |first3=E |last4=Haglund |first4=P |last5=Cousins |first5=IT |last6=Wiberg |first6=K |last7=Bignert |first7=A |title=Temporal trends in dioxins (polychlorinated dibenzo-p-dioxin and dibenzofurans) and dioxin-like polychlorinated biphenyls in Baltic herring (Clupea harengus). |journal=Marine pollution bulletin |date=15 August 2013 |volume=73 |issue=1 |pages=220-30 |doi=10.1016/j.marpolbul.2013.05.015 |pmid=23806670}}</ref><ref>{{cite journal |last1=Vuorinen |first1=Pekka J. |last2=Roots |first2=Ott |last3=Keinänen |first3=Marja |title=Review of organohalogen toxicants in fish from the Gulf of Finland |journal=Journal of Marine Systems |date=July 2017 |volume=171 |pages=141–150 |doi=10.1016/j.jmarsys.2016.12.002}}</ref> When the organochlorine levels have decreased, populations have recovered, e.g. white-tailed eagle<ref name=Helander08/><ref>{{cite journal |last1=Sulawa |first1=Justine |last2=Robert |first2=Alexandre |last3=Köppen |first3=Ulrich |last4=Hauff |first4=Peter |last5=Krone |first5=Oliver |title=Recovery dynamics and viability of the white-tailed eagle (Haliaeetus albicilla) in Germany |journal=Biodiversity and Conservation |date=13 August 2009 |volume=19 |issue=1 |pages=97–112 |doi=10.1007/s10531-009-9705-4}}</ref> and osprey.<ref>{{cite journal |last1=Rattner |first1=BA |last2=Lazarus |first2=RS |last3=Bean |first3=TG |last4=McGowan |first4=PC |last5=Callahan |first5=CR |last6=Erickson |first6=RA |last7=Hale |first7=RC |title=Examination of contaminant exposure and reproduction of ospreys (Pandion haliaetus) nesting in Delaware Bay and River in 2015. |journal=The Science of the total environment |date=15 October 2018 |volume=639 |pages=596-607 |doi=10.1016/j.scitotenv.2018.05.068 |pmid=29800853}}</ref> Brominated compounds have not decreased much so far, but they only contribute about 1 % of TEQs.<ref name=Bjurlid18/> Concentrations in fish and in birds are dependent on the age of the animal. Correcting for this is necessary to reliably calculate time trends in trout.<ref>{{cite journal |last1=Pagano |first1=JJ |last2=Garner |first2=AJ |last3=McGoldrick |first3=DJ |last4=Crimmins |first4=BS |last5=Hopke |first5=PK |last6=Milligan |first6=MS |last7=Holsen |first7=TM |title=Age-Corrected Trends and Toxic Equivalence of PCDD/F and CP-PCBs in Lake Trout and Walleye from the Great Lakes: 2004-2014. |journal=Environmental science & technology |date=16 January 2018 |volume=52 |issue=2 |pages=712-721 |doi=10.1021/acs.est.7b05568 |pmid=29249152}}</ref> In Baltic herring, concentrations of both PCBs and PCDD/Fs increase several fold from age 1 year to age 8–15 years.<ref>{{cite journal |last1=Kiviranta |first1=H |last2=Vartiainen |first2=T |last3=Parmanne |first3=R |last4=Hallikainen |first4=A |last5=Koistinen |first5=J |title=PCDD/Fs and PCBs in Baltic herring during the 1990s. |journal=Chemosphere |date=March 2003 |volume=50 |issue=9 |pages=1201-16 |pmid=12547334|doi=10.1016/S0045-6535(02)00481-2}}</ref><ref name=Airaksinen14/> In adult glaucous gulls, however, no age-correlation was found, suggesting that steady state levels are reached early in life.<ref>{{cite journal |last1=Bustnes |first1=JO |last2=Bakken |first2=V |last3=Skaare |first3=JU |last4=Erikstad |first4=KE |title=Age and accumulation of persistent organochlorines: a study of Arctic-breeding glaucous gulls (Larus hyperboreus)|doi=10.1897/02-456 |journal=Environmental toxicology and chemistry |date=September 2003 |volume=22 |issue=9 |pages=2173-9 |pmid=12959547}}</ref> This implies relatively rapid elimination and a short half-life. In eagle nestlings, PCB concentrations decrease after hatching<ref>{{cite journal |last1=Løseth |first1=ME |last2=Briels |first2=N |last3=Eulaers |first3=I |last4=Nygård |first4=T |last5=Malarvannan |first5=G |last6=Poma |first6=G |last7=Covaci |first7=A |last8=Herzke |first8=D |last9=Bustnes |first9=JO |last10=Lepoint |first10=G |last11=Jenssen |first11=BM |last12=Jaspers |first12=VLB |title=Plasma concentrations of organohalogenated contaminants in white-tailed eagle nestlings - The role of age and diet. |journal=Environmental pollution (Barking, Essex : 1987) |date=March 2019 |volume=246 |pages=527-534 |doi=10.1016/j.envpol.2018.12.028 |pmid=30583161}}</ref> indicating that maternal load transferred to eggs is initially more important than the content of PCBs in their diet during the rapid growth. == Human intake and concentrations == Animal source food is the most important source of dioxins for humans.<ref name=Liem00/> Fish is very important, and although meat and milk products have dominated in most countries, the concentrations in farming products have now declined due to active emission controls.<ref name=EFSAPanel18>{{cite journal |last1=EFSA Panel on Contaminants in the Food Chain |title=Risk for animal and human health related to the presence of dioxins and dioxin-like PCBs in feed and food |journal=EFSA Journal |date=2018 |volume=16 |page=5333 |doi=10.2903/j.efsa.2018.5333 |url=https://www.efsa.europa.eu/en/efsajournal/pub/5333}}</ref> In all foods the concentrations have decreased remarkably in the Western countries during the last 30 to 40 years, and the present daily intake is 1–2 pg/kg bw (TEQ). Human exposure from contaminated soil is very limited.<ref>{{cite journal |last1=Demond |first1=A |last2=Franzblau |first2=A |last3=Garabrant |first3=D |last4=Jiang |first4=X |last5=Adriaens |first5=P |last6=Chen |first6=Q |last7=Gillespie |first7=B |last8=Hao |first8=W |last9=Hong |first9=B |last10=Jolliet |first10=O |last11=Lepkowski |first11=J |title=Human exposure from dioxins in soil. |journal=Environmental science & technology |date=7 February 2012 |volume=46 |issue=3 |pages=1296-302 |doi=10.1021/es2022363 |pmid=22136605}}</ref> Dioxins accumulate during the whole lifetime, because their half-lives are very long (Fig. 6). PCDD/F concentrations in young people are 5–10 pg/g TEQ in fat, but 40–100 pg/g in older generations.<ref>{{cite journal |last1=Kiviranta |first1=H |last2=Tuomisto |first2=JT |last3=Tuomisto |first3=J |last4=Tukiainen |first4=E |last5=Vartiainen |first5=T |title=Polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls in the general population in Finland. |journal=Chemosphere |date=August 2005 |volume=60 |issue=7 |pages=854-69 |doi=10.1016/j.chemosphere.2005.01.064 |pmid=15992592}}</ref> Additionally, there is carry-over in older generations from earlier decades when the intake was 5 to 10 times higher than presently.<ref name=TuomistoSTS>{{cite journal |last1=Tuomisto |first1=JT |last2=Pekkanen |first2=J |last3=Kiviranta |first3=H |last4=Tukiainen |first4=E |last5=Vartiainen |first5=T |last6=Tuomisto |first6=J |title=Soft-tissue sarcoma and dioxin: A case-control study. |journal=International journal of cancer |date=1 March 2004 |volume=108 |issue=6 |pages=893-900 |doi=10.1002/ijc.11635 |pmid=14712494}}</ref><ref name=Tuomisto16>{{cite journal |last1=Tuomisto |first1=J |last2=Airaksinen |first2=R |last3=Kiviranta |first3=H |last4=Tukiainen |first4=E |last5=Pekkanen |first5=J |last6=Tuomisto |first6=JT |title=A pharmacokinetic analysis and dietary information are necessary to confirm or reject the hypothesis on persistent organic pollutants causing type 2 diabetes. |journal=Toxicology letters |date=2 November 2016 |volume=261 |pages=41-48 |doi=10.1016/j.toxlet.2016.08.024 |pmid=27575567}}</ref> For this reason concentrations (e.g. between population groups in epidemiological studies) cannot be compared without information on age and the year of sampling. {{Fig | number = 6 | image = Dioxin concentration by age.png | caption = Dioxin concentrations (in adipose tissue) are high in older generations for two reasons: dioxins accumulate over years, because their elimination is slow and half-lives are long, and the intake was much higher in the past than presently (cf. Fig. 7).<ref name=TuomistoSTS /> | attribution = courtesy Jouni T. Tuomisto }} Dioxin concentrations (but not all PCBs) in humans have been decreasing for over 30 years, in line with decreasing environmental levels.<ref>{{cite journal |last1=Consonni |first1=D |last2=Sindaco |first2=R |last3=Bertazzi |first3=PA |title=Blood levels of dioxins, furans, dioxin-like PCBs, and TEQs in general populations: a review, 1989-2010. |journal=Environment international |date=September 2012 |volume=44 |pages=151-62 |doi=10.1016/j.envint.2012.01.004 |pmid=22364893}}</ref> The World Health Organization has organized dioxin follow-up measurements in breast milk since 1987. In more recent surveys also PCBs and some other persistent chlorinated compounds have been measured.<ref name=Berg17b>{{cite journal |last1=van den Berg |first1=M |last2=Kypke |first2=K |last3=Kotz |first3=A |last4=Tritscher |first4=A |last5=Lee |first5=SY |last6=Magulova |first6=K |last7=Fiedler |first7=H |last8=Malisch |first8=R |title=WHO/UNEP global surveys of PCDDs, PCDFs, PCBs and DDTs in human milk and benefit-risk evaluation of breastfeeding. |journal=Archives of toxicology |date=January 2017 |volume=91 |issue=1 |pages=83-96 |doi=10.1007/s00204-016-1802-z |pmid=27438348}}</ref> Historical information is crucial, because effects on next generations are possible (see below), and if true in humans, the impact of high concentrations in 1970s would be seen during the 21^st century. Breast milk concentrations were very high in 1970s (Fig. 7), about 50 pg/g for PCDD/Fs and 50 pg/g for dl-PCBs (TEQ in fat).<ref name=Noren>{{cite journal |last1=Norén |first1=K |last2=Meironyté |first2=D |title=Certain organochlorine and organobromine contaminants in Swedish human milk in perspective of past 20-30 years. |journal=Chemosphere |date=NaN |volume=40 |issue=9-11 |pages=1111-23 |pmid=10739053|doi=10.1016/S0045-6535(99)00360-4}}</ref> During the first systematic round of breast milk measurements in 1987, PCDD/F concentrations in many countries were between 30 and 40 pg/g TEQ in milk fat<ref>WHO. Levels of PCBs, PCDDs, and PCDFs in breast milk. ''World Health Organisation, Environmental Health Series 34'' ; 1989.</ref> and during the last round in 2005–2010 between 5 and 10 pg/g in many European countries (generally below 10 pg/g<ref name=EFSAPanel18/>), and low in many African countries, but still high in e.g. India, Egypt and the Netherlands (over 20 pg/g).<ref name=Berg17b/> Thus the concentrations have decreased by 80–90 % in many but not all countries. {{Fig | number = 7 | image = Decrease of dioxins in milk.jpg | caption = Decrease of dioxin concentrations in breast milk in Sweden and Finland (Sweden, early data from Norén and Meironyté, 2000, others from van den Berg et al, 2017 and WHO database of the Institute for Health and Welfare, Finland, Hannu Kiviranta).<ref name=Noren /><ref name=Berg17b/> | attribution = }} == Toxic effects in humans == === Accidents, contamination episodes and occupational risks === A few dramatic accidental or deliberate cases of acute poisoning have taken place. Two women were poisoned in Vienna, Austria, in 1998 by huge doses of TCDD. Dioxin concentration in one of them was 144,000 pg/g in serum fat, the highest ever measured in humans.<ref name=Geusau01>{{cite journal |last1=Geusau |first1=A |last2=Abraham |first2=K |last3=Geissler |first3=K |last4=Sator |first4=MO |last5=Stingl |first5=G |last6=Tschachler |first6=E |title=Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: clinical and laboratory effects. |journal=Environmental health perspectives |date=August 2001 |volume=109 |issue=8 |pages=865-9 |doi=10.1289/ehp.01109865 |pmid=11564625}}</ref> The dose must have been about 25 µg/kg. For comparison, contemporary concentrations in young people are 5–10 pg TEQ/g fat, and in older people 50 pg TEQ/g fat or more (Fig. 6), and daily intake is 1–2 pg TEQ/kg body weight. This victim survived despite the extraordinarily high levels of TCDD in her serum, but had severe chloracne lasting for years and weight loss. There were few other symptoms or laboratory findings: gastrointestinal symptoms and amenorrhea.<ref name=Geusau01/> Victor Yushchenko, then presidential candidate of Ukraine, was deliberately poisoned in 2004 with a large dose of TCDD; the concentration in fat was 108,000 pg/g. He suffered from severe gastrointestinal symptoms, indicating pancreatitis and hepatitis, and then developed severe chloracne, but survived.<ref name=Sorg09/><ref name=Saurat12>{{cite journal |last1=Saurat |first1=JH |last2=Kaya |first2=G |last3=Saxer-Sekulic |first3=N |last4=Pardo |first4=B |last5=Becker |first5=M |last6=Fontao |first6=L |last7=Mottu |first7=F |last8=Carraux |first8=P |last9=Pham |first9=XC |last10=Barde |first10=C |last11=Fontao |first11=F |last12=Zennegg |first12=M |last13=Schmid |first13=P |last14=Schaad |first14=O |last15=Descombes |first15=P |last16=Sorg |first16=O |title=The cutaneous lesions of dioxin exposure: lessons from the poisoning of Victor Yushchenko. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=January 2012 |volume=125 |issue=1 |pages=310-7 |doi=10.1093/toxsci/kfr223 |pmid=21998131}}</ref> In both the Vienna poisoning and the Yushchenko poisoning the details of TCDD intake are unknown. Perhaps the best known dioxin accident took place in Seveso, Italy in 1976.<ref name=Mocarelli91>{{cite journal |last1=Mocarelli |first1=P |last2=Needham |first2=LL |last3=Marocchi |first3=A |last4=Patterson DG |first4=Jr |last5=Brambilla |first5=P |last6=Gerthoux |first6=PM |last7=Meazza |first7=L |last8=Carreri |first8=V |title=Serum concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin and test results from selected residents of Seveso, Italy. |journal=Journal of toxicology and environmental health |date=April 1991 |volume=32 |issue=4 |pages=357-66 |doi=10.1080/15287399109531490 |pmid=1826746}}</ref><ref>{{cite journal |last1=Eskenazi |first1=B |last2=Warner |first2=M |last3=Brambilla |first3=P |last4=Signorini |first4=S |last5=Ames |first5=J |last6=Mocarelli |first6=P |title=The Seveso accident: A look at 40 years of health research and beyond. |journal=Environment international |date=December 2018 |volume=121 |issue=Pt 1 |pages=71-84 |doi=10.1016/j.envint.2018.08.051 |pmid=30179766}}</ref> The town was contaminated by TCDD, after a tank containing 2,4,5-trichlorophenol released its contents to air. The highest levels (up to 56,000 pg/g in serum lipid) were found in children who ate local food and played outdoors. About 200 cases of chloracne occurred; other detectable human effects were few, although a number of animals such as rabbits died.<ref name=Mocarelli91/> Cancer studies have suggested a slightly increased number of hematopoietic and lymphatic tissue malignancies.<ref>{{cite journal |last1=Consonni |first1=D |last2=Pesatori |first2=AC |last3=Zocchetti |first3=C |last4=Sindaco |first4=R |last5=D'Oro |first5=LC |last6=Rubagotti |first6=M |last7=Bertazzi |first7=PA |title=Mortality in a population exposed to dioxin after the Seveso, Italy, accident in 1976: 25 years of follow-up. |journal=American journal of epidemiology |date=1 April 2008 |volume=167 |issue=7 |pages=847-58 |doi=10.1093/aje/kwm371 |pmid=18192277}}</ref><ref>{{cite journal |last1=Pesatori |first1=AC |last2=Consonni |first2=D |last3=Rubagotti |first3=M |last4=Grillo |first4=P |last5=Bertazzi |first5=PA |title=Cancer incidence in the population exposed to dioxin after the "Seveso accident": twenty years of follow-up. |journal=Environmental health : a global access science source |date=15 September 2009 |volume=8 |pages=39 |doi=10.1186/1476-069X-8-39 |pmid=19754930}}</ref> In a cohort of women with measured individual TCDD levels a slightly increased risk of all cancers was found (1.8 fold risk vs. tenfold increase in TCDD concentration) as well as a non-significant increased risk of breast cancer.<ref>{{cite journal |last1=Warner |first1=M |last2=Mocarelli |first2=P |last3=Samuels |first3=S |last4=Needham |first4=L |last5=Brambilla |first5=P |last6=Eskenazi |first6=B |title=Dioxin exposure and cancer risk in the Seveso Women's Health Study. |journal=Environmental health perspectives |date=December 2011 |volume=119 |issue=12 |pages=1700-5 |doi=10.1289/ehp.1103720 |pmid=21810551}}</ref> Several developmental consequences were detected after the Seveso incident. Dental aberrations associated with TCDD levels were found 25 years after the accident in persons who had been less than five years old at the time of the accident.<ref name=Alaluusua04>{{cite journal |last1=Alaluusua |first1=S |last2=Calderara |first2=P |last3=Gerthoux |first3=PM |last4=Lukinmaa |first4=PL |last5=Kovero |first5=O |last6=Needham |first6=L |last7=Patterson DG |first7=Jr |last8=Tuomisto |first8=J |last9=Mocarelli |first9=P |title=Developmental dental aberrations after the dioxin accident in Seveso. |journal=Environmental health perspectives |date=September 2004 |volume=112 |issue=13 |pages=1313-8 |doi=10.1289/ehp.6920 |pmid=15345345}}</ref> Lowered male/female sex ratios were found in the offspring of males exposed to high concentrations of TCDD.<ref name=Mocarelli00>{{cite journal |last1=Mocarelli |first1=P |last2=Gerthoux |first2=PM |last3=Ferrari |first3=E |last4=Patterson DG |first4=Jr |last5=Kieszak |first5=SM |last6=Brambilla |first6=P |last7=Vincoli |first7=N |last8=Signorini |first8=S |last9=Tramacere |first9=P |last10=Carreri |first10=V |last11=Sampson |first11=EJ |last12=Turner |first12=WE |last13=Needham |first13=LL |title=Paternal concentrations of dioxin and sex ratio of offspring. |journal=Lancet (London, England) |date=27 May 2000 |volume=355 |issue=9218 |pages=1858-63 |doi=10.1016/S0140-6736(00)02290-X |pmid=10866441}}</ref> Decreased sperm quality was observed in young men exposed to TCDD in utero and during lactation or during infancy or prepuberty.<ref>{{cite journal |last1=Mocarelli |first1=P |last2=Gerthoux |first2=PM |last3=Patterson DG |first3=Jr |last4=Milani |first4=S |last5=Limonta |first5=G |last6=Bertona |first6=M |last7=Signorini |first7=S |last8=Tramacere |first8=P |last9=Colombo |first9=L |last10=Crespi |first10=C |last11=Brambilla |first11=P |last12=Sarto |first12=C |last13=Carreri |first13=V |last14=Sampson |first14=EJ |last15=Turner |first15=WE |last16=Needham |first16=LL |title=Dioxin exposure, from infancy through puberty, produces endocrine disruption and affects human semen quality. |journal=Environmental health perspectives |date=January 2008 |volume=116 |issue=1 |pages=70-7 |doi=10.1289/ehp.10399 |pmid=18197302}}</ref><ref name=Mocarelli11>{{cite journal |last1=Mocarelli |first1=P |last2=Gerthoux |first2=PM |last3=Needham |first3=LL |last4=Patterson DG |first4=Jr |last5=Limonta |first5=G |last6=Falbo |first6=R |last7=Signorini |first7=S |last8=Bertona |first8=M |last9=Crespi |first9=C |last10=Sarto |first10=C |last11=Scott |first11=PK |last12=Turner |first12=WE |last13=Brambilla |first13=P |title=Perinatal exposure to low doses of dioxin can permanently impair human semen quality. |journal=Environmental health perspectives |date=May 2011 |volume=119 |issue=5 |pages=713-8 |doi=10.1289/ehp.1002134 |pmid=21262597}}</ref> Slightly increased risk of endometriosis<ref>{{cite journal |last1=Eskenazi |first1=B |last2=Mocarelli |first2=P |last3=Warner |first3=M |last4=Samuels |first4=S |last5=Vercellini |first5=P |last6=Olive |first6=D |last7=Needham |first7=LL |last8=Patterson DG |first8=Jr |last9=Brambilla |first9=P |last10=Gavoni |first10=N |last11=Casalini |first11=S |last12=Panazza |first12=S |last13=Turner |first13=W |last14=Gerthoux |first14=PM |title=Serum dioxin concentrations and endometriosis: a cohort study in Seveso, Italy. |journal=Environmental health perspectives |date=July 2002 |volume=110 |issue=7 |pages=629-34 |doi=10.1289/ehp.02110629 |pmid=12117638}}</ref> as well as a dose-dependently increased time to pregnancy and infertility were found among the most heavily exposed women.<ref>{{cite journal |last1=Eskenazi |first1=B |last2=Warner |first2=M |last3=Marks |first3=AR |last4=Samuels |first4=S |last5=Needham |first5=L |last6=Brambilla |first6=P |last7=Mocarelli |first7=P |title=Serum dioxin concentrations and time to pregnancy. |journal=Epidemiology (Cambridge, Mass.) |date=March 2010 |volume=21 |issue=2 |pages=224-31 |doi=10.1097/EDE.0b013e3181cb8b95 |pmid=20124903}}</ref> However, in 30 years’ follow-up no association between TCDD exposure and adverse pregnancy outcomes were detected except for a non-significant decrease in birthweight.<ref>{{cite journal |last1=Wesselink |first1=A |last2=Warner |first2=M |last3=Samuels |first3=S |last4=Parigi |first4=A |last5=Brambilla |first5=P |last6=Mocarelli |first6=P |last7=Eskenazi |first7=B |title=Maternal dioxin exposure and pregnancy outcomes over 30 years of follow-up in Seveso. |journal=Environment international |date=February 2014 |volume=63 |pages=143-8 |doi=10.1016/j.envint.2013.11.005 |pmid=24291766}}</ref> Some metabolic and endocrine effects were seen for a limited time period.<ref>{{cite journal |last1=Sweeney |first1=MH |last2=Mocarelli |first2=P |title=Human health effects after exposure to 2,3,7,8-TCDD. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=303-16 |doi=10.1080/026520300283379 |pmid=10912244}}</ref> Neonatal thyroid stimulating hormone levels were increased in newborns of mothers with high body burdens of TCDD.<ref>{{cite journal |last1=Baccarelli |first1=A |last2=Giacomini |first2=SM |last3=Corbetta |first3=C |last4=Landi |first4=MT |last5=Bonzini |first5=M |last6=Consonni |first6=D |last7=Grillo |first7=P |last8=Patterson |first8=DG |last9=Pesatori |first9=AC |last10=Bertazzi |first10=PA |title=Neonatal thyroid function in Seveso 25 years after maternal exposure to dioxin. |journal=PLoS medicine |date=29 July 2008 |volume=5 |issue=7 |pages=e161 |doi=10.1371/journal.pmed.0050161 |pmid=18666825}}</ref> There have also been several cases of food contamination. In Japan (Yusho incident, 1968) and in Taiwan (Yu-cheng incident, 1979) PCB oil used in heat exchangers leaked to rice bran oil. Consumption of contaminated oil caused over 2000<ref>{{cite journal |last1=Kashima |first1=S |last2=Yorifuji |first2=T |last3=Tsuda |first3=T |last4=Eboshida |first4=A |title=Cancer and non-cancer excess mortality resulting from mixed exposure to polychlorinated biphenyls and polychlorinated dibenzofurans from contaminated rice oil: "Yusho". |journal=International archives of occupational and environmental health |date=May 2015 |volume=88 |issue=4 |pages=419-30 |doi=10.1007/s00420-014-0966-1 |pmid=25091711}}</ref> and about 2000<ref name=Tsai07>{{cite journal |last1=Tsai |first1=PC |last2=Ko |first2=YC |last3=Huang |first3=W |last4=Liu |first4=HS |last5=Guo |first5=YL |title=Increased liver and lupus mortalities in 24-year follow-up of the Taiwanese people highly exposed to polychlorinated biphenyls and dibenzofurans. |journal=The Science of the total environment |date=15 March 2007 |volume=374 |issue=2-3 |pages=216-22 |doi=10.1016/j.scitotenv.2006.12.024 |pmid=17257654}}</ref> cases of poisoning, respectively. Most of the toxic effects have been attributed to PCDFs and dl-PCBs. The most dramatic health effects were caused by developmental toxicity during pregnancy. The average daily intake was calculated to have been 154,000 pg I-TEQ/kg in the Yusho incident,<ref>{{cite journal |last1=Masuda |first1=Y |title=Approach to risk assessment of chlorinated dioxins from Yusho PCB poisoning. |journal=Chemosphere |date=February 1996 |volume=32 |issue=3 |pages=583-94 |pmid=8907236|doi=10.1016/0045-6535(95)00314-2}}</ref> 100,000 fold higher than average background intake at present. The Yu-cheng incident was roughly similar, and the concentrations were still over 1300 pg I-TEQ/g fat about 15 years later.<ref>{{cite journal |last1=Hsu |first1=JF |last2=Guo |first2=YL |last3=Yang |first3=SY |last4=Liao |first4=PC |title=Congener profiles of PCBs and PCDD/Fs in Yucheng victims fifteen years after exposure to toxic rice-bran oils and their implications for epidemiologic studies. |journal=Chemosphere |date=December 2005 |volume=61 |issue=9 |pages=1231-43 |doi=10.1016/j.chemosphere.2005.03.081 |pmid=15893794}}</ref> There were many skin problems such as hypersecretion of Meibomian glands in the eyes, swelling of eyelids, abnormal pigmentation of skin, hyperkeratosis and chloracne. Babies born to Yusho and Yu-cheng mothers were smaller than normal. They had dark brown pigmentation, gingival hyperplasia, and sometimes dentition at birth or other tooth deformities. Foetal deaths and miscarriages were common.<ref name=Mitoma15/> Cancer studies initially gave inconsistent results in spite of the heavy exposure.<ref>{{cite journal |last1=Onozuka |first1=D |last2=Yoshimura |first2=T |last3=Kaneko |first3=S |last4=Furue |first4=M |title=Mortality after exposure to polychlorinated biphenyls and polychlorinated dibenzofurans: a 40-year follow-up study of Yusho patients. |journal=American journal of epidemiology |date=1 January 2009 |volume=169 |issue=1 |pages=86-95 |doi=10.1093/aje/kwn295 |pmid=18974082}}</ref><ref name=Tsai07/> Later, a combined analysis of both episodes indicated increased mortality from all causes, all cancers, lung cancer, and heart disease in men, and liver cancer in women.<ref>{{cite journal |last1=Li |first1=MC |last2=Chen |first2=PC |last3=Tsai |first3=PC |last4=Furue |first4=M |last5=Onozuka |first5=D |last6=Hagihara |first6=A |last7=Uchi |first7=H |last8=Yoshimura |first8=T |last9=Guo |first9=YL |title=Mortality after exposure to polychlorinated biphenyls and polychlorinated dibenzofurans: a meta-analysis of two highly exposed cohorts. |journal=International journal of cancer |date=15 September 2015 |volume=137 |issue=6 |pages=1427-32 |doi=10.1002/ijc.29504 |pmid=25754105}}</ref> Several feed and food contamination episodes with dioxin-like compounds have occurred also in Europe and elsewhere.<ref name=Malisch14>{{cite journal |last1=Malisch |first1=R |last2=Kotz |first2=A |title=Dioxins and PCBs in feed and food--review from European perspective. |journal=The Science of the total environment |date=1 September 2014 |volume=491-492 |pages=2-10 |doi=10.1016/j.scitotenv.2014.03.022 |pmid=24804623}}</ref><ref name=Hoogenboom15/> A tank of recycled fats was contaminated with at least 160 kg PCB oil in 1999 in Belgium, and used for animal feed. Low fertility of chickens and deformed chicks were noted. About 1 g of dioxins and 2 g dl-PCBs (TEQ) were involved.<ref name=Debacker07>{{cite journal |last1=Debacker |first1=N |last2=Sasse |first2=A |last3=van Wouwe |first3=N |last4=Goeyens |first4=L |last5=Sartor |first5=F |last6=van Oyen |first6=H |title=PCDD/F levels in plasma of a belgian population before and after the 1999 belgian PCB/DIOXIN incident. |journal=Chemosphere |date=April 2007 |volume=67 |issue=9 |pages=S217-23 |doi=10.1016/j.chemosphere.2006.05.101 |pmid=17208274}}</ref> This caused a major dioxin alarm, and European Union set very strict limits for dioxins in food and feed. Due to fairly rapid intervention, total dioxin concentrations in the population did not increase even in Belgium: 23.1 versus 22.9 pg TEQ/g fat.<ref name=Debacker07/> No health effects have been noted. Similar conclusions were drawn after a food contamination incident in Ireland: a short term exceedance of limit values is not likely to lead to health effects.<ref>{{Cite journal|last=Tlustos|first=C.|last2=Anderson|first2=W.|last3=Flynn|first3=A.|last4=Pratt|first4=I.|date=2014-05-04|title=Additional exposure of the Irish adult population to dioxins and PCBs from the diet as a consequence of the 2008 Irish dioxin food contamination incident|url=http://www.tandfonline.com/doi/abs/10.1080/19440049.2014.893399|journal=Food Additives & Contaminants: Part A|language=en|volume=31|issue=5|pages=889–904|doi=10.1080/19440049.2014.893399|issn=1944-0049}}</ref> The incidences show that careful food controls are necessary, but no individual health measures (e.g. abortions) are rational in case of short moderately increased intake, because human dioxin body burden (accumulated during the whole lifetime) is large compared with short-term additional exposures, and therefore levels increase very slowly. Phenoxy acid herbicides (Agent Orange and others, contaminated by dioxins, especially TCDD) were used in large quantities during the Vietnam War. The veterans have been thoroughly studied, but variable levels complicate assessments. There is some evidence for increased cancer, diabetes,<ref>{{cite journal |last1=Michalek |first1=JE |last2=Pavuk |first2=M |title=Diabetes and cancer in veterans of Operation Ranch Hand after adjustment for calendar period, days of spraying, and time spent in Southeast Asia. |journal=Journal of occupational and environmental medicine |date=March 2008 |volume=50 |issue=3 |pages=330-40 |doi=10.1097/JOM.0b013e31815f889b |pmid=18332783}}</ref> and hypertension<ref>{{cite journal |last1=Cypel |first1=YS |last2=Kress |first2=AM |last3=Eber |first3=SM |last4=Schneiderman |first4=AI |last5=Davey |first5=VJ |title=Herbicide Exposure, Vietnam Service, and Hypertension Risk in Army Chemical Corps Veterans. |journal=Journal of occupational and environmental medicine |date=November 2016 |volume=58 |issue=11 |pages=1127-1136 |doi=10.1097/JOM.0000000000000876 |pmid=27820763}}</ref> in the most highly exposed groups. However, causal relationship has been difficult to prove, and e.g. in case of diabetes a reverse causality has been suggested,<ref>{{Cite journal|last=Kerger|first=Brent D.|last2=Scott|first2=Paul K.|last3=Pavuk|first3=Marian|last4=Gough|first4=Michael|last5=Paustenbach|first5=Dennis J.|date=2012-06-21|title=Re-analysis of Ranch Hand study supports reverse causation hypothesis between dioxin and diabetes|url=http://dx.doi.org/10.3109/10408444.2012.694095|journal=Critical Reviews in Toxicology|volume=42|issue=8|pages=669–687|doi=10.3109/10408444.2012.694095|issn=1040-8444}}</ref> and dose-responses do not support causality.<ref>{{Cite journal|last=Steenland|first=K|date=2001-10-01|title=Dioxin and diabetes mellitus: an analysis of the combined NIOSH and Ranch Hand data|url=http://dx.doi.org/10.1136/oem.58.10.641|journal=Occupational and Environmental Medicine|volume=58|issue=10|pages=641–648|doi=10.1136/oem.58.10.641|issn=1351-0711}}</ref><ref name=Jaacks>{{Cite journal|last=Jaacks|first=Lindsay M.|last2=Staimez|first2=Lisa R.|date=2015-03|title=Association of persistent organic pollutants and non-persistent pesticides with diabetes and diabetes-related health outcomes in Asia: A systematic review|url=http://dx.doi.org/10.1016/j.envint.2014.12.001|journal=Environment International|volume=76|pages=57–70|doi=10.1016/j.envint.2014.12.001|issn=0160-4120}}</ref><ref name=Tuomisto16/> Effects on local population in Vietnam have been less scrutinized.<ref>{{cite journal |last1=Young |first1=Alvin |title=A Review of Public Health in Vietnam: 50 Years after Agent Orange was Sprayed |journal=Health Education and Public Health |date=2019 |volume=2 |issue=2 |pages=170-180 |doi=10.31488 /heph.119 |url=https://www.academia.edu/39168589/A_Review_of_Public_Health_in_Vietnam_50_Years_after_Agent_Orange_was_Sprayed |language=en}}</ref> Tooth enamel defects were found to be more common in dioxin-affected regions,<ref name=Pham19>{{cite journal |last1=Pham |first1=NT |last2=Nishijo |first2=M |last3=Pham |first3=TT |last4=Tran |first4=NN |last5=Le |first5=VQ |last6=Tran |first6=HA |last7=Phan |first7=HAV |last8=Nishino |first8=Y |last9=Nishijo |first9=H |title=Perinatal dioxin exposure and neurodevelopment of 2-year-old Vietnamese children in the most contaminated area from Agent Orange in Vietnam. |journal=The Science of the total environment |date=15 August 2019 |volume=678 |pages=217-226 |doi=10.1016/j.scitotenv.2019.04.425 |pmid=31075589}}</ref> as well as borderline impaired neurodevelopment<ref>{{cite journal |last1=Tran |first1=NN |last2=Pham |first2=TT |last3=Ozawa |first3=K |last4=Nishijo |first4=M |last5=Nguyen |first5=AT |last6=Tran |first6=TQ |last7=Hoang |first7=LV |last8=Tran |first8=AH |last9=Phan |first9=VH |last10=Nakai |first10=A |last11=Nishino |first11=Y |last12=Nishijo |first12=H |title=Impacts of Perinatal Dioxin Exposure on Motor Coordination and Higher Cognitive Development in Vietnamese Preschool Children: A Five-Year Follow-Up. |journal=PloS one |date=2016 |volume=11 |issue=1 |pages=e0147655 |doi=10.1371/journal.pone.0147655 |pmid=26824471}}</ref><ref name=Pham19/> and eating disorders.<ref>{{cite journal |last1=Nguyen |first1=Anh Thi Nguyet |last2=Nishijo |first2=Muneko |last3=Pham |first3=Tai The |last4=Tran |first4=Nghi Ngoc |last5=Tran |first5=Anh Hai |last6=Hoang |first6=Luong Van |last7=Boda |first7=Hitomi |last8=Morikawa |first8=Yuko |last9=Nishino |first9=Yoshikazu |last10=Nishijo |first10=Hisao |title=Sex-specific effects of perinatal dioxin exposure on eating behavior in 3-year-old Vietnamese children |journal=BMC Pediatrics |date=5 July 2018 |volume=18 |issue=1 |pages=213 |doi=10.1186/s12887-018-1171-2 |url=https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-018-1171-2 |issn=1471-2431}}</ref> Both modelling and monitoring results suggest that although somewhat higher than normal, highly elevated exposures to TCDD are not common in local people occasionally exposed to spraying.<ref>{{cite journal |last1=Armitage |first1=JM |last2=Ginevan |first2=ME |last3=Hewitt |first3=A |last4=Ross |first4=JH |last5=Watkins |first5=DK |last6=Solomon |first6=KR |title=Environmental fate and dietary exposures of humans to TCDD as a result of the spraying of Agent Orange in upland forests of Vietnam. |journal=The Science of the total environment |date=15 February 2015 |volume=506-507 |pages=621-30 |doi=10.1016/j.scitotenv.2014.11.026 |pmid=25433383}}</ref> However, there are remarkable differences in PCDD/F levels in breast milk in different locations, and hot spots exist.<ref>{{cite journal |last1=Hue |first1=NT |last2=Nam |first2=VD |last3=Thuong |first3=NV |last4=Huyen |first4=NT |last5=Phuong |first5=NT |last6=Hung |first6=NX |last7=Tuan |first7=NH |last8=Son |first8=LK |last9=Minh |first9=NH |title=Determination of PCDD/Fs in breast milk of women living in the vicinities of Da Nang Agent Orange hot spot (Vietnam) and estimation of the infant's daily intake. |journal=The Science of the total environment |date=1 September 2014 |volume=491-492 |pages=212-8 |doi=10.1016/j.scitotenv.2014.02.054 |pmid=24613651}}</ref> Several industrial settings have caused high exposures to dioxins when synthesizing chlorophenols or phenoxy acid herbicides.<ref>{{cite journal |last1=Flesch-Janys |first1=D |last2=Berger |first2=J |last3=Gurn |first3=P |last4=Manz |first4=A |last5=Nagel |first5=S |last6=Waltsgott |first6=H |last7=Dwyer |first7=JH |title=Exposure to polychlorinated dioxins and furans (PCDD/F) and mortality in a cohort of workers from a herbicide-producing plant in Hamburg, Federal Republic of Germany. |journal=American journal of epidemiology |date=1 December 1995 |volume=142 |issue=11 |pages=1165-75 |doi=10.1093/oxfordjournals.aje.a117575 |pmid=7485063}}</ref><ref>{{cite journal |last1=Ott |first1=MG |last2=Zober |first2=A |title=Cause specific mortality and cancer incidence among employees exposed to 2,3,7,8-TCDD after a 1953 reactor accident. |journal=Occupational and environmental medicine |date=September 1996 |volume=53 |issue=9 |pages=606-12 |doi=10.1136/oem.53.9.606 |pmid=8882118}}</ref><ref>{{cite journal |last1=Steenland |first1=K |last2=Piacitelli |first2=L |last3=Deddens |first3=J |last4=Fingerhut |first4=M |last5=Chang |first5=LI |title=Cancer, heart disease, and diabetes in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. |journal=Journal of the National Cancer Institute |date=5 May 1999 |volume=91 |issue=9 |pages=779-86 |doi=10.1093/jnci/91.9.779 |pmid=10328108}}</ref><ref>{{cite journal |last1=Boers |first1=D |last2=Portengen |first2=L |last3=Bueno-de-Mesquita |first3=HB |last4=Heederik |first4=D |last5=Vermeulen |first5=R |title=Cause-specific mortality of Dutch chlorophenoxy herbicide manufacturing workers. |journal=Occupational and environmental medicine |date=January 2010 |volume=67 |issue=1 |pages=24-31 |doi=10.1136/oem.2008.044222 |pmid=19736176}}</ref> Some of these main chemicals are carcinogenic which makes pinpointing the risk to a specific chemical problematic.<ref name=IARC16>{{Cite book|url=https://publications.iarc.fr/Book-And-Report-Series/Iarc-Monographs-On-The-Identification-Of-Carcinogenic-Hazards-To-Humans/Pentachlorophenol-And-Some-Related-Compounds-2019|date=2016|chapter=Pentachlorophenol and Some Related Compounds|title=IARC Monographs on the Evaluation of Carcinogenic Risks to Humans|publisher=IARC|volume=117|pages=33-168|isbn=978-92-832-0155-7|language=en}}</ref><ref name=Tuomisto12b/> Chloracne is a hallmark characteristic at the higher end of exposure levels. Occupational cancer studies have been pooled in a large international combined cohort, suggesting an increased risk of all cancers and of soft-tissue sarcoma.<ref name=Kogevinas97>{{cite journal |last1=Kogevinas |first1=M |last2=Becher |first2=H |last3=Benn |first3=T |last4=et al. |title=Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins |journal=Am J Epidemiol |date=1997 |volume=145 |pages=1061-1075 |doi=10.1093/oxfordjournals.aje.a009069 |pmid=9199536}}</ref> The difficulty in interpreting the effects is that exposure levels were not measured directly and appear to be highly variable, i.e. very high industrial levels and marginally increased levels in workers spraying phenoxy herbicides.<ref name=Tuomisto12b/> The study<ref name=Kogevinas97/> was crucial for IARC evaluations,<ref name=IARC97/><ref name="IARC12">{{Cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK304398/|title=2,3,7,8-tetrachlorodibenzopara-dioxin, 2,3,4,7,8-pentachlorodibenzofuran, and 3,3',4,4',5-pentachlorobiphenyl|last=IARC Working Group on the Evaluation of Carcinogenic Risk to Humans|first=|date=2012|publisher=International Agency for Research on Cancer|year=|isbn=|volume=100F|location=|pages=339-378|language=en}}</ref> which have also been criticized.<ref name=Yamaguchi99>{{Cite journal|last=Yamaguchi|first=N|date=1999-12|title=Uncertainty in Risk Characterization of Weak Carcinogens|url=http://dx.doi.org/10.1111/j.1749-6632.1999.tb08094.x|journal=Annals of the New York Academy of Sciences|volume=895|issue=1 UNCERTAINTY I|pages=338–347|doi=10.1111/j.1749-6632.1999.tb08094.x|issn=0077-8923}}</ref><ref name=Cole02/><ref name=Boffetta11>{{Cite journal|last=Boffetta|first=Paolo|last2=Mundt|first2=Kenneth A.|last3=Adami|first3=Hans-Olov|last4=Cole|first4=Philip|last5=Mandel|first5=Jack S.|date=2011-07|title=TCDD and cancer: A critical review of epidemiologic studies|url=http://dx.doi.org/10.3109/10408444.2011.560141|journal=Critical Reviews in Toxicology|volume=41|issue=7|pages=622–636|doi=10.3109/10408444.2011.560141|issn=1040-8444}}</ref> Especially the evidence on soft-tissue sarcoma is weak and based on very few cases,<ref name=Tuomisto12b>{{cite journal |last1=Tuomisto |first1=J |last2=Tuomisto |first2=JT |title=Is the fear of dioxin cancer more harmful than dioxin? |journal=Toxicology letters |date=5 May 2012 |volume=210 |issue=3 |pages=338-44 |doi=10.1016/j.toxlet.2012.02.007 |pmid=22387160}}</ref> but a slight increase of all cancers is likely to be real considering recent new evidence on Yusho, Yu-cheng and Seveso accidents. An increase in lung cancer risk would be logical among smokers due to promotion. A recent meta-analysis concluded that there is an association between dioxins and increased all cancer incidence and mortality and non-Hodgkin's lymphoma mortality.<ref name=Xu2017>{{Cite journal|last=Xu|first=Jinming|last2=Ye|first2=Yao|last3=Huang|first3=Fang|last4=Chen|first4=Hanwen|last5=Wu|first5=Han|last6=Huang|first6=Jian|last7=Hu|first7=Jian|last8=Xia|first8=Dajing|last9=Wu|first9=Yihua|date=2016-11-29|title=Association between dioxin and cancer incidence and mortality: a meta-analysis|url=http://dx.doi.org/10.1038/srep38012|journal=Scientific Reports|volume=6|issue=1|doi=10.1038/srep38012|issn=2045-2322}}</ref> The association was non-linear.<ref name=Xu2017/> A review of high-exposure studies suggests that dioxin exposure is associated with increased mortality from cardiovascular disease and, especially, ischemic heart disease.<ref>{{cite journal |last1=Humblet |first1=O |last2=Birnbaum |first2=L |last3=Rimm |first3=E |last4=Mittleman |first4=MA |last5=Hauser |first5=R |title=Dioxins and cardiovascular disease mortality. |journal=Environmental health perspectives |date=November 2008 |volume=116 |issue=11 |pages=1443-8 |doi=10.1289/ehp.11579 |pmid=19057694}}</ref> High industrial male dioxin levels were associated with lowered male/female ratio of offspring agreeing with the Seveso results.<ref>{{cite journal |last1=Ryan |first1=JJ |last2=Amirova |first2=Z |last3=Carrier |first3=G |title=Sex ratios of children of Russian pesticide producers exposed to dioxin. |journal=Environmental health perspectives |date=November 2002 |volume=110 |issue=11 |pages=A699-701 |doi=10.1289/ehp.021100699 |pmid=12417498}}</ref> === Risks connected with low exposures of general population === Tooth deformities have been considered a plausible developmental effect in a general population after a long breast-feeding with relatively high dioxin concentrations in breast milk (range 7.7–258) pg/g TEQ in fat.<ref name=Alaluusua96>{{cite journal |last1=Alaluusua |first1=S |last2=Lukinmaa |first2=PL |last3=Vartiainen |first3=T |last4=Partanen |first4=M |last5=Torppa |first5=J |last6=Tuomisto |first6=J |title=Polychlorinated dibenzo-p-dioxins and dibenzofurans via mother's milk may cause developmental defects in the child's teeth. |journal=Environmental toxicology and pharmacology |date=15 May 1996 |volume=1 |issue=3 |pages=193-7 |pmid=21781681|doi=10.1016/1382-6689(96)00007-5}}</ref><ref>{{cite journal |last1=Alaluusua |first1=S |last2=Lukinmaa |first2=PL |last3=Torppa |first3=J |last4=Tuomisto |first4=J |last5=Vartiainen |first5=T |title=Developing teeth as biomarker of dioxin exposure. |journal=Lancet (London, England) |date=16 January 1999 |volume=353 |issue=9148 |pages=206 |doi=10.1016/S0140-6736(05)77214-7 |pmid=9923879}}</ref> The effects were no longer seen when dioxin levels in milk decreased over the years. Cryptorchidism did not associate with placental levels of dioxins and PCBs,<ref name=Virtanen12/> but adipose tissue levels at the time of operation may support an association.<ref>{{cite journal |last1=Koskenniemi |first1=JJ |last2=Virtanen |first2=HE |last3=Kiviranta |first3=H |last4=Damgaard |first4=IN |last5=Matomäki |first5=J |last6=Thorup |first6=JM |last7=Hurme |first7=T |last8=Skakkebaek |first8=NE |last9=Main |first9=KM |last10=Toppari |first10=J |title=Association between levels of persistent organic pollutants in adipose tissue and cryptorchidism in early childhood: a case-control study. |journal=Environmental health : a global access science source |date=24 September 2015 |volume=14 |pages=78 |doi=10.1186/s12940-015-0065-0 |pmid=26403566}}</ref> Sperm counts at age 18–19 years were inversely associated with dioxin levels at age 8–9 years in a cohort of Russian boys.<ref name=MínguezAlarcon17>{{cite journal |last1=Mínguez-Alarcón |first1=L |last2=Sergeyev |first2=O |last3=Burns |first3=JS |last4=Williams |first4=PL |last5=Lee |first5=MM |last6=Korrick |first6=SA |last7=Smigulina |first7=L |last8=Revich |first8=B |last9=Hauser |first9=R |title=A Longitudinal Study of Peripubertal Serum Organochlorine Concentrations and Semen Parameters in Young Men: The Russian Children's Study. |journal=Environmental health perspectives |date=March 2017 |volume=125 |issue=3 |pages=460-466 |doi=10.1289/EHP25 |pmid=27713107}}</ref> The range of PCDD/F+PCB TEQ was 4.88–107 pg/g lipid, or relatively high for age due to local industrial emissions. Maternal levels of dioxins were 5 to 173 pg TEQ/g fat, but the levels in babies are not known.<ref>{{cite journal |last1=Humblet |first1=O |last2=Williams |first2=PL |last3=Korrick |first3=SA |last4=Sergeyev |first4=O |last5=Emond |first5=C |last6=Birnbaum |first6=LS |last7=Burns |first7=JS |last8=Altshul |first8=L |last9=Patterson |first9=DG |last10=Turner |first10=WE |last11=Lee |first11=MM |last12=Revich |first12=B |last13=Hauser |first13=R |title=Predictors of serum dioxin, furan, and PCB concentrations among women from Chapaevsk, Russia. |journal=Environmental science & technology |date=15 July 2010 |volume=44 |issue=14 |pages=5633-40 |doi=10.1021/es100976j |pmid=20578718}}</ref> Several endpoints in male sexual development including those in the Russian Children study have been reviewed and the most sensitive endpoint was interpreted to be sperm count due to epididymal factors.<ref name=Pilsner17>{{cite journal |last1=Pilsner |first1=JR |last2=Parker |first2=M |last3=Sergeyev |first3=O |last4=Suvorov |first4=A |title=Spermatogenesis disruption by dioxins: Epigenetic reprograming and windows of susceptibility. |journal=Reproductive toxicology (Elmsford, N.Y.) |date=April 2017 |volume=69 |pages=221-229 |doi=10.1016/j.reprotox.2017.03.002 |pmid=28286111}}</ref> It was hypothesized that the mechanism is associated with sperm DNA methylation in young adults.<ref>{{cite journal |last1=Pilsner |first1=JR |last2=Shershebnev |first2=A |last3=Medvedeva |first3=YA |last4=et al. |title=Peripubertal serum dioxin concentrations and subsequent sperm methylome profiles of young Russian adults. |journal=Reproductive toxicology (Elmsford, N.Y.) |date=June 2018 |volume=78 |pages=40-49 |doi=10.1016/j.reprotox.2018.03.007 |pmid=29550351}}</ref> Recently a number of cross-sectional studies have shown associations between type 2 diabetes and several POP compounds including dioxins (reviewed by Magliano et al.).<ref name=Magliano14>{{cite journal |last1=Magliano |first1=DJ |last2=Loh |first2=VH |last3=Harding |first3=JL |last4=Botton |first4=J |last5=Shaw |first5=JE |title=Persistent organic pollutants and diabetes: a review of the epidemiological evidence. |journal=Diabetes & metabolism |date=February 2014 |volume=40 |issue=1 |pages=1-14 |doi=10.1016/j.diabet.2013.09.006 |pmid=24262435}}</ref> Their significance remains uncertain, however, because ecological observational studies cannot prove causality, and prospective studies have been inconsistent.<ref name=Magliano14/><ref name=Tornevi19>{{cite journal |last1=Tornevi |first1=A |last2=Sommar |first2=J |last3=Rantakokko |first3=P |last4=Åkesson |first4=A |last5=Donat-Vargas |first5=C |last6=Kiviranta |first6=H |last7=Rolandsson |first7=O |last8=Rylander |first8=L |last9=Wennberg |first9=M |last10=Bergdahl |first10=IA |title=Chlorinated persistent organic pollutants and type 2 diabetes - A population-based study with pre- and post- diagnostic plasma samples. |journal=Environmental research |date=July 2019 |volume=174 |pages=35-45 |doi=10.1016/j.envres.2019.04.017 |pmid=31029940}}</ref> One of the problems is that similar results have been obtained with a large variety of chlorinated pesticides, non-dioxin-like PCBs, dl-PCBs, PCDDs and PCDFs. These compounds have different mechanisms of action, and the only common denominator is long half-life leading to unpredictable toxicokinetics. This suggests that the results may be confounded by diet and obesity which are by far the most important risk factors of type 2 diabetes.<ref name=Magliano14/><ref name=Tuomisto16/><ref name=Tornevi19/> Well-planned controlled studies are clearly needed.<ref name=Jaacks/> An international panel met in 1998, organized by the World Health Organization and International Programme on Chemical Safety, to give guidance for assessing tolerable daily intake (TDI) values.<ref>{{cite journal |editor1-last=Van Leeuwen |editor1-first=F.X.R. |editor2-last=Younes, |editor2-first=M.M. |title=Assessment of the health risk of dioxins: re-evaluation of the tolerable daily intake (TDI). Geneva, Switzerland, 25-29 May 1998. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=223-369 |pmid=10960271|doi=10.1080/713810655}}</ref> Critical body burdens were compared in humans and animals, and the respective estimated human intake was calculated. The most relevant effects were found to be sperm count, immune suppression, genital malformations, and neurobehavioural effects in offspring and endometriosis in adults.<ref name=WHO00>{{cite journal |last1=WHO temporary advisor group |title=Consultation on assessment of the health risk of dioxins; re-evaluation of the tolerable daily intake (TDI): executive summary. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=223-40 |doi=10.1080/713810655 |pmid=10912238}}</ref> Thus the safety margins for different developmental effects were considered lowest. The TDI recommendation was 1-4 pg/kg TEQ, with an ultimate goal to reduce it to 1 pg/kg. This recommendation was based on the intake of dioxins by women in fertile age subsequently delivering dioxins during pregnancy and breast feeding to the child. Dioxin concentration in breast milk fat is about the same as in mother's adipose tissue. Therefore a baby is exposed to higher daily amounts of dioxins during breastfeeding than at any later stage of life. Considering the amount of fat transported from mother to child during a long breast feeding period, this was considered the most vulnerable situation. Therefore the TDI does not directly guide intake in any other population group, including older children.<ref name=WHO00/> It should be noted that the body burden of dioxins at steady state is about 5000 daily doses meaning that only long-term intake is important.<ref name=TuomistoSynopsis/> The Joint FAO/WHO Expert Committee on Food Additives (JECFA) derived in 2001 a provisional tolerable monthly intake (PTMI) of 70 pg TEQ/kg body weight.<ref name=Malisch14/> The Scientific Committee on Food (SCI) of the European Commission applied a tolerable weekly intake (TWI) of 14 pg TEQ/kg, which is very close to the JECFA PTMI.<ref>{{Cite web|url=https://ec.europa.eu/food/sites/food/files/safety/docs/cs_contaminants_catalogue_dioxins_out90_en.pdf|title=Opinion of the scientific committee on food on the risk assessment of dioxins and dioxin-like PCBs in food (S/CNTM/DIOXIN/20 final)|publisher=European Commission|date=2001|website=hero.epa.gov|language=en|access-date=2019-12-17}}</ref> (Table 3) The U.S. Environmental Protection Agency (U.S. EPA) established an oral reference dose (RfD) of 0.7 pg/kg b.w. per day for TCDD.<ref>{{Cite web|url=https://cfpub.epa.gov/ncea/risk/recordisplay.cfm?deid=222203|title=EPA's Reanalysis of Key Issues Related to Dioxin Toxicity and Response to NAS Comments (External Review Draft)|publisher=US EPA National Center for Environmental Assessment,Cincinnati Oh|last=Rice|first=Glenn|website=cfpub.epa.gov|language=en|access-date=2019-12-16}}</ref> The differences are based on two factors, EPA assessment is based on human data and tenfold uncertainty factor, the others on animal data and a threefold safety factor. In view of different approaches European Food Safety Authority (EFSA) recommended a new comprehensive risk assessment,<ref name=EFSA15b>{{cite journal |last1=EFSA (European Food Safety Authority) |title=Scientific statement on the health‐based guidance values for dioxins and dioxin‐like PCBs |journal=EFSA Journal |date=May 2015 |volume=13 |issue=5 |doi=10.2903/j.efsa.2015.4124}}</ref> and recently EFSA Panel on Contaminants in the Food Chain (CONTAM) recommended a TWI of 2 pg TEQ/kg which is pending.<ref name=EFSAPanel18/> (Table 3) '''Table 3 {{!}}''' Tolerable intake estimates by different agencies in Europe and the United States. {| class="wikitable sortable" !Agency !class="unsortable"|Tolerable dose !Tolerable dose expressed as TDI |- |WHO 2000 | |1-4 pg TEQ/kg |- |SCF 2001 |14 pg TEQ/kg weekly |2 pg TEQ/kg |- |JECFA 2001 |70 pg TEQ/kg monthly |2.3 pg TEQ/kg |- |USEPA 2012 |0.7 pg TCDD/kg daily (reference dose) | |- |EFSA CONTAM Panel 2018 |2 pg TEQ/kg weekly |0.29 TEQ/kg |} The CONTAM panel of EFSA recommended a TWI of 2 pg/kg based heavily on the Russian Children Study.<ref name=EFSAPanel18/> There is an uncertainty in that we do not know the sensitive time period, and if it is e.g. two first years of life associated with breast feeding, we do not know the concentrations that may have been higher than at 8–9 years. Modelling is limited by the lack of exact information on kinetics in small children. Decreasing sperm counts in many countries while the concentrations of dioxins have been decreasing, do not support a causal role of present dioxin intake. If multigenerational mechanisms are involved, it would be more important to evaluate the concentrations some decades back, and contemporary restrictions no longer help. Setting strict arbitrary limits may fire back, and changes in diet, e.g. avoiding fish consumption could lead to harmful health effects.<ref>{{Cite journal|last=Olsen|first=Sjúrđur Fróđi|last2=Secher|first2=Niels Jørgen|date=2002-10|title=Low Consumption of Seafood in Early Pregnancy as a Risk Factor for Preterm Delivery: Prospective Cohort Study|url=http://dx.doi.org/10.1097/00006254-200210000-00004|journal=Obstetrical & Gynecological Survey|volume=57|issue=10|pages=651–652|doi=10.1097/00006254-200210000-00004|issn=0029-7828}}</ref><ref name=Cohen2005>{{Cite journal|last=Cohen|first=Joshua T.|last2=Bellinger|first2=David C.|last3=Connor|first3=William E.|last4=Kris-Etherton|first4=Penny M.|last5=Lawrence|first5=Robert S.|last6=Savitz|first6=David A.|last7=Shaywitz|first7=Bennett A.|last8=Teutsch|first8=Steven M.|last9=Gray|first9=George M.|date=2005-11-01|title=A Quantitative Risk–Benefit Analysis of Changes in Population Fish Consumption|url=https://www.ajpmonline.org/article/S0749-3797(05)00253-9/abstract|journal=American Journal of Preventive Medicine|language=English|volume=29|issue=4|pages=325–334.e6|doi=10.1016/j.amepre.2005.07.003|issn=0749-3797}}</ref><ref>{{Cite journal|last=Mozaffarian|first=Dariush|last2=Rimm|first2=Eric B.|date=2006-10-18|title=Fish Intake, Contaminants, and Human Health|url=http://dx.doi.org/10.1001/jama.296.15.1885|journal=JAMA|volume=296|issue=15|pages=1885|doi=10.1001/jama.296.15.1885|issn=0098-7484}}</ref><ref name=Starling>{{Cite journal|last=Starling|first=Phoebe|last2=Charlton|first2=Karen|last3=McMahon|first3=Anne|last4=Lucas|first4=Catherine|date=2015-03-18|title=Fish Intake during Pregnancy and Foetal Neurodevelopment—A Systematic Review of the Evidence|url=http://dx.doi.org/10.3390/nu7032001|journal=Nutrients|volume=7|issue=3|pages=2001–2014|doi=10.3390/nu7032001|issn=2072-6643}}</ref><ref name="Tuomisto19">{{Cite journal|last=Tuomisto|first=Jouni T.|last2=Asikainen|first2=Arja|last3=Meriläinen|first3=Päivi|last4=Haapasaari|first4=Päivi|date=2020-01-15|title=Health effects of nutrients and environmental pollutants in Baltic herring and salmon: a quantitative benefit-risk assessment|url=https://doi.org/10.1186/s12889-019-8094-1|journal=BMC Public Health|volume=20|issue=1|pages=64|doi=10.1186/s12889-019-8094-1|issn=1471-2458|pmc=PMC6964011|pmid=31941472}}</ref> It is also a problem that potentially harmful intake may only concern certain age categories (esp. young women before their first pregnancy affecting the child), and otherwise fish consumption unquestionably means a health benefit.<ref name=Cohen2005/><ref name=Tuomisto19/> Cancer risk from dioxin exposures has been hotly debated. IARC<ref name="IARC97">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK409980/|title=Polychlorinated Dibenzo-para-dioxins and Polychlorinated Dibenzofurans|last1=IARC Working Group on the Evaluation of Carcinogenic Risk to Humans|first1=|date=1997|publisher=International Agency for Research on Cancer|year=|isbn=|volume=69|location=|pages=1-636}}</ref><ref name=IARC12/> has deemed TCDD and 2,3,4,7,8-TCDF as carcinogenic to humans (class 1). However, the assessments are based on animal experiments and high accidental or occupational exposures.<ref name=Schrenk12/> IARC only assesses the certainty of evidence regardless of the dose, and it remains unclear what is the risk for the general population. The high-exposure populations<ref>{{cite journal |last1=Kogevinas |first1=M |title=Studies of cancer in humans. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=317-24 |doi=10.1080/026520300283388 |pmid=10912245}}</ref> were exposed to 100–1000 or more times higher levels than the general population. Thus both animal studies and epidemiological studies refer to high doses and require extrapolation to low population levels. The assessment has been challenged in several papers on various grounds.<ref name=Yamaguchi99/><ref>{{Cite journal|last=Kayajanian|first=Gary Michael|date=2002-01|title=The J-Shaped Dioxin Dose Response Curve|url=http://dx.doi.org/10.1006/eesa.2001.2115|journal=Ecotoxicology and Environmental Safety|volume=51|issue=1|pages=1–4|doi=10.1006/eesa.2001.2115|issn=0147-6513}}</ref><ref name=Cole02>{{cite journal |last1=Cole |first1=P |last2=Trichopoulos |first2=D |last3=Pastides |first3=H |last4=Starr |first4=T |last5=Mandel |first5=JS |title=Dioxin and cancer: a critical review. |journal=Regulatory toxicology and pharmacology : RTP |date=December 2003 |volume=38 |issue=3 |pages=378-88 |pmid=14623487|doi=10.1016/j.yrtph.2003.08.002}}</ref><ref name=Boffetta11/><ref name=Tuomisto12b/> It may be concluded that dioxins are carcinogenic in animals and probably carcinogenic at high dose levels in humans. However, there is no good evidence that there would be any significant increase in cancer risk at the present levels detected in the general population. The WHO consultation group<ref name=WHO00/> concluded that the potential cancer risk is taken care of, if TDI is determined on the basis of developmental effects. A population risk in humans is unlikely on several grounds. Dioxins do not cause carcinogenic mutations of DNA.<ref name=IARC12/> Therefore linear extrapolation is not likely to be valid,<ref name=Xu2017/> and safety margins can be applied as in other forms of toxicity. The important physiological role of the AH receptor means that an appropriate receptor activation is beneficial. Only inappropriate stimulation is harmful, which is the case with other receptors such as steroid and thyroid receptors.<ref name=Tuomisto12b/> Cancer interpretation based on case-control studies relying on exposure assessment by questionnaires after diagnosing cancer is problematic because of recall bias.<ref>{{cite journal |last1=Tuomisto |first1=J |last2=Airaksinen |first2=R |last3=Pekkanen |first3=J |last4=Tukiainen |first4=E |last5=Kiviranta |first5=H |last6=Tuomisto |first6=JT |title=Comparison of questionnaire data and analyzed dioxin concentrations as a measure of exposure in soft-tissue sarcoma studies. |journal=Toxicology letters |date=15 March 2017 |volume=270 |pages=8-11 |doi=10.1016/j.toxlet.2017.02.011 |pmid=28189645}}</ref> Cohort studies have given equivocal results.<ref name=Tuomisto12b/> A specific cancer that many studies associate with dioxins is soft tissue sarcoma. In a large case-control study with individual measured concentration data, no positive associations were found between soft-tissue sarcoma and TEQs or individual dioxins or PCBs.<ref name=TuomistoSTS/> Rather there was a trend of decreasing risk at higher exposure groups suggesting a hormetic effect.<ref>{{cite journal |last1=Tuomisto |first1=J |last2=Pekkanen |first2=J |last3=Kiviranta |first3=H |last4=Tukiainen |first4=E |last5=Vartiainen |first5=T |last6=Viluksela |first6=M |last7=Tuomisto |first7=JT |title=Dioxin cancer risk--example of hormesis? |journal=Dose-response : a publication of International Hormesis Society |date=1 May 2006 |volume=3 |issue=3 |pages=332-41 |doi=10.2203/dose-response.003.03.004 |pmid=18648613}}</ref> Other side of the coin may even be that AH receptor agonists could be used in search for drugs in treating cancer.<ref name=Kolluri17/> Recently a few among a large number of POPs analysed were found to correlate with breast cancer metastasis.<ref>{{Cite journal|last=Koual|first=Meriem|last2=Cano-Sancho|first2=German|last3=Bats|first3=Anne-Sophie|last4=Tomkiewicz|first4=Céline|last5=Kaddouch-Amar|first5=Yael|last6=Douay-Hauser|first6=Nathalie|last7=Ngo|first7=Charlotte|last8=Bonsang|first8=Hélène|last9=Deloménie|first9=Myriam|date=2019-11|title=Associations between persistent organic pollutants and risk of breast cancer metastasis|url=http://dx.doi.org/10.1016/j.envint.2019.105028|journal=Environment International|volume=132|pages=105028|doi=10.1016/j.envint.2019.105028|issn=0160-4120}}</ref> In addition to chance effects there is a problem of causality: what is primary and what is secondary.<ref name=Tuomisto16/> In conclusion the safety margins seem to be lowest for developmental effects. Sex ratio changes were seen at concentrations about 20 times the present levels,<ref name=Mocarelli00/> and for enamel defects in teeth and the sperm quality the margin may be slightly lower.<ref name=Alaluusua96/><ref name=Alaluusua04/><ref name=MínguezAlarcon17/><ref name=Pilsner17/> These are in line with the assessment by the WHO panel.<ref name=WHO00/> The WHO panel based their assessment in the exposure of child-bearing women who excrete much of their body burden to the child during pregnancy and lactation. In other population groups the risks are low. The panel concluded that even if the safety margin concerning the child is fairly narrow, the benefits of breast feeding clearly exceed the risks. Similarly, the health benefits of fish consumption clearly exceed the risks of dioxins or other persistent organic compounds.<ref name=Starling/><ref>{{cite journal |last1=Tuomisto |first1=JT |last2=Tuomisto |first2=J |last3=Tainio |first3=M |last4=Niittynen |first4=M |last5=Verkasalo |first5=P |last6=Vartiainen |first6=T |last7=Kiviranta |first7=H |last8=Pekkanen |first8=J |title=Risk-benefit analysis of eating farmed salmon. |journal=Science (New York, N.Y.) |date=23 July 2004 |volume=305 |issue=5683 |pages=476-7; author reply 476-7 |doi=10.1126/science.305.5683.476 |pmid=15273377}}</ref><ref name=Tuomisto19/> In case of competing risks (e.g. cardiovascular disease) the application of precautionary principle may be dangerous. This means that while acknowledging the modest safety margins concerning food, it is more relevant to emphasize the importance of decreasing dioxin emissions to the environment and reducing environmental levels.<ref name=Assefa/><ref name=White09/> == Effects in laboratory animals and their relevance in risk assessment == Effects of dioxins in animals can be broadly divided to clearly toxic effects (such as lethality, wasting syndrome, liver injury, developmental toxicity), and metabolic effects that often can be classified as adaptive responses (such as induction of enzymes metabolizing xenobiotic chemicals).<ref name=WHO00/> Highly detailed descriptions on dioxin toxicity in animals can be found in several reviews.<ref name=Poland82/><ref name=Pohjanvirta94/><ref name=Birnbaum00>{{cite journal |last1=Birnbaum |first1=LS |last2=Tuomisto |first2=J |title=Non-carcinogenic effects of TCDD in animals. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=275-88 |doi=10.1080/026520300283351 |pmid=10912242}}</ref><ref name=TuomistoDeich>{{cite journal |last1=Tuomisto |first1=J |title=Does mechanistic understanding help in risk assessment--the example of dioxins. |journal=Toxicology and applied pharmacology |date=1 September 2005 |volume=207 |issue=2 Suppl |pages=2-10 |doi=10.1016/j.taap.2005.01.053 |pmid=15996698}}</ref><ref name=Okey07/><ref name=White09/><ref name=Linden10/><ref name=Pohjanvirta12/> === The most conspicuous acute toxic effects in adult animals === Acute toxicity of dioxins differs highly among species (Table 4). Guinea pig is considered to be the most sensitive mammal; the LD50 of TCDD is about 1-2 µg/kg. Hamsters tolerate more than a thousand fold dose. The differences between and within species are sometimes based on different ligand binding affinities (e.g. C57BL/6 mice and ten times more resistant DBA2/2J mice), sometimes to the structure of the transactivation domain of the receptor (such as a thousand fold difference between Long-Evans and Han/Wistar/Kuo rats, and possibly between guinea pig and hamster). These differences have complicated risk assessment on the basis of animal studies. It is typical that even after a high single dose the animals do not die immediately, but following a reduced feed intake and wasting (so called wasting syndrome) in two to three weeks.<ref name=Pohjanvirta94/> The syndrome is associated with decreased appetite and food intake, but the exact mechanism is not clear.<ref name=Linden10/> A wasting-syndrome-like poisoning has never been seen in humans even after huge doses (see above).<ref name=Geusau01/><ref name=Saurat12/> At very low doses there is a clear aversion response to novel foods which may not be related to the fatal wasting syndrome, but is rather an adaptive safety response preventing consumption of toxic food items.<ref name=Lensu17>{{cite journal |last1=Lensu |first1=S |last2=Tuomisto |first2=JT |last3=Tuomisto |first3=J |last4=Pohjanvirta |first4=R |title=Characterization of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-provoked strong and rapid aversion to unfamiliar foodstuffs in rats. |journal=Toxicology |date=10 May 2011 |volume=283 |issue=2-3 |pages=140-50 |doi=10.1016/j.tox.2011.03.007 |pmid=21435369}}</ref><ref name=Lensu2011>{{cite journal |last1=Lensu |first1=S |last2=Tuomisto |first2=JT |last3=Tuomisto |first3=J |last4=Viluksela |first4=M |last5=Niittynen |first5=M |last6=Pohjanvirta |first6=R |title=Immediate and highly sensitive aversion response to a novel food item linked to AH receptor stimulation. |journal=Toxicology letters |date=24 June 2011 |volume=203 |issue=3 |pages=252-7 |doi=10.1016/j.toxlet.2011.03.025 |pmid=21458548}}</ref> '''Table 4 {{!}}''' Lethal dose in some animal species<ref name=Pohjanvirta94/> {| class="wikitable" !Species !LD50 (μg/kg body weight) |- |Guinea pig |2 |- |Rat |10-60 |- |Rhesus monkey |~70 |- |Rabbit |115 |- |Mouse |100-300 |- |Dog |>300 |- |Bullfrog |>500 |- |Hamster |~3,000 |- |Han/Wistar(Kuopio) rat |>10,000 |} Some changes in the transactivation domain of AH receptor influence drastically the wasting syndrome and lethality whereas biochemical effects such as CYP1A1 enzyme induction are unaffected as well as AHR binding.<ref>{{cite journal |last1=Pohjanvirta |first1=R |last2=Wong |first2=JM |last3=Li |first3=W |last4=Harper |first4=PA |last5=Tuomisto |first5=J |last6=Okey |first6=AB |title=Point mutation in intron sequence causes altered carboxyl-terminal structure in the aryl hydrocarbon receptor of the most 2,3,7,8-tetrachlorodibenzo-p-dioxin-resistant rat strain. |journal=Molecular pharmacology |date=July 1998 |volume=54 |issue=1 |pages=86-93 |doi=10.1124/mol.54.1.86 |pmid=9658193}}</ref> Therefore two types of dioxin effects have been proposed (Table 5). Type I responses include developmental effects, aversion to novel foods, and the typical induction of CYP1A1 and other oxidative enzymes which occur at the same dose levels regardless of the structure of the AHR. Type II responses with great variation between species and strains include several high-dose effects such as wasting syndrome, lethality, and liver toxicity.<ref>{{cite journal |last1=Tuomisto |first1=JT |last2=Viluksela |first2=M |last3=Pohjanvirta |first3=R |last4=Tuomisto |first4=J |title=The AH receptor and a novel gene determine acute toxic responses to TCDD: segregation of the resistant alleles to different rat lines. |journal=Toxicology and applied pharmacology |date=15 February 1999 |volume=155 |issue=1 |pages=71-81 |doi=10.1006/taap.1998.8564 |pmid=10036220}}</ref><ref>{{cite journal |last1=Simanainen |first1=U |last2=Tuomisto |first2=JT |last3=Tuomisto |first3=J |last4=Viluksela |first4=M |title=Dose-response analysis of short-term effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in three differentially susceptible rat lines. |journal=Toxicology and applied pharmacology |date=1 March 2003 |volume=187 |issue=2 |pages=128-36 |doi=10.1016/s0041-008x(02)00068-6 |pmid=12649045}}</ref> There is some evidence that tumour promotion might belong to type II responses.<ref name="Viluksela00">{{cite journal |last1=Viluksela |first1=M |last2=Bager |first2=Y |last3=Tuomisto |first3=JT |last4=Scheu |first4=G |last5=Unkila |first5=M |last6=Pohjanvirta |first6=R |last7=Flodström |first7=S |last8=Kosma |first8=VM |last9=Mäki-Paakkanen |first9=J |last10=Vartiainen |first10=T |last11=Klimm |first11=C |last12=Schramm |first12=KW |last13=Wärngård |first13=L |last14=Tuomisto |first14=J |title=Liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive and TCDD-resistant rat strains. |journal=Cancer research |date=15 December 2000 |volume=60 |issue=24 |pages=6911-20 |pmid=11156390}}</ref> '''Table 5 {{!}}''' Examples of toxic and adaptive responses to TCDD in very differently sensitive rat lines, the resistant Han/Wistar Kuopio and the sensitive Long-Evans strains<ref name=TuomistoDeich/> (novel food aversion, resistant line A and sensitive line C developed from H/W and L-E strains<ref name=Lensu2011/>). {| class="wikitable" !Response !H/W or line A !L-E or line C |- | colspan="3" |'''The most sensitive toxic effects and adaptive responses (type I)''' |- |Enzyme induction |0.1-1 μg/kg |0.1-1 μg/kg |- |Aversion to novel foods<ref name=Lensu17/><ref name=Lensu2011/> |0.1-0.6 μg/kg |0.2-0.4 μg/kg |- |Developmental effects (teeth)<ref name=Kattainen01/><ref name=Miettinen2006>{{cite journal |last1=Miettinen |first1=HM |last2=Sorvari |first2=R |last3=Alaluusua |first3=S |last4=Murtomaa |first4=M |last5=Tuukkanen |first5=J |last6=Viluksela |first6=M |title=The effect of perinatal TCDD exposure on caries susceptibility in rats. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=June 2006 |volume=91 |issue=2 |pages=568-75 |doi=10.1093/toxsci/kfj158 |pmid=16543294}}</ref> |0.1-1 μg/kg (dam) |0.1-1 μg/kg (dam) |- | colspan="3" |'''Robust toxic outcomes (type II)''' |- |Lethality |> 10,000 μg/kg |10 μg/kg |- |Liver damage |mild |severe |- |Severe anorexia and wasting syndrome |transient |to lethality |- |Tumour promotion |>100 μg/kg |>1 μg/kg |- | colspan="3" |'''Other''' |- |AH receptor binding |23 fmol/mg |20 fmol/mg |} Thus type I effects are relatively similar among species or strains (see also<ref name=WHO00/><ref name=Birnbaum00/><ref>{{Cite journal|last=Kransler|first=Kevin M.|last2=McGarrigle|first2=Barbara P.|last3=Olson|first3=James R.|date=2007-01|title=Comparative developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the hamster, rat and guinea pig|url=http://dx.doi.org/10.1016/j.tox.2006.10.019|journal=Toxicology|volume=229|issue=3|pages=214–225|doi=10.1016/j.tox.2006.10.019|issn=0300-483X}}</ref>), but type II effects cannot be reliably predicted over species. It is of interest that many of the type I responses can be interpreted as defence mechanisms toward noxious chemicals via the AH receptor (induction of metabolism, aversion of toxic foods) and can therefore be considered adaptive and protective. Dioxins cause various pleiotropic effects. There may be both proliferative responses and atrophic responses. Thymic atrophy and some immunological effects are consistent findings in multiple laboratory species. Liver toxicity is variable, it is typical in rabbits, but some effects are seen in other species, e.g. disturbances of porphyrin metabolism, oxidative damage, and fatty infiltration. There are also multiple high-dose effects on the nervous system, such as tryptophan metabolism or neuropathies.<ref>{{cite journal |last1=Unkila |first1=M |last2=Pohjanvirta |first2=R |last3=Tuomisto |first3=J |title=Dioxin-induced perturbations in tryptophan homeostasis in laboratory animals. |journal=Advances in experimental medicine and biology |date=1999 |volume=467 |pages=433-42 |doi=10.1007/978-1-4615-4709-9_55 |pmid=10721086}}</ref> Generally speaking, adverse effects at low doses in adult animals are few.<ref name=Poland82/><ref name=Pohjanvirta94/> === Developmental effects === Developmental effects have been found to be the most sensitive adverse effects of TCDD in several animal species. Transfer of dioxins through placenta varies by compound and animal species,<ref name=Hamm01>{{cite journal |last1=Chen |first1=CY |last2=Hamm |first2=JT |last3=Hass |first3=JR |last4=Birnbaum |first4=LS |title=Disposition of polychlorinated dibenzo-p-dioxins, dibenzofurans, and non-ortho polychlorinated biphenyls in pregnant long evans rats and the transfer to offspring. |journal=Toxicology and applied pharmacology |date=1 June 2001 |volume=173 |issue=2 |pages=65-88 |doi=10.1006/taap.2001.9143 |pmid=11384209}}</ref> and the amount transferred by lactation in rodents seems to be more than placental transfer.<ref>{{cite journal |last1=Li |first1=X |last2=Weber |first2=LW |last3=Rozman |first3=KK |title=Toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Sprague-Dawley rats including placental and lactational transfer to fetuses and neonates. |journal=Fundamental and applied toxicology: Official journal of the Society of Toxicology |date=August 1995 |volume=27 |issue=1 |pages=70-6 |pmid=7589930|doi=10.1006/faat.1995.1109}}</ref><ref name=Hamm01/> Comparison of single-dose studies to continuous daily intake studies resulting in a similar body burden is problematic, because distribution of dioxins during the peak concentration in the dam is different from long-term distribution.<ref name=Bell10>{{cite journal |last1=Bell |first1=DR |last2=Clode |first2=S |last3=Fan |first3=MQ |last4=Fernandes |first4=A |last5=Foster |first5=PM |last6=Jiang |first6=T |last7=Loizou |first7=G |last8=MacNicoll |first8=A |last9=Miller |first9=BG |last10=Rose |first10=M |last11=Tran |first11=L |last12=White |first12=S |title=Interpretation of studies on the developmental reproductive toxicology of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male offspring. |journal=Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association |date=June 2010 |volume=48 |issue=6 |pages=1439-47 |doi=10.1016/j.fct.2010.04.005 |pmid=20388530}}</ref> Some of the effects are observed at exposure levels indicating relatively small safety margins to the human background exposure.<ref name=Birnbaum00/><ref name=Viluksela19/> The sensitive targets include developing male and female reproductive system, immune system, nervous system, and teeth and bone. Clear teratogenic effects such as cleft palate and hydronephrosis were detected early after relatively high doses in mice.<ref name=Birnbaum95>{{cite journal |last1=Birnbaum |first1=LS |title=Developmental effects of dioxins. |journal=Environmental health perspectives |date=October 1995 |volume=103 Suppl 7 |pages=89-94 |doi=10.1289/ehp.95103s789 |pmid=8593882}}</ref><ref name=Yoshioka19/> Some developmental effects may be caused by indirect mechanisms, e.g. enzyme induction may lead to accelerated metabolism of thyroid hormones resulting in decreased hormone levels. Thyroid hormones are essential for normal development, notably the development of the nervous system. In many other cases the mechanisms seem to involve local growth factors, and the phenomenon cannot be described as endocrine disruption in strict sense. Development of teeth and the skeleton are highly sensitive targets of dioxin toxicity in several vertebrate species.<ref name=Viluksela12>{{cite book |last1=Viluksela |first1=M |last2=Miettinen |first2=HM |last3=Korkalainen |first3=M |editor1-last=Pohjanvirta |editor1-first=Raimo |title=The AH receptor in biology and toxicology |date=2012 |publisher=Wiley |isbn=9780470601822 |pages=285-297 |chapter=Effects of dioxins on teeth and bone: The role of AHR|doi=10.1002/9781118140574.ch20}}</ref> Teeth are useful indicators of developmental toxicity, because they do not undergo continuous remodelling after mineralization like bone, where remodelling may repair mineralization defects. Developmental defects of teeth can therefore be detected later in life, as in the case of the Seveso accident, when dental defects were observed 25 years after the accident.<ref name=Alaluusua04/> In utero and lactational exposure to TCDD was shown to result in wide range of alterations in rats and mice at doses below 1 μg/kg to the dam. They included smaller molar size, delayed eruption, increased susceptibility to caries, altered mineral composition of enamel, increased fluctuating asymmetry of molars and complete arrest of development of the third molars.<ref name=Kattainen01/><ref>{{cite journal |last1=Miettinen |first1=HM |last2=Alaluusua |first2=S |last3=Tuomisto |first3=J |last4=Viluksela |first4=M |title=Effect of in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on rat molar development: the role of exposure time. |journal=Toxicology and applied pharmacology |date=1 October 2002 |volume=184 |issue=1 |pages=57-66 |pmid=12392969|doi=10.1006/taap.2002.9490}}</ref><ref name=Miettinen2006/><ref>{{cite journal |last1=Keller |first1=JM |last2=Allen |first2=DE |last3=Davis |first3=CR |last4=Leamy |first4=LJ |title=2,3,7,8-Tetrachlorodibenzo-p-dioxin affects fluctuating asymmetry of molar shape in mice, and an epistatic interaction of two genes for molar size. |journal=Heredity |date=May 2007 |volume=98 |issue=5 |pages=259-67 |doi=10.1038/sj.hdy.6800928 |pmid=17213866}}</ref><ref>{{cite journal |last1=Keller |first1=JM |last2=Huet-Hudson |first2=YM |last3=Leamy |first3=LJ |title=Qualitative effects of dioxin on molars vary among inbred mouse strains. |journal=Archives of oral biology |date=May 2007 |volume=52 |issue=5 |pages=450-4 |doi=10.1016/j.archoralbio.2006.10.017 |pmid=17141729}}</ref> Sensitivity of tooth development to TCDD was also shown in rhesus monkeys, minks, rainbow trout and zebrafish.<ref>{{cite journal |last1=Yasuda |first1=I |last2=Yasuda |first2=M |last3=Sumida |first3=H |last4=Tsusaki |first4=H |last5=Arima |first5=A |last6=Ihara |first6=T |last7=Kubota |first7=S |last8=Asaoka |first8=K |last9=Tsuga |first9=K |last10=Akagawa |first10=Y |title=In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects tooth development in rhesus monkeys. |journal=Reproductive toxicology (Elmsford, N.Y.) |date=NaN |volume=20 |issue=1 |pages=21-30 |doi=10.1016/j.reprotox.2004.12.016 |pmid=15808782}}</ref><ref>{{cite journal |last1=Render |first1=JA |last2=Bursian |first2=SJ |last3=Rosenstein |first3=DS |last4=Aulerich |first4=RJ |title=Squamous epithelial proliferation in the jaws of mink fed diets containing 3,3',4,4',5-pentachlorobiphenyl (PCB 126) or 2,3,7,8-tetrachlorodibenzo-P-dioxin (TCDD). |journal=Veterinary and human toxicology |date=February 2001 |volume=43 |issue=1 |pages=22-6 |pmid=11205072}}</ref><ref>{{cite journal |last1=Hornung |first1=MW |last2=Spitsbergen |first2=JM |last3=Peterson |first3=RE |title=2,3,7,8-Tetrachlorodibenzo-p-dioxin alters cardiovascular and craniofacial development and function in sac fry of rainbow trout (Oncorhynchus mykiss). |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=January 1999 |volume=47 |issue=1 |pages=40-51 |doi=10.1093/toxsci/47.1.40 |pmid=10048152}}</ref><ref>{{cite journal |last1=Planchart |first1=A |last2=Mattingly |first2=CJ |title=2,3,7,8-Tetrachlorodibenzo-p-dioxin upregulates FoxQ1b in zebrafish jaw primordium. |journal=Chemical research in toxicology |date=15 March 2010 |volume=23 |issue=3 |pages=480-7 |doi=10.1021/tx9003165 |pmid=20055451}}</ref> In tooth development (as well as in the development of several other organs), the target of toxicity seems to be the developing epithelium. Developmental defects are the consequence of impaired epithelial-mesenchymal signalling, and AHR, epidermal growth factor (EGF), transforming growth factor α (TGFα) and perhaps Jun kinases are involved in mediating the effects.<ref>{{cite journal |last1=Partanen |first1=AM |last2=Alaluusua |first2=S |last3=Miettinen |first3=PJ |last4=Thesleff |first4=I |last5=Tuomisto |first5=J |last6=Pohjanvirta |first6=R |last7=Lukinmaa |first7=PL |title=Epidermal growth factor receptor as a mediator of developmental toxicity of dioxin in mouse embryonic teeth. |journal=Laboratory investigation; a journal of technical methods and pathology |date=December 1998 |volume=78 |issue=12 |pages=1473-81 |pmid=9881947}}</ref><ref>{{cite journal |last1=Abbott |first1=BD |last2=Buckalew |first2=AR |last3=DeVito |first3=MJ |last4=Ross |first4=D |last5=Bryant |first5=PL |last6=Schmid |first6=JE |title=EGF and TGF-alpha expression influence the developmental toxicity of TCDD: dose response and AhR phenotype in EGF, TGF-alpha, and EGF + TGF-alpha knockout mice. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=January 2003 |volume=71 |issue=1 |pages=84-95 |doi=10.1093/toxsci/71.1.84 |pmid=12520078}}</ref><ref>{{cite journal |last1=Alaluusua |first1=S |last2=Lukinmaa |first2=PL |title=Developmental dental toxicity of dioxin and related compounds--a review. |journal=International dental journal |date=December 2006 |volume=56 |issue=6 |pages=323-31 |pmid=17243464|doi=10.1111/j.1875-595X.2006.tb00336.x}}</ref><ref name=Viluksela12/><ref>{{Cite journal|last=Diry|first=M|last2=Tomkiewicz|first2=C|last3=Koehle|first3=C|last4=Coumoul|first4=X|last5=Bock|first5=K Walter|last6=Barouki|first6=R|last7=Transy|first7=C|date=2006-04-17|title=Activation of the dioxin/aryl hydrocarbon receptor (AhR) modulates cell plasticity through a JNK-dependent mechanism|url=http://dx.doi.org/10.1038/sj.onc.1209553|journal=Oncogene|volume=25|issue=40|pages=5570–5574|doi=10.1038/sj.onc.1209553|issn=0950-9232}}</ref> Cleft palate is the best-known skeletal effect of dioxins at relatively high maternal doses.<ref name=Birnbaum95/><ref name=Yoshioka19>{{cite journal |last1=Yoshioka |first1=W |last2=Tohyama |first2=C |title=Mechanisms of Developmental Toxicity of Dioxins and Related Compounds. |journal=International journal of molecular sciences |date=31 January 2019 |volume=20 |issue=3 |doi=10.3390/ijms20030617 |pmid=30708991}}</ref> In utero and lactational exposure to lower doses of TCDD was shown to affect long bones of rats, mice and rhesus monkeys by inducing altered bone geometry, decreased bone mineral density and biomechanical strength and retardation of bone matrix maturation.<ref>{{cite journal |last1=Miettinen |first1=HM |last2=Pulkkinen |first2=P |last3=Jämsä |first3=T |last4=Koistinen |first4=J |last5=Simanainen |first5=U |last6=Tuomisto |first6=J |last7=Tuukkanen |first7=J |last8=Viluksela |first8=M |title=Effects of in utero and lactational TCDD exposure on bone development in differentially sensitive rat lines. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=June 2005 |volume=85 |issue=2 |pages=1003-12 |doi=10.1093/toxsci/kfi136 |pmid=15746008}}</ref><ref>{{cite journal |last1=Hermsen |first1=SA |last2=Larsson |first2=S |last3=Arima |first3=A |last4=Muneoka |first4=A |last5=Ihara |first5=T |last6=Sumida |first6=H |last7=Fukusato |first7=T |last8=Kubota |first8=S |last9=Yasuda |first9=M |last10=Lind |first10=PM |title=In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects bone tissue in rhesus monkeys. |journal=Toxicology |date=20 November 2008 |volume=253 |issue=1-3 |pages=147-52 |doi=10.1016/j.tox.2008.09.005 |pmid=18835322}}</ref><ref>{{cite journal |last1=Nishimura |first1=N |last2=Nishimura |first2=H |last3=Ito |first3=T |last4=Miyata |first4=C |last5=Izumi |first5=K |last6=Fujimaki |first6=H |last7=Matsumura |first7=F |title=Dioxin-induced up-regulation of the active form of vitamin D is the main cause for its inhibitory action on osteoblast activities, leading to developmental bone toxicity. |journal=Toxicology and applied pharmacology |date=1 May 2009 |volume=236 |issue=3 |pages=301-9 |doi=10.1016/j.taap.2009.01.025 |pmid=19367694}}</ref><ref>{{cite journal |last1=Finnilä |first1=MA |last2=Zioupos |first2=P |last3=Herlin |first3=M |last4=Miettinen |first4=HM |last5=Simanainen |first5=U |last6=Håkansson |first6=H |last7=Tuukkanen |first7=J |last8=Viluksela |first8=M |last9=Jämsä |first9=T |title=Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on bone material properties. |journal=Journal of biomechanics |date=19 April 2010 |volume=43 |issue=6 |pages=1097-103 |doi=10.1016/j.jbiomech.2009.12.011 |pmid=20132933}}</ref> Further studies indicated that differentiation of bone marrow stem cells to bone forming osteoblasts and bone resorbing osteoclasts is disrupted by TCDD in AHR-dependent manner.<ref>{{cite journal |last1=Korkalainen |first1=M |last2=Kallio |first2=E |last3=Olkku |first3=A |last4=Nelo |first4=K |last5=Ilvesaro |first5=J |last6=Tuukkanen |first6=J |last7=Mahonen |first7=A |last8=Viluksela |first8=M |title=Dioxins interfere with differentiation of osteoblasts and osteoclasts. |journal=Bone |date=June 2009 |volume=44 |issue=6 |pages=1134-42 |doi=10.1016/j.bone.2009.02.019 |pmid=19264158}}</ref> Several studies from different laboratories have indicated a variety of adverse effects on the male reproductive system after in utero or lactational exposure of rats to low doses of TCDD. These include reduction of cauda epididymal sperm counts, daily sperm production, weight of accessory sex organs as well as increased proportion of abnormal sperm and delayed puberty (reviewed by Bell ''et al''.).<ref name=Bell10/> There is remarkable variability among different studies, but the delay in developmental milestones for male reproductive endpoints seems to be the most consistent and sensitive finding. Also decreased male/female sex ratios were reported in the offspring of male mice exposed to TCDD for 12 weeks prior to mating.<ref>{{cite journal |last1=Ishihara |first1=K |last2=Warita |first2=K |last3=Tanida |first3=T |last4=Sugawara |first4=T |last5=Kitagawa |first5=H |last6=Hoshi |first6=N |title=Does paternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affect the sex ratio of offspring? |journal=The Journal of veterinary medical science |date=April 2007 |volume=69 |issue=4 |pages=347-52 |doi=10.1292/jvms.69.347 |pmid=17485921}}</ref> However, maternal exposure did not affect the sex ratio of rat offspring.<ref>{{cite journal |last1=Bell |first1=DR |last2=Clode |first2=S |last3=Fan |first3=MQ |last4=Fernandes |first4=A |last5=Foster |first5=PM |last6=Jiang |first6=T |last7=Loizou |first7=G |last8=MacNicoll |first8=A |last9=Miller |first9=BG |last10=Rose |first10=M |last11=Tran |first11=L |last12=White |first12=S |title=Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the developing male Wistar(Han) rat. II: Chronic dosing causes developmental delay. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=September 2007 |volume=99 |issue=1 |pages=224-33 |doi=10.1093/toxsci/kfm141 |pmid=17545211}}</ref> The mechanism has been suggested to be reduced fertility of Y-bearing sperm.<ref name=Viluksela19/> === Multigenerational and transgenerational effects === Understanding possible effects on next generations is essential for risk assessment, because dioxin concentrations in the environment and human intake have decreased, but effects initiated several decades ago might still linger with us. This was illustrated by the Seveso studies (see above).<ref name=Mocarelli00/><ref name=Mocarelli11/> Epigenetically mediated multigenerational or transgenerational effects of TCDD have been found in rats and mice (reviewed by Viluksela and Pohjanvirta).<ref name=Viluksela19/> Some of them were paternally mediated or resulted in adult onset disease states. Toxic effects are considered transgenerational if neither the parent nor the offspring is directly exposed (i.e. F3 generation is the first generation without direct exposure). TCDD has been shown to cause typical epigenetic modifications (e.g. methylation, histone acetylation) in a number of studies.<ref name=Viluksela19/> When these occur in gametes they may affect the future generations. When pregnant rats were exposed to low doses of TCDD several endpoints of toxicity were found in F1-F3 (or F4) generations: primordial follicle loss, polycystic ovaries and early onset of puberty were observed in female F1 and F3 offspring, and histopathological alterations of testis and kidney abnormalities in male F1 and F3 offspring.<ref>{{cite journal |last1=Manikkam |first1=Mohan |last2=Tracey |first2=Rebecca |last3=Guerrero-Bosagna |first3=Carlos |last4=Skinner |first4=Michael K. |last5=Shioda |first5=Toshi |title=Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations |journal=PLoS ONE |date=26 September 2012 |volume=7 |issue=9 |pages=e46249 |doi=10.1371/journal.pone.0046249 |pmid=23049995}}</ref> These changes were associated with differentially methylated DNA regions in F3 generation sperm epigenome. Relatively high doses of TCDD (10 μg/kg) in female mice indicated robust transgenerational changes in pregnancy outcomes and progesterone receptor density. In the offspring of exposed mice reduced fertility, increased incidence of premature birth and increased uterine sensitivity to inflammation were found in F1-F4 generations.<ref>{{cite journal |last1=Bruner-Tran |first1=KL |last2=Osteen |first2=KG |title=Developmental exposure to TCDD reduces fertility and negatively affects pregnancy outcomes across multiple generations. |journal=Reproductive toxicology (Elmsford, N.Y.) |date=April 2011 |volume=31 |issue=3 |pages=344-50 |doi=10.1016/j.reprotox.2010.10.003 |pmid=20955784}}</ref><ref>{{cite journal |last1=Bruner-Tran |first1=KL |last2=Gnecco |first2=J |last3=Ding |first3=T |last4=Glore |first4=DR |last5=Pensabene |first5=V |last6=Osteen |first6=KG |title=Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: Translating lessons from murine models. |journal=Reproductive toxicology (Elmsford, N.Y.) |date=March 2017 |volume=68 |pages=59-71 |doi=10.1016/j.reprotox.2016.07.007 |pmid=27423904}}</ref> Interestingly, infertility and increased incidence of premature birth was also found in unexposed female mice mated with males exposed to TCDD in utero.<ref>{{cite journal |last1=Ding |first1=T |last2=McConaha |first2=M |last3=Boyd |first3=KL |last4=Osteen |first4=KG |last5=Bruner-Tran |first5=KL |title=Developmental dioxin exposure of either parent is associated with an increased risk of preterm birth in adult mice. |journal=Reproductive toxicology (Elmsford, N.Y.) |date=April 2011 |volume=31 |issue=3 |pages=351-8 |doi=10.1016/j.reprotox.2010.11.003 |pmid=21093581}}</ref> Premature birth was associated with reduced progesterone receptor expression and inflammation of placenta. In male mice infertility and increased premature births in unexposed mating partners that persisted to F2 and F3 generations were associated with testicular inflammation and apoptosis of developing spermatocytes.<ref>{{cite journal |last1=Bruner-Tran |first1=KL |last2=Ding |first2=T |last3=Yeoman |first3=KB |last4=Archibong |first4=A |last5=Arosh |first5=JA |last6=Osteen |first6=KG |title=Developmental exposure of mice to dioxin promotes transgenerational testicular inflammation and an increased risk of preterm birth in unexposed mating partners. |journal=PloS one |date=2014 |volume=9 |issue=8 |pages=e105084 |doi=10.1371/journal.pone.0105084 |pmid=25127480}}</ref> The role of paternal exposure was also studied in male rat offspring (F1) exposed in utero and lactationally to low doses of TCDD and mated with unexposed females to obtain the F2 generation and further the F3 generation.<ref>{{cite journal |last1=Sanabria |first1=M |last2=Cucielo |first2=MS |last3=Guerra |first3=MT |last4=Dos Santos Borges |first4=C |last5=Banzato |first5=TP |last6=Perobelli |first6=JE |last7=Leite |first7=GA |last8=Anselmo-Franci |first8=JA |last9=De Grava Kempinas |first9=W |title=Sperm quality and fertility in rats after prenatal exposure to low doses of TCDD: A three-generation study. |journal=Reproductive toxicology (Elmsford, N.Y.) |date=October 2016 |volume=65 |pages=29-38 |doi=10.1016/j.reprotox.2016.06.019 |pmid=27352640}}</ref> The proportion of implantations per corpus luteum was significantly decreased in all three generations. Thus both maternal and paternal changes can lead to effects in offspring. Small zebra fish have been extensively used to study the mechanisms of toxicity in fish in the laboratory, especially cardiovascular toxicity, craniofacial malformations, and reproductive toxicity (reviewed by King-Heiden ''et al''.).<ref name=KingHeiden12/> Apart from rats and mice, transgenerationally inherited dioxin-induced effects have also been studied in the zebrafish model.<ref>{{cite journal |last1=Baker |first1=TR |last2=King-Heiden |first2=TC |last3=Peterson |first3=RE |last4=Heideman |first4=W |title=Dioxin induction of transgenerational inheritance of disease in zebrafish. |journal=Molecular and cellular endocrinology |date=December 2014 |volume=398 |issue=1-2 |pages=36-41 |doi=10.1016/j.mce.2014.08.011 |pmid=25194296}}</ref><ref>{{cite journal |last1=Baker |first1=TR |last2=Peterson |first2=RE |last3=Heideman |first3=W |title=Using zebrafish as a model system for studying the transgenerational effects of dioxin. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=April 2014 |volume=138 |issue=2 |pages=403-11 |doi=10.1093/toxsci/kfu006 |pmid=24470537}}</ref><ref>{{cite journal |last1=Meyer |first1=DN |last2=Baker |first2=BB |last3=Baker |first3=TR |title=Ancestral TCDD Exposure Induces Multigenerational Histologic and Transcriptomic Alterations in Gonads of Male Zebrafish. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=1 August 2018 |volume=164 |issue=2 |pages=603-612 |doi=10.1093/toxsci/kfy115 |pmid=29788325}}</ref> In zebrafish, TCDD-induced transgenerational and partly paternally-mediated effects include reproductive dysfunction, reduced fertility, skeletal malformations and lowered male/female sex ratio. These effects seem to be phenotypically very similar across these vertebrate classes. === Cancer in laboratory animals === Dioxins are clear multisite carcinogens in animal studies, but are not genotoxic as indicated both by mutagenicity assays and tumour promotion studies. Also the ability of TCDD to inhibit apoptosis and enhance proliferation supports a nongenotoxic mechanism of carcinogenicity. Much of the cancer risk assessment has been based on an early rat study,<ref>{{cite journal |last1=Kociba |first1=RJ |last2=Keyes |first2=DG |last3=Beyer |first3=JE |last4=Carreon |first4=RM |last5=Wade |first5=CE |last6=Dittenber |first6=DA |last7=Kalnins |first7=RP |last8=Frauson |first8=LE |last9=Park |first9=CN |last10=Barnard |first10=SD |last11=Hummel |first11=RA |last12=Humiston |first12=CG |title=Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. |journal=Toxicology and applied pharmacology |date=November 1978 |volume=46 |issue=2 |pages=279-303 |doi=10.1016/0041-008x(78)90075-3 |pmid=734660}}</ref> demonstrating liver tumours in female rats at low doses (10 ng/kg/day TCDD for 2 years). Other studies have confirmed multisite carcinogenicity in several species, but the doses have usually been higher. Toxic hepatitis has also been found in animals with tumours. Nongenotoxic or promoting mechanisms are favoured, especially inhibition of apoptosis of cancer precursor cells.<ref>{{cite journal |last1=Dragan |first1=YP |last2=Schrenk |first2=D |title=Animal studies addressing the carcinogenicity of TCDD (or related compounds) with an emphasis on tumour promotion. |journal=Food additives and contaminants |date=April 2000 |volume=17 |issue=4 |pages=289-302 |doi=10.1080/026520300283360 |pmid=10912243}}</ref><ref name=Schrenk12>{{cite book |last1=Schrenk |first1=D |last2=Chopra |first2=M |editor1-last=Pohjanvirta |editor1-first=R |title=The AH receptor in biology and toxicology |publisher=Wiley |isbn=9780470601822 |chapter=Dioxin activated AHR and cancer in laboratory animals}}</ref> When differently sensitive Long-Evans (Turku/AB) (L-E) and H/W (Kuopio) rat substrains were compared in a 3-month tumour promotion study, there was a difference in effective dose of almost two orders of magnitude, and in both strains tumour promotion was associated with signs of liver toxicity.<ref name=Viluksela00/> Such findings suggest that carcinogenicity may be secondary to organ toxicity. It has been speculated that induction of oxidative enzymes such as CYP1A1 would produce excessive reactive carcinogenic intermediates, and dioxins would thus indirectly increase cancer risk. Oxidation combined with subsequent conjugating reactions is, however, essentially a protective mechanism, and conjugation enzymes are induced simultaneously.<ref>{{Cite journal|last=Nebert|first=Daniel W.|last2=Dalton|first2=Timothy P.|last3=Okey|first3=Allan B.|last4=Gonzalez|first4=Frank J.|date=2004-03-17|title=Role of Aryl Hydrocarbon Receptor-mediated Induction of the CYP1 Enzymes in Environmental Toxicity and Cancer|url=http://dx.doi.org/10.1074/jbc.r400004200|journal=Journal of Biological Chemistry|volume=279|issue=23|pages=23847–23850|doi=10.1074/jbc.r400004200|issn=0021-9258}}</ref> Thus, while plausible, this mechanism would require disproportionate induction of oxidation over conjugation and be likely only at relatively high doses. In tumour promotion studies with two rat strains enzyme induction did not correlate with tumour promoting activity.<ref name=Viluksela00/> == Interactions of dioxins with microbes and the immune system == Microbiomes related to the gut, skin and respiratory tract are in frontline of encountering xenobiotics. The microbiome of our intestinal system metabolizes many chemicals in our food, and on the other hand the chemicals may influence the microbes. There are complex interrelationships between chemicals, microbes and our immune systems. The host and microbiome together can even be seen as a “superorganism”.<ref>{{cite journal |last1=Dietert |first1=RR |last2=Silbergeld |first2=EK |title=Biomarkers for the 21st century: listening to the microbiome. |journal=Toxicological sciences : an official journal of the Society of Toxicology |date=April 2015 |volume=144 |issue=2 |pages=208-16 |doi=10.1093/toxsci/kfv013 |pmid=25795652}}</ref> AH receptors and therefore dioxins are deeply involved in these interactions. Active research has started to meet the challenge of understanding these phenomena during the last few years, but obviously only the tip of the iceberg has been revealed as yet, and there is limited information about specific microorganisms, enzymes and genes involved.<ref name=Atashgani18/> The simplest part of these interactions is the effects of the microbiome on chemicals. Intestinal microbes can metabolize xenobiotics before they are absorbed into the body. This may increase or decrease physicochemical properties and toxicity. As to dioxins, not much is known; dehalogenation is possible,<ref name=Atashgani18/> but obviously not very effective. On the other hand, several bacteria are able to metabolize polycyclic aromatic hydrocarbons also binding to AH receptors such as benzo''(a)''pyrene to carcinogenic metabolites prior to absorption.<ref>{{cite journal |last1=Sowada |first1=J |last2=Schmalenberger |first2=A |last3=Ebner |first3=I |last4=Luch |first4=A |last5=Tralau |first5=T |title=Degradation of benzo[a]pyrene by bacterial isolates from human skin. |journal=FEMS microbiology ecology |date=April 2014 |volume=88 |issue=1 |pages=129-39 |doi=10.1111/1574-6941.12276 |pmid=24372170}}</ref> As to the effect of dioxins on microbes, relatively high doses have been shown to cause remarkable changes in the overall population, and e.g. somewhat ambiguous changes in the ''Firmicutes'' vs. ''Bacteroides'' ratio in mice and increases in ''Lactobacillaceae'' and ''Desulfovibrionaceae'' have been noticed.<ref>{{cite journal |last1=Zhang |first1=L |last2=Nichols |first2=RG |last3=Correll |first3=J |last4=Murray |first4=IA |last5=Tanaka |first5=N |last6=Smith |first6=PB |last7=Hubbard |first7=TD |last8=Sebastian |first8=A |last9=Albert |first9=I |last10=Hatzakis |first10=E |last11=Gonzalez |first11=FJ |last12=Perdew |first12=GH |last13=Patterson |first13=AD |title=Persistent Organic Pollutants Modify Gut Microbiota-Host Metabolic Homeostasis in Mice Through Aryl Hydrocarbon Receptor Activation. |journal=Environmental health perspectives |date=July 2015 |volume=123 |issue=7 |pages=679-88 |doi=10.1289/ehp.1409055 |pmid=25768209}}</ref><ref>{{cite journal |last1=Lefever |first1=DE |last2=Xu |first2=J |last3=Chen |first3=Y |last4=Huang |first4=G |last5=Tamas |first5=N |last6=Guo |first6=TL |title=TCDD modulation of gut microbiome correlated with liver and immune toxicity in streptozotocin (STZ)-induced hyperglycemic mice. |journal=Toxicology and applied pharmacology |date=1 August 2016 |volume=304 |pages=48-58 |doi=10.1016/j.taap.2016.05.016 |pmid=27221631}}</ref> These changes might be in part involved in the toxic effects, e.g. liver toxicity. AH receptors seem to sense microbial toxins and stimulate their neutralization by enzyme induction as well as regulating cytokine and chemokine production and leukocyte activation.<ref name=MouraAlves14>{{cite journal |last1=Moura-Alves |first1=P |last2=Faé |first2=K |last3=Houthuys |first3=E |last4=Dorhoi |first4=A |last5=Kreuchwig |first5=A |last6=Furkert |first6=J |last7=Barison |first7=N |last8=Diehl |first8=A |last9=Munder |first9=A |last10=Constant |first10=P |last11=Skrahina |first11=T |last12=Guhlich-Bornhof |first12=U |last13=Klemm |first13=M |last14=Koehler |first14=AB |last15=Bandermann |first15=S |last16=Goosmann |first16=C |last17=Mollenkopf |first17=HJ |last18=Hurwitz |first18=R |last19=Brinkmann |first19=V |last20=Fillatreau |first20=S |last21=Daffe |first21=M |last22=Tümmler |first22=B |last23=Kolbe |first23=M |last24=Oschkinat |first24=H |last25=Krause |first25=G |last26=Kaufmann |first26=SH |title=AhR sensing of bacterial pigments regulates antibacterial defence. |journal=Nature |date=28 August 2014 |volume=512 |issue=7515 |pages=387-92 |doi=10.1038/nature13684 |pmid=25119038}}</ref> An interesting field in these interactions is the highly complex influence of chemicals via the AH receptors on the immune systems.<ref>{{cite journal |last1=Hao |first1=N |last2=Whitelaw |first2=ML |title=The emerging roles of AhR in physiology and immunity. |journal=Biochemical pharmacology |date=1 September 2013 |volume=86 |issue=5 |pages=561-70 |doi=10.1016/j.bcp.2013.07.004 |pmid=23856287}}</ref><ref name=Boule18/><ref name=Rothhammer19/> This is mostly outside the scope of this review, and only dealt with briefly. Interested readers are encouraged to read the thorough recent review of Rothhammer and Quintana.<ref name=Rothhammer19/> AHR activation seems to be crucial in maintaining intraepithelial lymphocytes in the intestines and skin as a first line of defence against microorganisms.<ref>{{cite journal |last1=Li |first1=Y |last2=Innocentin |first2=S |last3=Withers |first3=DR |last4=Roberts |first4=NA |last5=Gallagher |first5=AR |last6=Grigorieva |first6=EF |last7=Wilhelm |first7=C |last8=Veldhoen |first8=M |title=Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. |journal=Cell |date=28 October 2011 |volume=147 |issue=3 |pages=629-40 |doi=10.1016/j.cell.2011.09.025 |pmid=21999944}}</ref> By using several genetically modified mouse models it was shown that high constitutive activity of CYP1A1 depletes natural AHR ligands in the gut and this leads to similar deficiencies in immune defence mechanisms and increased susceptibility to infections as seen in AHR knockout animals. Interestingly this deficiency can be counteracted by increased supply of natural AHR ligands such as 6-formylindolo[3,2-b]carbazole (FICZ) many of which are present e.g. in vegetables.<ref name=Schiering17/> This implies that CYP enzymes act as feedback controls metabolizing more or less of the AHR ligand supply to keep the receptor activity at an optimal level. In fact AHR activity in intestinal epithelial cells, intraepithelial lymphocytes and innate lymphoid cells seems important for tissue homeostasis at the structural and functional level.<ref name=Rothhammer19/> Respiratory system is the other important pathway for environmental noxious agents to the body, especially viral infections, and the AHR seems to be intrinsically involved in defence mechanisms.<ref name=Boule18/><ref>{{cite journal |last1=Guerrina |first1=N |last2=Traboulsi |first2=H |last3=Eidelman |first3=DH |last4=Baglole |first4=CJ |title=The Aryl Hydrocarbon Receptor and the Maintenance of Lung Health. |journal=International journal of molecular sciences |date=5 December 2018 |volume=19 |issue=12 |doi=10.3390/ijms19123882 |pmid=30563036}}</ref> An interesting indole derivative is malassezin produced by pathogenic skin yeast ''Malassezia furfur''.<ref>{{cite journal |last1=Wille |first1=G |last2=Mayser |first2=P |last3=Thoma |first3=W |last4=Monsees |first4=T |last5=Baumgart |first5=A |last6=Schmitz |first6=HJ |last7=Schrenk |first7=D |last8=Polborn |first8=K |last9=Steglich |first9=W |title=Malassezin--A novel agonist of the arylhydrocarbon receptor from the yeast Malassezia furfur. |journal=Bioorganic & medicinal chemistry |date=April 2001 |volume=9 |issue=4 |pages=955-60 |pmid=11354679|doi=10.1016/S0968-0896(00)00319-9}}</ref> The question has been how AHR can mediate protective effects in some contexts and toxicity in others. This is partially an open question, but it may simply include the impact of time and dose. FICZ and other similar ligands are metabolized rapidly, and so their concentrations will never increase very high and persistent. Therefore their toxicity is not apparent. Microglia are specialized macrophages in the central nervous system, and as such important for immune surveillance, debris removal and defence against microorganisms as well as for the development of immune functions and synapse maturation.<ref name=Rothhammer19/> AHR expression is upregulated in the CNS traumatic or autoimmune injury, and may control the inflammatory activities. Here AHR ligands produced by microbes may be important and deficits of AHR agonists have been reported in multiple conditions.<ref name=Rothhammer19/> Thus there may be option of therapeutic development of AHR ligands in autoimmune, neoplastic and degenerative diseases. Although the AHR signalling may be fundamental in neuronal development, overactivation seems harmful.<ref>{{cite journal |last1=Kobayashi |first1=Y |last2=Hirano |first2=T |last3=Omotehara |first3=T |last4=Hashimoto |first4=R |last5=Umemura |first5=Y |last6=Yuasa |first6=H |last7=Masuda |first7=N |last8=Kubota |first8=N |last9=Minami |first9=K |last10=Yanai |first10=S |last11=Ishihara-Sugano |first11=M |last12=Mantani |first12=Y |last13=Yokoyama |first13=T |last14=Kitagawa |first14=H |last15=Hoshi |first15=N |title=Immunohistochemical analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity on the developmental dentate gyrus and hippocampal fimbria in fetal mice. |journal=The Journal of veterinary medical science |date=November 2015 |volume=77 |issue=11 |pages=1355-61 |doi=10.1292/jvms.15-0238 |pmid=26096965}}</ref><ref>{{cite journal |last1=Kimura |first1=E |last2=Kubo |first2=KI |last3=Endo |first3=T |last4=Ling |first4=W |last5=Nakajima |first5=K |last6=Kakeyama |first6=M |last7=Tohyama |first7=C |title=Impaired dendritic growth and positioning of cortical pyramidal neurons by activation of aryl hydrocarbon receptor signaling in the developing mouse. |journal=PloS one |date=2017 |volume=12 |issue=8 |pages=e0183497 |doi=10.1371/journal.pone.0183497 |pmid=28820910}}</ref> Thus the current understanding is limited and active research is needed. == Conclusions == Dioxins are a group of related persistent, bioaccumulating environmental poisons that act via the AH receptor, an intracellular receptor which also serves to regulate multiple physiological functions. Hence a certain level of AH receptor activity is important in normal biology, but inappropriate activation leads to a number of deleterious effects. The most sensitive adverse effects of dioxins are developmental consequences in different structures, from teeth and bones to sexual organs. This concerns specifically women in child-bearing age, because a child is exposed prenatally during pregnancy as well as postnatally via breast milk. The exposure is higher than in other population groups. The safety margins between the current environmental exposure levels and the levels required for sensitive adverse effects are presently about an order of magnitude, but the safe level was probably exceeded in the 1970s and 1980s. Transgenerational effects of these historical high exposures (causing milk dioxin levels of 50 to 100 pg TEQ per g fat, tenfold to contemporary levels) are of concern, but are so far poorly known. Carcinogenicity has caused confusion, because it probably occurs at high industrial or accidental exposure levels, but dioxins are not genotoxic, and there is neither good evidence nor logical reason to assume that dioxins would cause cancer at levels below those causing developmental effects. It is essential to understand dioxins as one risk factor among others rather than as a sole causative agent. This means that dose-responses should be appreciated in regulations as with any other chemical, and benefit-risk aspects should be carefully taken into account. Otherwise unwise remedy may turn out to be worse than the disease. It is risk management and political issue to decide how large safety margins are necessary. In conclusion, strict environmental controls of dioxin emissions are still important and they should be the first priority. Limitations of important food items are problematic, and it is important to avoid measures that would increase competing risks. This danger is obvious when overregulating the levels in food. The benefits of e.g. breast feeding are estimated clearly greater than possible risks of contaminants, and the nutritional benefits of fish consumption also outweigh toxic effects, if any. == Additional information == === Acknowledgements === I appreciate the comments of several colleagues screening through the manuscript: Prof. Allan B. Okey, Toronto, Prof. Dieter Schrenk, Kaiserslautern, Prof. Robert Barouki, Paris, Prof. Xavier Coumoul, Paris, Prof. Raimo Pohjanvirta, Helsinki, Prof. Matti Viluksela, Kuopio, Dr. Jouni T. Tuomisto, Kuopio, and Dr. Hanna Miettinen, Kuopio. I also want to thank expert rewiewers Prof. Helmut Greim, Munich, Dr. Martin Rose, Manchester, and Prof. Helen Håkansson, Stockholm, for their constructive comments. === Competing interests === It is acknowledged that after writing a textbook chapter on the same topic, it was not possible to avoid some repetition of both style and details (Tuomisto and Viluksela).<ref>{{Cite book|url=https://www.worldcat.org/oclc/1085638074|last1=Tuomisto|first1=J|last2=Viluksela |first2=M|editor-last=D’Mello|editor-first=J. P. F.|chapter=Dioxins II. human exposure and health risks|title=A handbook of environmental toxicology : human disorders and ecotoxicology|isbn=978-1-78639-467-5|location=Wallingford, Oxfordshire, UK|oclc=1085638074}}</ref> Otherwise there are no conflicts of interests. There was no funding for writing this article. == References == {{reflist|35em}} s2yeazp9y3zi9pdvdh40n65s03208zm 2 257428 2408043 2407423 2022-07-19T19:37:54Z Archie97305 2915204 wikitext text/x-wiki mohammed agbadi youtube https://www.youtube.com/watch?v=4TCYjw88JSY http://kaomoji.ru/en/ https://period.co/collections/all ∨↯∧|序 https://www.freepik.com/ [http://themetawiki.clu ⚟十⚞][https://www.deviantart.com/team/art/Draw-a-Tiger-with-JoJoesArt-921502228 🐯][https://en.wikiversity.org/wiki/Embracing_Ambiguity ⸎][https://sharkonline.org/index.php/take-action/rodeo-video-tips 🦈][https://en.wikiversity.org/wiki/Wikiversity:Main_Page ⚞⸰⸰⸰△] https://tailwindcss.com/docs/dark-mode [https://play.tailwindcss.com/ tailwind][https://www.youtube.com/watch?v=lG5dNhabwBk&list=PLa1F2ddGya_87HJ72v_IgKUTNLIXSMfvB blender weekly][https://www.youtube.com/c/BlenderFoundation bf] [https://www.youtube.com/watch?v=3Sqm_v49zno acai] #https://momentjs.com/ #https://innocenceproject.org/ ⍱⍲⍑⍢⍐⎀⏀⌰⏢∨↯∧|序 [https://en.wikiversity.org/wiki/User:VeronicaJeanAnderson/Abe ⚞Abe⚟] [http://themetawiki.clu/w/index.php/Abe ⚟Abe⚞] [https://old.reddit.com/ ∞ꖉ∞⚟a⚞b⚟e⚞∞ꖉ∞] = ∞ꖉ⚞A⚟ꖉ∞ = https://www.youtube.com/watch?v=EtoZOqbwH9E :: success measured by how many car alarms go off ;) :: discord.gg/onlyinjapan instagram.com/onlyinjapantv twitter.com/onlyinjapantv facebook.com/onlyinjapantv https://www.youtube.com/watch?v=pE5h2kk0NTI == Color keywords == == Basic Colors == <table class="colortable"> <tr> <th>Named </th><th>Numeric </th><th>Color&nbsp;name </th><th>Hex&nbsp;rgb </th><th>Decimal </th></tr><tr> <td class="c" style="background-color:black;">&nbsp; </td><td class="c" style="background-color:rgb(0, 0, 0);">&nbsp; </td><td>black </td><td class="c" style="background-color:silver;">#000000 </td><td class="c" style="background-color:silver;">0,0,0 </td></tr><tr> <td class="c" style="background-color:silver;">&nbsp; </td><td class="c" style="background-color:rgb(192, 192, 192);">&nbsp; </td><td>silver </td><td class="c" style="background-color:silver;">#C0C0C0 </td><td class="c" style="background-color:silver;">192,192,192 </td></tr><tr> <td class="c" style="background-color:gray;">&nbsp; </td><td class="c" style="background-color:rgb(128, 128, 128);">&nbsp; </td><td>gray </td><td class="c" style="background-color:silver;">#808080 </td><td class="c" style="background-color:silver;">128,128,128 </td></tr><tr> <td class="c" style="background-color:white;">&nbsp; </td><td class="c" style="background-color:rgb(255, 255, 255);">&nbsp; </td><td>white </td><td class="c" style="background-color:silver;">#FFFFFF </td><td class="c" style="background-color:silver;">255,255,255 </td></tr><tr> <td class="c" style="background-color:maroon;">&nbsp; </td><td class="c" style="background-color:rgb(128, 0, 0);">&nbsp; </td><td>maroon </td><td class="c" style="background-color:silver;">#800000 </td><td class="c" style="background-color:silver;">128,0,0 </td></tr><tr> <td class="c" style="background-color:red;">&nbsp; </td><td class="c" style="background-color:rgb(255, 0, 0);">&nbsp; </td><td>red </td><td class="c" style="background-color:silver;">#FF0000 </td><td class="c" style="background-color:silver;">255,0,0 </td></tr><tr> <td class="c" style="background-color:purple;">&nbsp; </td><td class="c" style="background-color:rgb(128, 0, 128);">&nbsp; </td><td>purple </td><td class="c" style="background-color:silver;">#800080 </td><td class="c" style="background-color:silver;">128,0,128 </td></tr><tr> <td class="c" style="background-color:fuchsia;">&nbsp; </td><td class="c" style="background-color:rgb(255, 0, 255);">&nbsp; </td><td>fuchsia </td><td class="c" style="background-color:silver;">#FF00FF </td><td class="c" style="background-color:silver;">255,0,255 </td></tr><tr> <td class="c" style="background-color:green;">&nbsp; </td><td class="c" style="background-color:rgb(0, 128, 0);">&nbsp; </td><td>green </td><td class="c" style="background-color:silver;">#008000 </td><td class="c" style="background-color:silver;">0,128,0 </td></tr><tr> <td class="c" style="background-color:lime;">&nbsp; </td><td class="c" style="background-color:rgb(0, 255, 0);">&nbsp; </td><td>lime </td><td class="c" style="background-color:silver;">#00FF00 </td><td class="c" style="background-color:silver;">0,255,0 </td></tr><tr> <td class="c" style="background-color:olive;">&nbsp; </td><td class="c" style="background-color:rgb(128, 128, 0);">&nbsp; </td><td>olive </td><td class="c" style="background-color:silver;">#808000 </td><td class="c" style="background-color:silver;">128,128,0 </td></tr><tr> <td class="c" style="background-color:yellow;">&nbsp; </td><td class="c" style="background-color:rgb(255, 255, 0);">&nbsp; </td><td>yellow </td><td class="c" style="background-color:silver;">#FFFF00 </td><td class="c" style="background-color:silver;">255,255,0 </td></tr><tr> <td class="c" style="background-color:navy;">&nbsp; </td><td class="c" style="background-color:rgb(0, 0, 128);">&nbsp; </td><td>navy </td><td class="c" style="background-color:silver;">#000080 </td><td class="c" style="background-color:silver;">0,0,128 </td></tr><tr> <td class="c" style="background-color:blue;">&nbsp; </td><td class="c" style="background-color:rgb(0, 0, 255);">&nbsp; </td><td>blue </td><td class="c" style="background-color:silver;">#0000FF </td><td class="c" style="background-color:silver;">0,0,255 </td></tr><tr> <td class="c" style="background-color:teal;">&nbsp; </td><td class="c" style="background-color:rgb(0, 128, 128);">&nbsp; </td><td>teal </td><td class="c" style="background-color:silver;">#008080 </td><td class="c" style="background-color:silver;">0,128,128 </td></tr><tr> <td class="c" style="background-color:aqua;">&nbsp; </td><td class="c" style="background-color:rgb(0, 255, 255);">&nbsp; </td><td>aqua </td><td class="c" style="background-color:silver;">#00FFFF </td><td class="c" style="background-color:silver;">0,255,255 </td></tr></table> == Extended colors == <table> <tr> <th>Named </th><th>Numeric </th><th>Color&nbsp;name </th><th>Hex&nbsp;rgb </th><th>Decimal </th></tr><tr> <td class="c" style="background-color:aliceblue;">&nbsp; </td><td class="c" style="background-color:rgb(240, 248, 255);">&nbsp; </td><td>aliceblue </td><td class="c" style="background-color:silver;">#f0f8ff </td><td class="c" style="background-color:silver;">240,248,255 </td></tr><tr> <td class="c" style="background-color:antiquewhite;">&nbsp; </td><td class="c" style="background-color:rgb(250, 235, 215);">&nbsp; </td><td>antiquewhite </td><td class="c" style="background-color:silver;">#faebd7 </td><td class="c" style="background-color:silver;">250,235,215 </td></tr><tr> <td class="c" style="background-color:aqua;">&nbsp; </td><td class="c" style="background-color:rgb(0, 255, 255);">&nbsp; </td><td>aqua </td><td class="c" style="background-color:silver;">#00ffff </td><td class="c" style="background-color:silver;">0,255,255 </td></tr><tr> <td class="c" style="background-color:aquamarine;">&nbsp; </td><td class="c" style="background-color:rgb(127, 255, 212);">&nbsp; </td><td>aquamarine </td><td class="c" style="background-color:silver;">#7fffd4 </td><td class="c" style="background-color:silver;">127,255,212 </td></tr><tr> <td class="c" style="background-color:azure;">&nbsp; </td><td class="c" style="background-color:rgb(240, 255, 255);">&nbsp; </td><td>azure </td><td class="c" style="background-color:silver;">#f0ffff </td><td class="c" style="background-color:silver;">240,255,255 </td></tr><tr> <td class="c" style="background-color:beige;">&nbsp; </td><td class="c" style="background-color:rgb(245, 245, 220);">&nbsp; </td><td>beige </td><td class="c" style="background-color:silver;">#f5f5dc </td><td class="c" style="background-color:silver;">245,245,220 </td></tr><tr> <td class="c" style="background-color:bisque;">&nbsp; </td><td class="c" style="background-color:rgb(255, 228, 196);">&nbsp; </td><td>bisque </td><td class="c" style="background-color:silver;">#ffe4c4 </td><td class="c" style="background-color:silver;">255,228,196 </td></tr><tr> <td class="c" style="background-color:black;">&nbsp; </td><td class="c" style="background-color:rgb(0, 0, 0);">&nbsp; </td><td>black </td><td class="c" style="background-color:silver;">#000000 </td><td class="c" style="background-color:silver;">0,0,0 </td></tr><tr> <td class="c" style="background-color:blanchedalmond;">&nbsp; </td><td class="c" style="background-color:rgb(255, 235, 205);">&nbsp; </td><td>blanchedalmond </td><td class="c" style="background-color:silver;">#ffebcd </td><td class="c" style="background-color:silver;">255,235,205 </td></tr><tr> <td class="c" style="background-color:blue;">&nbsp; </td><td class="c" style="background-color:rgb(0, 0, 255);">&nbsp; </td><td>blue </td><td class="c" style="background-color:silver;">#0000ff </td><td class="c" style="background-color:silver;">0,0,255 </td></tr><tr> <td class="c" style="background-color:blueviolet;">&nbsp; </td><td class="c" style="background-color:rgb(138, 43, 226);">&nbsp; </td><td>blueviolet </td><td class="c" style="background-color:silver;">#8a2be2 </td><td class="c" style="background-color:silver;">138,43,226 </td></tr><tr> <td class="c" style="background-color:brown;">&nbsp; </td><td class="c" style="background-color:rgb(165, 42, 42);">&nbsp; </td><td>brown </td><td class="c" style="background-color:silver;">#a52a2a </td><td class="c" style="background-color:silver;">165,42,42 </td></tr><tr> <td class="c" style="background-color:burlywood;">&nbsp; </td><td class="c" style="background-color:rgb(222, 184, 135);">&nbsp; </td><td>burlywood </td><td class="c" style="background-color:silver;">#deb887 </td><td class="c" style="background-color:silver;">222,184,135 </td></tr><tr> <td class="c" style="background-color:cadetblue;">&nbsp; </td><td class="c" style="background-color:rgb(95, 158, 160);">&nbsp; </td><td>cadetblue </td><td class="c" style="background-color:silver;">#5f9ea0 </td><td class="c" style="background-color:silver;">95,158,160 </td></tr><tr> <td class="c" style="background-color:chartreuse;">&nbsp; </td><td class="c" style="background-color:rgb(127, 255, 0);">&nbsp; </td><td>chartreuse </td><td class="c" style="background-color:silver;">#7fff00 </td><td class="c" style="background-color:silver;">127,255,0 </td></tr><tr> <td class="c" style="background-color:chocolate;">&nbsp; </td><td class="c" style="background-color:rgb(210, 105, 30);">&nbsp; </td><td>chocolate </td><td class="c" style="background-color:silver;">#d2691e </td><td class="c" style="background-color:silver;">210,105,30 </td></tr><tr> <td class="c" style="background-color:coral;">&nbsp; </td><td class="c" style="background-color:rgb(255, 127, 80);">&nbsp; </td><td>coral </td><td class="c" style="background-color:silver;">#ff7f50 </td><td class="c" style="background-color:silver;">255,127,80 </td></tr><tr> <td class="c" style="background-color:cornflowerblue;">&nbsp; </td><td class="c" style="background-color:rgb(100, 149, 237);">&nbsp; </td><td>cornflowerblue </td><td class="c" style="background-color:silver;">#6495ed </td><td class="c" style="background-color:silver;">100,149,237 </td></tr><tr> <td class="c" style="background-color:cornsilk;">&nbsp; </td><td class="c" style="background-color:rgb(255, 248, 220);">&nbsp; </td><td>cornsilk </td><td class="c" style="background-color:silver;">#fff8dc </td><td class="c" style="background-color:silver;">255,248,220 </td></tr><tr> <td class="c" style="background-color:crimson;">&nbsp; </td><td class="c" style="background-color:rgb(220, 20, 60);">&nbsp; </td><td>crimson </td><td class="c" style="background-color:silver;">#dc143c </td><td class="c" style="background-color:silver;">220,20,60 </td></tr><tr> <td class="c" style="background-color:cyan;">&nbsp; </td><td class="c" style="background-color:rgb(0, 255, 255);">&nbsp; </td><td>cyan </td><td class="c" style="background-color:silver;">#00ffff </td><td class="c" style="background-color:silver;">0,255,255 </td></tr><tr> <td class="c" style="background-color:darkblue;">&nbsp; </td><td class="c" style="background-color:rgb(0, 0, 139);">&nbsp; </td><td>darkblue </td><td class="c" style="background-color:silver;">#00008b </td><td class="c" style="background-color:silver;">0,0,139 </td></tr><tr> <td class="c" style="background-color:darkcyan;">&nbsp; </td><td class="c" style="background-color:rgb(0, 139, 139);">&nbsp; </td><td>darkcyan </td><td class="c" style="background-color:silver;">#008b8b </td><td class="c" style="background-color:silver;">0,139,139 </td></tr><tr> <td class="c" style="background-color:darkgoldenrod;">&nbsp; </td><td class="c" style="background-color:rgb(184, 134, 11);">&nbsp; </td><td>darkgoldenrod </td><td class="c" style="background-color:silver;">#b8860b </td><td class="c" style="background-color:silver;">184,134,11 </td></tr><tr> <td class="c" style="background-color:darkgray;">&nbsp; </td><td class="c" style="background-color:rgb(169, 169, 169);">&nbsp; </td><td>darkgray </td><td class="c" style="background-color:silver;">#a9a9a9 </td><td class="c" style="background-color:silver;">169,169,169 </td></tr><tr> <td class="c" style="background-color:darkgreen;">&nbsp; </td><td class="c" style="background-color:rgb(0, 100, 0);">&nbsp; </td><td>darkgreen </td><td class="c" style="background-color:silver;">#006400 </td><td class="c" style="background-color:silver;">0,100,0 </td></tr><tr> <td class="c" style="background-color:darkgrey;">&nbsp; </td><td class="c" style="background-color:rgb(169, 169, 169);">&nbsp; </td><td>darkgrey </td><td class="c" style="background-color:silver;">#a9a9a9 </td><td class="c" style="background-color:silver;">169,169,169 </td></tr><tr> <td class="c" style="background-color:darkkhaki;">&nbsp; </td><td class="c" style="background-color:rgb(189, 183, 107);">&nbsp; </td><td>darkkhaki </td><td class="c" style="background-color:silver;">#bdb76b </td><td class="c" style="background-color:silver;">189,183,107 </td></tr><tr> <td class="c" style="background-color:darkmagenta;">&nbsp; </td><td class="c" style="background-color:rgb(139, 0, 139);">&nbsp; </td><td>darkmagenta </td><td class="c" style="background-color:silver;">#8b008b </td><td class="c" style="background-color:silver;">139,0,139 </td></tr><tr> <td class="c" style="background-color:darkolivegreen;">&nbsp; </td><td class="c" style="background-color:rgb(85, 107, 47);">&nbsp; </td><td>darkolivegreen </td><td class="c" style="background-color:silver;">#556b2f </td><td class="c" style="background-color:silver;">85,107,47 </td></tr><tr> <td class="c" style="background-color:darkorange;">&nbsp; </td><td class="c" style="background-color:rgb(255, 140, 0);">&nbsp; </td><td>darkorange </td><td class="c" style="background-color:silver;">#ff8c00 </td><td class="c" style="background-color:silver;">255,140,0 </td></tr><tr> <td class="c" style="background-color:darkorchid;">&nbsp; </td><td class="c" style="background-color:rgb(153, 50, 204);">&nbsp; </td><td>darkorchid </td><td class="c" style="background-color:silver;">#9932cc </td><td class="c" style="background-color:silver;">153,50,204 </td></tr><tr> <td class="c" style="background-color:darkred;">&nbsp; </td><td class="c" style="background-color:rgb(139, 0, 0);">&nbsp; </td><td>darkred </td><td class="c" style="background-color:silver;">#8b0000 </td><td class="c" style="background-color:silver;">139,0,0 </td></tr><tr> <td class="c" style="background-color:darksalmon;">&nbsp; </td><td class="c" style="background-color:rgb(233, 150, 122);">&nbsp; </td><td>darksalmon </td><td class="c" style="background-color:silver;">#e9967a </td><td class="c" style="background-color:silver;">233,150,122 </td></tr><tr> <td class="c" style="background-color:darkseagreen;">&nbsp; </td><td class="c" style="background-color:rgb(143, 188, 143);">&nbsp; </td><td>darkseagreen </td><td class="c" style="background-color:silver;">#8fbc8f </td><td class="c" style="background-color:silver;">143,188,143 </td></tr><tr> <td class="c" style="background-color:darkslateblue;">&nbsp; </td><td class="c" style="background-color:rgb(72, 61, 139);">&nbsp; </td><td>darkslateblue </td><td class="c" style="background-color:silver;">#483d8b </td><td class="c" style="background-color:silver;">72,61,139 </td></tr><tr> <td class="c" style="background-color:darkslategray;">&nbsp; </td><td class="c" style="background-color:rgb(47, 79, 79);">&nbsp; </td><td>darkslategray </td><td class="c" style="background-color:silver;">#2f4f4f </td><td class="c" style="background-color:silver;">47,79,79 </td></tr><tr> <td class="c" style="background-color:darkslategrey;">&nbsp; </td><td class="c" style="background-color:rgb(47, 79, 79);">&nbsp; </td><td>darkslategrey </td><td class="c" style="background-color:silver;">#2f4f4f </td><td class="c" style="background-color:silver;">47,79,79 </td></tr><tr> <td class="c" style="background-color:darkturquoise;">&nbsp; </td><td class="c" style="background-color:rgb(0, 206, 209);">&nbsp; </td><td>darkturquoise </td><td class="c" style="background-color:silver;">#00ced1 </td><td class="c" style="background-color:silver;">0,206,209 </td></tr><tr> <td class="c" style="background-color:darkviolet;">&nbsp; </td><td class="c" style="background-color:rgb(148, 0, 211);">&nbsp; </td><td>darkviolet </td><td class="c" style="background-color:silver;">#9400d3 </td><td class="c" style="background-color:silver;">148,0,211 </td></tr><tr> <td class="c" style="background-color:deeppink;">&nbsp; </td><td class="c" style="background-color:rgb(255, 20, 147);">&nbsp; </td><td>deeppink </td><td class="c" style="background-color:silver;">#ff1493 </td><td class="c" style="background-color:silver;">255,20,147 </td></tr><tr> <td class="c" style="background-color:deepskyblue;">&nbsp; </td><td class="c" style="background-color:rgb(0, 191, 255);">&nbsp; </td><td>deepskyblue </td><td class="c" style="background-color:silver;">#00bfff </td><td class="c" style="background-color:silver;">0,191,255 </td></tr><tr> <td class="c" style="background-color:dimgray;">&nbsp; </td><td class="c" style="background-color:rgb(105, 105, 105);">&nbsp; </td><td>dimgray </td><td class="c" style="background-color:silver;">#696969 </td><td class="c" style="background-color:silver;">105,105,105 </td></tr><tr> <td class="c" style="background-color:dimgrey;">&nbsp; </td><td class="c" style="background-color:rgb(105, 105, 105);">&nbsp; </td><td>dimgrey </td><td class="c" style="background-color:silver;">#696969 </td><td class="c" style="background-color:silver;">105,105,105 </td></tr><tr> <td class="c" style="background-color:dodgerblue;">&nbsp; </td><td class="c" style="background-color:rgb(30, 144, 255);">&nbsp; </td><td>dodgerblue </td><td class="c" style="background-color:silver;">#1e90ff </td><td class="c" style="background-color:silver;">30,144,255 </td></tr><tr> <td class="c" style="background-color:firebrick;">&nbsp; </td><td class="c" style="background-color:rgb(178, 34, 34);">&nbsp; </td><td>firebrick </td><td class="c" style="background-color:silver;">#b22222 </td><td class="c" style="background-color:silver;">178,34,34 </td></tr><tr> <td class="c" style="background-color:floralwhite;">&nbsp; </td><td class="c" style="background-color:rgb(255, 250, 240);">&nbsp; </td><td>floralwhite </td><td class="c" style="background-color:silver;">#fffaf0 </td><td class="c" style="background-color:silver;">255,250,240 </td></tr><tr> <td class="c" style="background-color:forestgreen;">&nbsp; </td><td class="c" style="background-color:rgb(34, 139, 34);">&nbsp; </td><td>forestgreen </td><td class="c" style="background-color:silver;">#228b22 </td><td class="c" style="background-color:silver;">34,139,34 </td></tr><tr> <td class="c" style="background-color:fuchsia;">&nbsp; </td><td class="c" style="background-color:rgb(255, 0, 255);">&nbsp; </td><td>fuchsia </td><td class="c" style="background-color:silver;">#ff00ff </td><td class="c" style="background-color:silver;">255,0,255 </td></tr><tr> <td class="c" style="background-color:gainsboro;">&nbsp; </td><td class="c" style="background-color:rgb(220, 220, 220);">&nbsp; </td><td>gainsboro </td><td class="c" style="background-color:silver;">#dcdcdc </td><td class="c" style="background-color:silver;">220,220,220 </td></tr><tr> <td class="c" style="background-color:ghostwhite;">&nbsp; </td><td class="c" style="background-color:rgb(248, 248, 255);">&nbsp; </td><td>ghostwhite </td><td class="c" style="background-color:silver;">#f8f8ff </td><td class="c" style="background-color:silver;">248,248,255 </td></tr><tr> <td class="c" style="background-color:gold;">&nbsp; </td><td class="c" style="background-color:rgb(255, 215, 0);">&nbsp; </td><td>gold </td><td class="c" style="background-color:silver;">#ffd700 </td><td class="c" style="background-color:silver;">255,215,0 </td></tr><tr> <td class="c" style="background-color:goldenrod;">&nbsp; </td><td class="c" style="background-color:rgb(218, 165, 32);">&nbsp; </td><td>goldenrod </td><td class="c" style="background-color:silver;">#daa520 </td><td class="c" style="background-color:silver;">218,165,32 </td></tr><tr> <td class="c" style="background-color:gray;">&nbsp; </td><td class="c" style="background-color:rgb(128, 128, 128);">&nbsp; </td><td>gray </td><td class="c" style="background-color:silver;">#808080 </td><td class="c" style="background-color:silver;">128,128,128 </td></tr><tr> <td class="c" style="background-color:green;">&nbsp; </td><td class="c" style="background-color:rgb(0, 128, 0);">&nbsp; </td><td>green </td><td class="c" style="background-color:silver;">#008000 </td><td class="c" style="background-color:silver;">0,128,0 </td></tr><tr> <td class="c" style="background-color:greenyellow;">&nbsp; </td><td class="c" style="background-color:rgb(173, 255, 47);">&nbsp; </td><td>greenyellow </td><td class="c" style="background-color:silver;">#adff2f </td><td class="c" style="background-color:silver;">173,255,47 </td></tr><tr> <td class="c" style="background-color:grey;">&nbsp; </td><td class="c" style="background-color:rgb(128, 128, 128);">&nbsp; </td><td>grey </td><td class="c" style="background-color:silver;">#808080 </td><td class="c" style="background-color:silver;">128,128,128 </td></tr><tr> <td class="c" style="background-color:honeydew;">&nbsp; </td><td class="c" style="background-color:rgb(240, 255, 240);">&nbsp; </td><td>honeydew </td><td class="c" style="background-color:silver;">#f0fff0 </td><td class="c" style="background-color:silver;">240,255,240 </td></tr><tr> <td class="c" style="background-color:hotpink;">&nbsp; </td><td class="c" style="background-color:rgb(255, 105, 180);">&nbsp; </td><td>hotpink </td><td class="c" style="background-color:silver;">#ff69b4 </td><td class="c" style="background-color:silver;">255,105,180 </td></tr><tr> <td class="c" style="background-color:indianred;">&nbsp; </td><td class="c" style="background-color:rgb(205, 92, 92);">&nbsp; </td><td>indianred </td><td class="c" style="background-color:silver;">#cd5c5c </td><td class="c" style="background-color:silver;">205,92,92 </td></tr><tr> <td class="c" style="background-color:indigo;">&nbsp; </td><td class="c" style="background-color:rgb(75, 0, 130);">&nbsp; </td><td>indigo </td><td class="c" style="background-color:silver;">#4b0082 </td><td class="c" style="background-color:silver;">75,0,130 </td></tr><tr> <td class="c" style="background-color:ivory;">&nbsp; </td><td class="c" style="background-color:rgb(255, 255, 240);">&nbsp; </td><td>ivory </td><td class="c" style="background-color:silver;">#fffff0 </td><td class="c" style="background-color:silver;">255,255,240 </td></tr><tr> <td class="c" style="background-color:khaki;">&nbsp; </td><td class="c" style="background-color:rgb(240, 230, 140);">&nbsp; </td><td>khaki </td><td class="c" style="background-color:silver;">#f0e68c </td><td class="c" style="background-color:silver;">240,230,140 </td></tr><tr> <td class="c" style="background-color:lavender;">&nbsp; </td><td class="c" style="background-color:rgb(230, 230, 250);">&nbsp; </td><td>lavender </td><td class="c" style="background-color:silver;">#e6e6fa </td><td class="c" style="background-color:silver;">230,230,250 </td></tr><tr> <td class="c" style="background-color:lavenderblush;">&nbsp; </td><td class="c" style="background-color:rgb(255, 240, 245);">&nbsp; </td><td>lavenderblush </td><td class="c" style="background-color:silver;">#fff0f5 </td><td class="c" style="background-color:silver;">255,240,245 </td></tr><tr> <td class="c" style="background-color:lawngreen;">&nbsp; </td><td class="c" style="background-color:rgb(124, 252, 0);">&nbsp; </td><td>lawngreen </td><td class="c" style="background-color:silver;">#7cfc00 </td><td class="c" style="background-color:silver;">124,252,0 </td></tr><tr> <td class="c" style="background-color:lemonchiffon;">&nbsp; </td><td class="c" style="background-color:rgb(255, 250, 205);">&nbsp; </td><td>lemonchiffon </td><td class="c" style="background-color:silver;">#fffacd </td><td class="c" style="background-color:silver;">255,250,205 </td></tr><tr> <td class="c" style="background-color:lightblue;">&nbsp; </td><td class="c" style="background-color:rgb(173, 216, 230);">&nbsp; </td><td>lightblue </td><td class="c" style="background-color:silver;">#add8e6 </td><td class="c" style="background-color:silver;">173,216,230 </td></tr><tr> <td class="c" style="background-color:lightcoral;">&nbsp; </td><td class="c" style="background-color:rgb(240, 128, 128);">&nbsp; </td><td>lightcoral </td><td class="c" style="background-color:silver;">#f08080 </td><td class="c" style="background-color:silver;">240,128,128 </td></tr><tr> <td class="c" style="background-color:lightcyan;">&nbsp; </td><td class="c" style="background-color:rgb(224, 255, 255);">&nbsp; </td><td>lightcyan </td><td class="c" style="background-color:silver;">#e0ffff </td><td class="c" style="background-color:silver;">224,255,255 </td></tr><tr> <td class="c" style="background-color:lightgoldenrodyellow;">&nbsp; </td><td class="c" style="background-color:rgb(250, 250, 210);">&nbsp; </td><td>lightgoldenrodyellow </td><td class="c" style="background-color:silver;">#fafad2 </td><td class="c" style="background-color:silver;">250,250,210 </td></tr><tr> <td class="c" style="background-color:lightgray;">&nbsp; </td><td class="c" style="background-color:rgb(211, 211, 211);">&nbsp; </td><td>lightgray </td><td class="c" style="background-color:silver;">#d3d3d3 </td><td class="c" style="background-color:silver;">211,211,211 </td></tr><tr> <td class="c" style="background-color:lightgreen;">&nbsp; </td><td class="c" style="background-color:rgb(144, 238, 144);">&nbsp; </td><td>lightgreen </td><td class="c" style="background-color:silver;">#90ee90 </td><td class="c" style="background-color:silver;">144,238,144 </td></tr><tr> <td class="c" style="background-color:lightgrey;">&nbsp; </td><td class="c" style="background-color:rgb(211, 211, 211);">&nbsp; </td><td>lightgrey </td><td class="c" style="background-color:silver;">#d3d3d3 </td><td class="c" style="background-color:silver;">211,211,211 </td></tr><tr> <td class="c" style="background-color:lightpink;">&nbsp; </td><td class="c" style="background-color:rgb(255, 182, 193);">&nbsp; </td><td>lightpink </td><td class="c" style="background-color:silver;">#ffb6c1 </td><td class="c" style="background-color:silver;">255,182,193 </td></tr><tr> <td class="c" style="background-color:lightsalmon;">&nbsp; </td><td class="c" style="background-color:rgb(255, 160, 122);">&nbsp; </td><td>lightsalmon </td><td class="c" style="background-color:silver;">#ffa07a </td><td class="c" style="background-color:silver;">255,160,122 </td></tr><tr> <td class="c" style="background-color:lightseagreen;">&nbsp; </td><td class="c" style="background-color:rgb(32, 178, 170);">&nbsp; </td><td>lightseagreen </td><td class="c" style="background-color:silver;">#20b2aa </td><td class="c" style="background-color:silver;">32,178,170 </td></tr><tr> <td class="c" style="background-color:lightskyblue;">&nbsp; </td><td class="c" style="background-color:rgb(135, 206, 250);">&nbsp; </td><td>lightskyblue </td><td class="c" style="background-color:silver;">#87cefa </td><td class="c" style="background-color:silver;">135,206,250 </td></tr><tr> <td class="c" style="background-color:lightslategray;">&nbsp; </td><td class="c" style="background-color:rgb(119, 136, 153);">&nbsp; </td><td>lightslategray </td><td class="c" style="background-color:silver;">#778899 </td><td class="c" style="background-color:silver;">119,136,153 </td></tr><tr> <td class="c" style="background-color:lightslategrey;">&nbsp; </td><td class="c" style="background-color:rgb(119, 136, 153);">&nbsp; </td><td>lightslategrey </td><td class="c" style="background-color:silver;">#778899 </td><td class="c" style="background-color:silver;">119,136,153 </td></tr><tr> <td class="c" style="background-color:lightsteelblue;">&nbsp; </td><td class="c" style="background-color:rgb(176, 196, 222);">&nbsp; </td><td>lightsteelblue </td><td class="c" style="background-color:silver;">#b0c4de </td><td class="c" style="background-color:silver;">176,196,222 </td></tr><tr> <td class="c" style="background-color:lightyellow;">&nbsp; </td><td class="c" style="background-color:rgb(255, 255, 224);">&nbsp; </td><td>lightyellow </td><td class="c" style="background-color:silver;">#ffffe0 </td><td class="c" style="background-color:silver;">255,255,224 </td></tr><tr> <td class="c" style="background-color:lime;">&nbsp; </td><td class="c" style="background-color:rgb(0, 255, 0);">&nbsp; </td><td>lime </td><td class="c" style="background-color:silver;">#00ff00 </td><td class="c" style="background-color:silver;">0,255,0 </td></tr><tr> <td class="c" style="background-color:limegreen;">&nbsp; </td><td class="c" style="background-color:rgb(50, 205, 50);">&nbsp; </td><td>limegreen </td><td class="c" style="background-color:silver;">#32cd32 </td><td class="c" style="background-color:silver;">50,205,50 </td></tr><tr> <td class="c" style="background-color:linen;">&nbsp; </td><td class="c" style="background-color:rgb(250, 240, 230);">&nbsp; </td><td>linen </td><td class="c" style="background-color:silver;">#faf0e6 </td><td class="c" style="background-color:silver;">250,240,230 </td></tr><tr> <td class="c" style="background-color:magenta;">&nbsp; </td><td class="c" style="background-color:rgb(255, 0, 255);">&nbsp; </td><td>magenta </td><td class="c" style="background-color:silver;">#ff00ff </td><td class="c" style="background-color:silver;">255,0,255 </td></tr><tr> <td class="c" style="background-color:maroon;">&nbsp; </td><td class="c" style="background-color:rgb(128, 0, 0);">&nbsp; </td><td>maroon </td><td class="c" style="background-color:silver;">#800000 </td><td class="c" style="background-color:silver;">128,0,0 </td></tr><tr> <td class="c" style="background-color:mediumaquamarine;">&nbsp; </td><td class="c" style="background-color:rgb(102, 205, 170);">&nbsp; </td><td>mediumaquamarine </td><td class="c" style="background-color:silver;">#66cdaa </td><td class="c" style="background-color:silver;">102,205,170 </td></tr><tr> <td class="c" style="background-color:mediumblue;">&nbsp; </td><td class="c" style="background-color:rgb(0, 0, 205);">&nbsp; </td><td>mediumblue </td><td class="c" style="background-color:silver;">#0000cd </td><td class="c" style="background-color:silver;">0,0,205 </td></tr><tr> <td class="c" style="background-color:mediumorchid;">&nbsp; </td><td class="c" style="background-color:rgb(186, 85, 211);">&nbsp; </td><td>mediumorchid </td><td class="c" style="background-color:silver;">#ba55d3 </td><td class="c" style="background-color:silver;">186,85,211 </td></tr><tr> <td class="c" style="background-color:mediumpurple;">&nbsp; </td><td class="c" style="background-color:rgb(147, 112, 219);">&nbsp; </td><td>mediumpurple </td><td class="c" style="background-color:silver;">#9370db </td><td class="c" style="background-color:silver;">147,112,219 </td></tr><tr> <td class="c" style="background-color:mediumseagreen;">&nbsp; </td><td class="c" style="background-color:rgb(60, 179, 113);">&nbsp; </td><td>mediumseagreen </td><td class="c" style="background-color:silver;">#3cb371 </td><td class="c" style="background-color:silver;">60,179,113 </td></tr><tr> <td class="c" style="background-color:mediumslateblue;">&nbsp; </td><td class="c" style="background-color:rgb(123, 104, 238);">&nbsp; </td><td>mediumslateblue </td><td class="c" style="background-color:silver;">#7b68ee </td><td class="c" style="background-color:silver;">123,104,238 </td></tr><tr> <td class="c" style="background-color:mediumspringgreen;">&nbsp; </td><td class="c" style="background-color:rgb(0, 250, 154);">&nbsp; </td><td>mediumspringgreen </td><td class="c" style="background-color:silver;">#00fa9a </td><td class="c" style="background-color:silver;">0,250,154 </td></tr><tr> <td class="c" style="background-color:mediumturquoise;">&nbsp; </td><td class="c" style="background-color:rgb(72, 209, 204);">&nbsp; </td><td>mediumturquoise </td><td class="c" style="background-color:silver;">#48d1cc </td><td class="c" style="background-color:silver;">72,209,204 </td></tr><tr> <td class="c" style="background-color:mediumvioletred;">&nbsp; </td><td class="c" style="background-color:rgb(199, 21, 133);">&nbsp; </td><td>mediumvioletred </td><td class="c" style="background-color:silver;">#c71585 </td><td class="c" style="background-color:silver;">199,21,133 </td></tr><tr> <td class="c" style="background-color:midnightblue;">&nbsp; </td><td class="c" style="background-color:rgb(25, 25, 112);">&nbsp; </td><td>midnightblue </td><td class="c" style="background-color:silver;">#191970 </td><td class="c" style="background-color:silver;">25,25,112 </td></tr><tr> <td class="c" style="background-color:mintcream;">&nbsp; </td><td class="c" style="background-color:rgb(245, 255, 250);">&nbsp; </td><td>mintcream </td><td class="c" style="background-color:silver;">#f5fffa </td><td class="c" style="background-color:silver;">245,255,250 </td></tr><tr> <td class="c" style="background-color:mistyrose;">&nbsp; </td><td class="c" style="background-color:rgb(255, 228, 225);">&nbsp; </td><td>mistyrose </td><td class="c" style="background-color:silver;">#ffe4e1 </td><td class="c" style="background-color:silver;">255,228,225 </td></tr><tr> <td class="c" style="background-color:moccasin;">&nbsp; </td><td class="c" style="background-color:rgb(255, 228, 181);">&nbsp; </td><td>moccasin </td><td class="c" style="background-color:silver;">#ffe4b5 </td><td class="c" style="background-color:silver;">255,228,181 </td></tr><tr> <td class="c" style="background-color:navajowhite;">&nbsp; </td><td class="c" style="background-color:rgb(255, 222, 173);">&nbsp; </td><td>navajowhite </td><td class="c" style="background-color:silver;">#ffdead </td><td class="c" style="background-color:silver;">255,222,173 </td></tr><tr> <td class="c" style="background-color:navy;">&nbsp; </td><td class="c" style="background-color:rgb(0, 0, 128);">&nbsp; </td><td>navy </td><td class="c" style="background-color:silver;">#000080 </td><td class="c" style="background-color:silver;">0,0,128 </td></tr><tr> <td class="c" style="background-color:oldlace;">&nbsp; </td><td class="c" style="background-color:rgb(253, 245, 230);">&nbsp; </td><td>oldlace </td><td class="c" style="background-color:silver;">#fdf5e6 </td><td class="c" style="background-color:silver;">253,245,230 </td></tr><tr> <td class="c" style="background-color:olive;">&nbsp; </td><td class="c" style="background-color:rgb(128, 128, 0);">&nbsp; </td><td>olive </td><td class="c" style="background-color:silver;">#808000 </td><td class="c" style="background-color:silver;">128,128,0 </td></tr><tr> <td class="c" style="background-color:olivedrab;">&nbsp; </td><td class="c" style="background-color:rgb(107, 142, 35);">&nbsp; </td><td>olivedrab </td><td class="c" style="background-color:silver;">#6b8e23 </td><td class="c" style="background-color:silver;">107,142,35 </td></tr><tr> <td class="c" style="background-color:orange;">&nbsp; </td><td class="c" style="background-color:rgb(255, 165, 0);">&nbsp; </td><td>orange </td><td class="c" style="background-color:silver;">#ffa500 </td><td class="c" style="background-color:silver;">255,165,0 </td></tr><tr> <td class="c" style="background-color:orangered;">&nbsp; </td><td class="c" style="background-color:rgb(255, 69, 0);">&nbsp; </td><td>orangered </td><td class="c" style="background-color:silver;">#ff4500 </td><td class="c" style="background-color:silver;">255,69,0 </td></tr><tr> <td class="c" style="background-color:orchid;">&nbsp; </td><td class="c" style="background-color:rgb(218, 112, 214);">&nbsp; </td><td>orchid </td><td class="c" style="background-color:silver;">#da70d6 </td><td class="c" style="background-color:silver;">218,112,214 </td></tr><tr> <td class="c" style="background-color:palegoldenrod;">&nbsp; </td><td class="c" style="background-color:rgb(238, 232, 170);">&nbsp; </td><td>palegoldenrod </td><td class="c" style="background-color:silver;">#eee8aa </td><td class="c" style="background-color:silver;">238,232,170 </td></tr><tr> <td class="c" style="background-color:palegreen;">&nbsp; </td><td class="c" style="background-color:rgb(152, 251, 152);">&nbsp; </td><td>palegreen </td><td class="c" style="background-color:silver;">#98fb98 </td><td class="c" style="background-color:silver;">152,251,152 </td></tr><tr> <td class="c" style="background-color:paleturquoise;">&nbsp; </td><td class="c" style="background-color:rgb(175, 238, 238);">&nbsp; </td><td>paleturquoise </td><td class="c" style="background-color:silver;">#afeeee </td><td class="c" style="background-color:silver;">175,238,238 </td></tr><tr> <td class="c" style="background-color:palevioletred;">&nbsp; </td><td class="c" style="background-color:rgb(219, 112, 147);">&nbsp; </td><td>palevioletred </td><td class="c" style="background-color:silver;">#db7093 </td><td class="c" style="background-color:silver;">219,112,147 </td></tr><tr> <td class="c" style="background-color:papayawhip;">&nbsp; </td><td class="c" style="background-color:rgb(255, 239, 213);">&nbsp; </td><td>papayawhip </td><td class="c" style="background-color:silver;">#ffefd5 </td><td class="c" style="background-color:silver;">255,239,213 </td></tr><tr> <td class="c" style="background-color:peachpuff;">&nbsp; </td><td class="c" style="background-color:rgb(255, 218, 185);">&nbsp; </td><td>peachpuff </td><td class="c" style="background-color:silver;">#ffdab9 </td><td class="c" style="background-color:silver;">255,218,185 </td></tr><tr> <td class="c" style="background-color:peru;">&nbsp; </td><td class="c" style="background-color:rgb(205, 133, 63);">&nbsp; </td><td>peru </td><td class="c" style="background-color:silver;">#cd853f </td><td class="c" style="background-color:silver;">205,133,63 </td></tr><tr> <td class="c" style="background-color:pink;">&nbsp; </td><td class="c" style="background-color:rgb(255, 192, 203);">&nbsp; </td><td>pink </td><td class="c" style="background-color:silver;">#ffc0cb </td><td class="c" style="background-color:silver;">255,192,203 </td></tr><tr> <td class="c" style="background-color:plum;">&nbsp; </td><td class="c" style="background-color:rgb(221, 160, 221);">&nbsp; </td><td>plum </td><td class="c" style="background-color:silver;">#dda0dd </td><td class="c" style="background-color:silver;">221,160,221 </td></tr><tr> <td class="c" style="background-color:powderblue;">&nbsp; </td><td class="c" style="background-color:rgb(176, 224, 230);">&nbsp; </td><td>powderblue </td><td class="c" style="background-color:silver;">#b0e0e6 </td><td class="c" style="background-color:silver;">176,224,230 </td></tr><tr> <td class="c" style="background-color:purple;">&nbsp; </td><td class="c" style="background-color:rgb(128, 0, 128);">&nbsp; </td><td>purple </td><td class="c" style="background-color:silver;">#800080 </td><td class="c" style="background-color:silver;">128,0,128 </td></tr><tr> <td class="c" style="background-color:red;">&nbsp; </td><td class="c" style="background-color:rgb(255, 0, 0);">&nbsp; </td><td>red </td><td class="c" style="background-color:silver;">#ff0000 </td><td class="c" style="background-color:silver;">255,0,0 </td></tr><tr> <td class="c" style="background-color:rosybrown;">&nbsp; </td><td class="c" style="background-color:rgb(188, 143, 143);">&nbsp; </td><td>rosybrown </td><td class="c" style="background-color:silver;">#bc8f8f </td><td class="c" style="background-color:silver;">188,143,143 </td></tr><tr> <td class="c" style="background-color:royalblue;">&nbsp; </td><td class="c" style="background-color:rgb(65, 105, 225);">&nbsp; </td><td>royalblue </td><td class="c" style="background-color:silver;">#4169e1 </td><td class="c" style="background-color:silver;">65,105,225 </td></tr><tr> <td class="c" style="background-color:saddlebrown;">&nbsp; </td><td class="c" style="background-color:rgb(139, 69, 19);">&nbsp; </td><td>saddlebrown </td><td class="c" style="background-color:silver;">#8b4513 </td><td class="c" style="background-color:silver;">139,69,19 </td></tr><tr> <td class="c" style="background-color:salmon;">&nbsp; </td><td class="c" style="background-color:rgb(250, 128, 114);">&nbsp; </td><td>salmon </td><td class="c" style="background-color:silver;">#fa8072 </td><td class="c" style="background-color:silver;">250,128,114 </td></tr><tr> <td class="c" style="background-color:sandybrown;">&nbsp; </td><td class="c" style="background-color:rgb(244, 164, 96);">&nbsp; </td><td>sandybrown </td><td class="c" style="background-color:silver;">#f4a460 </td><td class="c" style="background-color:silver;">244,164,96 </td></tr><tr> <td class="c" style="background-color:seagreen;">&nbsp; </td><td class="c" style="background-color:rgb(46, 139, 87);">&nbsp; </td><td>seagreen </td><td class="c" style="background-color:silver;">#2e8b57 </td><td class="c" style="background-color:silver;">46,139,87 </td></tr><tr> <td class="c" style="background-color:seashell;">&nbsp; </td><td class="c" style="background-color:rgb(255, 245, 238);">&nbsp; </td><td>seashell </td><td class="c" style="background-color:silver;">#fff5ee </td><td class="c" style="background-color:silver;">255,245,238 </td></tr><tr> <td class="c" style="background-color:sienna;">&nbsp; </td><td class="c" style="background-color:rgb(160, 82, 45);">&nbsp; </td><td>sienna </td><td class="c" style="background-color:silver;">#a0522d </td><td class="c" style="background-color:silver;">160,82,45 </td></tr><tr> <td class="c" style="background-color:silver;">&nbsp; </td><td class="c" style="background-color:rgb(192, 192, 192);">&nbsp; </td><td>silver </td><td class="c" style="background-color:silver;">#c0c0c0 </td><td class="c" style="background-color:silver;">192,192,192 </td></tr><tr> <td class="c" style="background-color:skyblue;">&nbsp; </td><td class="c" style="background-color:rgb(135, 206, 235);">&nbsp; </td><td>skyblue </td><td class="c" style="background-color:silver;">#87ceeb </td><td class="c" style="background-color:silver;">135,206,235 </td></tr><tr> <td class="c" style="background-color:slateblue;">&nbsp; </td><td class="c" style="background-color:rgb(106, 90, 205);">&nbsp; </td><td>slateblue </td><td class="c" style="background-color:silver;">#6a5acd </td><td class="c" style="background-color:silver;">106,90,205 </td></tr><tr> <td class="c" style="background-color:slategray;">&nbsp; </td><td class="c" style="background-color:rgb(112, 128, 144);">&nbsp; </td><td>slategray </td><td class="c" style="background-color:silver;">#708090 </td><td class="c" style="background-color:silver;">112,128,144 </td></tr><tr> <td class="c" style="background-color:slategrey;">&nbsp; </td><td class="c" style="background-color:rgb(112, 128, 144);">&nbsp; </td><td>slategrey </td><td class="c" style="background-color:silver;">#708090 </td><td class="c" style="background-color:silver;">112,128,144 </td></tr><tr> <td class="c" style="background-color:snow;">&nbsp; </td><td class="c" style="background-color:rgb(255, 250, 250);">&nbsp; </td><td>snow </td><td class="c" style="background-color:silver;">#fffafa </td><td class="c" style="background-color:silver;">255,250,250 </td></tr><tr> <td class="c" style="background-color:springgreen;">&nbsp; </td><td class="c" style="background-color:rgb(0, 255, 127);">&nbsp; </td><td>springgreen </td><td class="c" style="background-color:silver;">#00ff7f </td><td class="c" style="background-color:silver;">0,255,127 </td></tr><tr> <td class="c" style="background-color:steelblue;">&nbsp; </td><td class="c" style="background-color:rgb(70, 130, 180);">&nbsp; </td><td>steelblue </td><td class="c" style="background-color:silver;">#4682b4 </td><td class="c" style="background-color:silver;">70,130,180 </td></tr><tr> <td class="c" style="background-color:tan;">&nbsp; </td><td class="c" style="background-color:rgb(210, 180, 140);">&nbsp; </td><td>tan </td><td class="c" style="background-color:silver;">#d2b48c </td><td class="c" style="background-color:silver;">210,180,140 </td></tr><tr> <td class="c" style="background-color:teal;">&nbsp; </td><td class="c" style="background-color:rgb(0, 128, 128);">&nbsp; </td><td>teal </td><td class="c" style="background-color:silver;">#008080 </td><td class="c" style="background-color:silver;">0,128,128 </td></tr><tr> <td class="c" style="background-color:thistle;">&nbsp; </td><td class="c" style="background-color:rgb(216, 191, 216);">&nbsp; </td><td>thistle </td><td class="c" style="background-color:silver;">#d8bfd8 </td><td class="c" style="background-color:silver;">216,191,216 </td></tr><tr> <td class="c" style="background-color:tomato;">&nbsp; </td><td class="c" style="background-color:rgb(255, 99, 71);">&nbsp; </td><td>tomato </td><td class="c" style="background-color:silver;">#ff6347 </td><td class="c" style="background-color:silver;">255,99,71 </td></tr><tr> <td class="c" style="background-color:turquoise;">&nbsp; </td><td class="c" style="background-color:rgb(64, 224, 208);">&nbsp; </td><td>turquoise </td><td class="c" style="background-color:silver;">#40e0d0 </td><td class="c" style="background-color:silver;">64,224,208 </td></tr><tr> <td class="c" style="background-color:violet;">&nbsp; </td><td class="c" style="background-color:rgb(238, 130, 238);">&nbsp; </td><td>violet </td><td class="c" style="background-color:silver;">#ee82ee </td><td class="c" style="background-color:silver;">238,130,238 </td></tr><tr> <td class="c" style="background-color:wheat;">&nbsp; </td><td class="c" style="background-color:rgb(245, 222, 179);">&nbsp; </td><td>wheat </td><td class="c" style="background-color:silver;">#f5deb3 </td><td class="c" style="background-color:silver;">245,222,179 </td></tr><tr> <td class="c" style="background-color:white;">&nbsp; </td><td class="c" style="background-color:rgb(255, 255, 255);">&nbsp; </td><td>white </td><td class="c" style="background-color:silver;">#ffffff </td><td class="c" style="background-color:silver;">255,255,255 </td></tr><tr> <td class="c" style="background-color:whitesmoke;">&nbsp; </td><td class="c" style="background-color:rgb(245, 245, 245);">&nbsp; </td><td>whitesmoke </td><td class="c" style="background-color:silver;">#f5f5f5 </td><td class="c" style="background-color:silver;">245,245,245 </td></tr><tr> <td class="c" style="background-color:yellow;">&nbsp; </td><td class="c" style="background-color:rgb(255, 255, 0);">&nbsp; </td><td>yellow </td><td class="c" style="background-color:silver;">#ffff00 </td><td class="c" style="background-color:silver;">255,255,0 </td></tr><tr> <td class="c" style="background-color:yellowgreen;">&nbsp; </td><td class="c" style="background-color:rgb(154, 205, 50);">&nbsp; </td><td>yellowgreen </td><td class="c" style="background-color:silver;">#9acd32 </td><td class="c" style="background-color:silver;">154,205,50 </td></tr></table> == System Colors == <b>Note:</b> As of [[http://www.w3.org/TR/css3-color/ CSS Color]], the CSS2 System Color values have been deprecated in favor of the CSS3 UI ‘[[http://www.w3.org/TR/css3-ui/#appearance appearance]]’ property. *<code>ActiveBorder</code><br />Active window border. * <code>ActiveCaption</code><br />Active window caption. * <code>AppWorkspace</code><br />Background color of multiple document interface. * <code>Background</code><br />Desktop background. * <code>ButtonFace</code><br />The face background color for 3-D elements that appear 3-D due to one layer of surrounding border. * <code>ButtonHighlight</code><br />The color of the border facing the light source for 3-D elements that appear 3-D due to one layer of surrounding border. * <code>ButtonShadow</code><br />The color of the border away from the light source for 3-D elements that appear 3-D due to one layer of surrounding border. * <code>ButtonText</code><br />Text on push buttons. * <code>CaptionText</code><br />Text in caption, size box, and scrollbar arrow box. * <code>GrayText</code><br />Grayed (disabled) text. This color is set to #000 if the current display driver does not support a solid gray color. * <code>Highlight</code><br />Item(s) selected in a control. * <code>HighlightText</code><br />Text of item(s) selected in a control. * <code>InactiveBorder</code><br />Inactive window border. * <code>InactiveCaption</code><br />Inactive window caption. * <code>InactiveCaptionText</code><br />Color of text in an inactive caption. * <code>InfoBackground</code><br />Background color for tooltip controls. * <code>InfoText</code><br />Text color for tooltip controls. * <code>Menu</code><br />Menu background. * <code>MenuText</code><br />Text in menus. * <code>Scrollbar</code><br />Scroll bar gray area. * <code>ThreeDDarkShadow</code><br />The color of the darker (generally outer) of the two borders away from the light source for 3-D elements that appear 3-D due to two concentric layers of surrounding border. * <code>ThreeDFace</code><br />The face background color for 3-D elements that appear 3-D due to two concentric layers of surrounding border. * <code>ThreeDHighlight</code><br />The color of the lighter (generally outer) of the two borders facing the light source for 3-D elements that appear 3-D due to two concentric layers of surrounding border. * <code>ThreeDLightShadow</code><br />The color of the darker (generally inner) of the two borders facing the light source for 3-D elements that appear 3-D due to two concentric layers of surrounding border. * <code>ThreeDShadow</code><br />The color of the lighter (generally inner) of the two borders away from the light source for 3-D elements that appear 3-D due to two concentric layers of surrounding border. * <code>Window</code><br />Window background. * <code>WindowFrame</code><br />Window frame. * <code>WindowText</code><br />Text in windows. hikikomori aged 40-64: 610, 000 https://www.deviantart.com/ryky/art/How-to-draw-hair-568446916 'concierge' following viral tweet https://www.dropbox.com/contact U+2218 ∘ RING OPERATOR ( &compfn;, &SmallCircle;); huuzah https://japaneseparticlesmaster.xyz/yaruki-in-japanese/ "Take Me To Your Leader" "Recognizance Scout" "Actively Amazing" TASK for implementation 7/18 - 7/24th :: J's Deliverable: V [https://www.youtube.com/watch?v=-sk9kXyfGvU "unmotivated wood"] https://www.youtube.com/results?search_query=YARUKI https://www.roland.com/global/support/by_product/sp-404mk2/owners_manuals/ todo: what does a day @ wikiversity look like? https://nazarene.quora.com/ https://www.twitch.tv/archie97305 https://anchor.fm/ providence Bus 48 arrives @ HTC @ 7:43 p/u @ 7:29 [1 earlier: arrives @ HTC @ 7:10 p/u @ 6:57] Max Blue 7:52 = "1 route early" 8:07 = "on time" fleet armada ruminate https://en.wikipedia.org/wiki/Streisand_effect jackie anderson s4e10 [https://en.wikipedia.org/wiki/Schadenfreude ^]Schadenfreude (/ˈʃɑːdənfrɔɪdə/; German: [ˈʃaːdn̩ˌfʁɔʏ̯də] (listen); lit. 'harm-joy') is the experience of pleasure, joy, or self-satisfaction that comes from learning of or witnessing the troubles, failures, or humiliation of another. It is a borrowed word from German, with no direct translation, that originated in the 18th century. Schadenfreude has been detected in children as young as 24 months and may be an important social emotion establishing "inequity aversion".[1] [https://util.unicode.org/UnicodeJsps/character.jsp?a=2219 `] [https://tex.stackexchange.com/questions/19180/which-dot-character-to-use-in-which-context ^] 00B7 · MIDDLE DOT = midpoint (in typography) = Georgian comma = Greek middle dot (ano teleia) → 0387 · greek ano teleia → 16EB ᛫ runic single punctuation → 2022 • bullet → 2024 . one dot leader → 2027 ‧ hyphenation point → 2219 ∙ bullet operator → 22C5 ⋅ dot operator → 2E31 ⸱ word separator middle dot → 2E33 ⸳ raised dot → 30FB ・ katakana middle dot Block “General Punctuation” 2022 • BULLET = black small circle → 00B7 · middle dot → 2024 . one dot leader → 2219 ∙ bullet operator → 25D8 ◘ inverse bullet → 25E6 ◦ white bullet Block “Mathematical Operators” 2219 ∙ BULLET OPERATOR → 00B7 · middle dot → 2022 • bullet → 2024 . one dot leader 22C5 ⋅ DOT OPERATOR → 00B7 · middle dot <h1>⸰⸰⸰△∙•･⋅·‧ᐧ᛫ꞏ⸱·・ⷵ ⷶ ⷷ ⷸ ⷹ ⷺ ⷻ ⷼ ⷽ ⷾ ⷿ ⸀ ⸁ · ⸂ ⸃ ⸄ ⸅ ⸆ ⸇ ⸈ ⸉ ⸊ ⸋ ⸌ ⸍ ⸎ · ⸏ ⸐ ⸑ ⸒ ⸓ ⸔ ⸕ ⸖ ⸗ ⸘ ⸙ ⸚ ⸛.ᘛ⁐̤ᕐᐷ ⸱៰ ͘ ࣭⸰</h1> ·[U+00B7 MIDDLE DOT],★ 。⸰ 日 {| |- |style="font-size: 22px; color: pink; background-color: #333; padding: 11px"| Royal•週We |style="font-size: 22px; color: salmon; background-color: #333; padding: 11px"| 1wiki |style="font-size: 22px; color: powderblue; background-color: #333; padding: 11px"| 2ver |style="font-size: 22px; color: cadetblue; background-color: #333; padding: 11px"| 3s |style="font-size: 22px; color: #fff; background-color: #000; padding: 11px"| 4ity |style="font-size: 22px; color: #fff; background-color: #111; padding: 11px"| 5North |style="font-size: 22px; color: #fff; background-color: #222; padding: 11px"| 6West |style="font-size: 22px; color: #fff; background-color: #333; padding: 11px"| 7[https://en.wikipedia.org/wiki/Human_taxonomy#Subspecies ^] superfamily: hominoidea |style="font-size: 22px; color: #fff; background-color: #444; padding: 11px"| 8hominidae |style="font-size: 22px; color: #fff; background-color: #555; padding: 11px"| 9homininae |style="font-size: 22px; color: #fff; background-color: #666; padding: 11px"| +hominini |style="font-size: 22px; color: #fff; background-color: #777; padding: 11px"| 11 |style="font-size: 22px; color: #fff; background-color: #888; padding: 11px"| 12 |style="font-size: 22px; color: #fff; background-color: #999; padding: 11px"| 13 |style="font-size: 22px; color: #fff; background-color: #aaa; padding: 11px"| 14 |style="font-size: 22px; color: #fff; background-color: #bbb; padding: 11px"| 15 |style="font-size: 22px; color: #fff; background-color: #ccc; padding: 11px"| 16 |style="font-size: 22px; color: #fff; background-color: #ddd; padding: 11px"| 17 |style="font-size: 22px; color: #fff; background-color: #eee; padding: 11px"| 18 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 19 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 20 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 21 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 22 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 23 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 24 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 25 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 26 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 27 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 28 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 29 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 30 |style="font-size: 22px; color: #fff; background-color: #a020f0; padding: 11px"| 31 |- |style="font-size: 22px; color: pink; background-color: #333; padding: 11px"| 0Royal•:⋮\週Week |style="font-size: 22px; color: salmon; background-color: #333; padding: 11px"| 1wiki |style="font-size: 22px; color: powderblue; background-color: #333; padding: 11px"| 2ver |style="font-size: 22px; color: cadetblue; background-color: #333; padding: 11px"| 3s |style="font-size: 22px; color: #fff; background-color: #000; padding: 11px"| 4ity |style="font-size: 22px; color: #fff; background-color: #111; padding: 11px"| 5North |style="font-size: 22px; color: #fff; background-color: #222; padding: 11px"| 6West |style="font-size: 22px; color: #fff; background-color: #333; padding: 11px"| 7[https://en.wikipedia.org/wiki/Human_taxonomy#Subspecies ^] superfamily: hominoidea |style="font-size: 22px; color: #fff; background-color: #444; padding: 11px"| 8hominidae |style="font-size: 22px; color: #fff; background-color: #555; padding: 11px"| 9homininae |style="font-size: 22px; color: #fff; background-color: #666; padding: 11px"| +hominini |style="font-size: 22px; color: #fff; background-color: #777; padding: 11px"| 11 |style="font-size: 22px; color: #fff; background-color: #888; padding: 11px"| 12 |style="font-size: 22px; color: #fff; background-color: #999; padding: 11px"| 13 |style="font-size: 22px; color: #fff; background-color: #aaa; padding: 11px"| 14 |style="font-size: 22px; color: #fff; background-color: #bbb; padding: 11px"| 15 |style="font-size: 22px; color: #fff; background-color: #ccc; padding: 11px"| 16 |style="font-size: 22px; color: #fff; background-color: #ddd; padding: 11px"| 17 |style="font-size: 22px; color: #fff; background-color: #eee; padding: 11px"| 18 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 19 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 20 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 21 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 22 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 23 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 24 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 25 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 26 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 27 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 28 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 29 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 30 |style="font-size: 22px; color: #fff; background-color: #a020f0; padding: 11px"| 31 |} https://www.vim.org/ https://www.uscis.gov/citizenship/learn-about-citizenship/the-naturalization-interview-and-test/naturalization-oath-of-allegiance-to-the-united-states-of-america https://en.wikipedia.org/wiki/Holding_Out_for_a_Hero {| |- || ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 |- || A Major Scale || 1 || 2 || 3 || 4 || 5 || 6 || 7 || 8 || 9 || 十 || 11 || 12 || 1 |- || AM || A || ◯ || B || ◯ || C# || D || ◯ || E || ◯ || F# || ◯ || G# || A |- || F# minor || F# || ◯ || G# || A || ◯ || B || ◯ || C# || D || ◯ || E || ◯ || F# || F sharp minor is the Relative key to A Major |- || A minor || A || ◯ || B || C || ◯ || D || ◯ || E || F || ◯ || G || ◯ || A || A minor is the Parallel key to A Major |- || E Major || E || ◯ || F# || ◯ || G# || A || ◯ || B || ◯ || C# || D# || ◯ || E || E Major is the Dominant key to A major |- || D Major || D || ◯ || E || ◯ || F# || ◯ || G# || A || ◯ || B || ◯ || C# || D || D Major is the Subdominant key to A major || According to Paolo Pietropaolo, D major is Miss Congeniality: it is persistent, sunny, and energetic[https://en.wikipedia.org/wiki/D_major DM] |- || [https://en.wikipedia.org/wiki/A_major A major] |} A ◯ B ◯ C# ◠ D ◯ E ◯ F# ◯ G# ◠ A Major Scale 3⁄2 C D E F G A B C 1 +9⁄8 +5⁄4 +4⁄3 +3⁄2 +5⁄3 +15⁄8 2 {| |- || 0 || 1 || 2 || 3 || 4 || 5 || 6 || 7 || 8 || 9 || 十 || 11 || 12 |- || 0 || M || U || W || H || F || A || N |- || ▣ || 🟨 || 🟧 || 🟥 || 🟪 || 🟦 || 🟩 || ⬜ || ⬛ || ▤ || ▥ || ▦ || ▧ || ▨ || ▩ || ❏ || ❐ || ❑ |- ||a ||b ||c ||d ||e ||f ||g ||h ||i ||j ||k ||l ||m ||n ||o ||p ||q ||r ||s ||t ||u ||v ||w ||x ||y ||z |- ||🢄 ||🢁 ||🢅 ||🢀 ||⯐ ||🢂 ||🢇 ||🢃 ||🢆 |- ||🢀 ||⯐ ||🢂 |- ||🢇 ||🢃 ||🢆 |- ||𝄞 ||𝄡 ||𝄢 |} https://en.wikiversity.org/wiki/Portal:Music == Evens And Odds == West trends even East trends odd <h1> Hackers of the Whirled Unite </h1> "cultural de-real i zation" https://en.wikipedia.org/wiki/Arrow_(symbol) https://en.wikipedia.org/wiki/Amber_Ruffin hex #ffbf00 (also known as Amber, Fluorescent orange) is composed of 100% red, 74.9% green and 0% blue. == "I lost the game" == ==.slug:b**⋮:.== gma andy was a sister mon sig nor [https://en.wikipedia.org/wiki/Punch_buggy slug a bobby game per evil on paramount+&] =👀= ¼ task: properly document and opine re: Nazarene 👁 ½ task: properly document and opine re: univers-sity 👁👄 ¾ task: properly document and opine re: cross 👁👄👁 一 task: properly document and opine re: this real life ❌ generational event: https://www.instagram.com/p/CfO7fCwLn1Z/?utm_source=ig_embed&utm_campaign=loading ⭕️ ==¼👁.svg== ==½👁👄.ico== ==¾👁👄👁.png== ==一⭕️.html== ==❌index.== ==⭕️❌index.html== ==👀_cv-== =!👀= https://drive.google.com/drive/folders/1ku_XmbHOZ5ypgKCAjpzX6hlXaOJT7Uoq {||+ |- || 0 || 1 || 2 || 3 || 4 || 5 || 6 || 7 || 8 || 9 || 十 || 11 || 12 |- || 0 || M || U || W || H || F || A || N |- || ▣ || 🟨 || 🟧 || 🟥 || 🟪 || 🟦 || 🟩 || ⬜ || ⬛ || ▤ || ▥ || ▦ || ▧ || ▨ || ▩ || ❏ || ❐ || ❑ |} ◜+◝ = ◠ ◟+◞ = ◡ ◠+◡ = ◯ ◣+◥ or ◤+◢ = ◼ ◸+◿ or ◺+◹ = ◻ https://drive.google.com/drive/folders/1-sKzV5R8k_f8bOrGNtIf4CWuVL3LJJcL https://quaternius.com/packs/modularplatformer.html https://quaternius.com/tutorials.html 🈁🚌🟨🟥🟦🚍〇丁鼎 Royal_We : have work flows; will train! 🚂 = .:⋮ 🟨 🟥 🟦 = [https://en.wikiversity.org/wiki/User:VeronicaJeanAnderson/🟨 🟨] [https://en.wikiversity.org/wiki/User:VeronicaJeanAnderson/🟥 🟥] [https://en.wikiversity.org/wiki/User:VeronicaJeanAnderson/🟦 🟦] == 👤¹== [https://en.wikiversity.org/wiki/User:VeronicaJeanAnderson ∨↯∧|序] [http://themetawiki.clu/w/index.php/Main_Page 🈁] == 👥² == [https://en.wikiversity.org/wiki/User:VeronicaJeanAnderson/DAM ∨↯∧|DAM] == 👣³ == [https://en.wikiversity.org/wiki/User:VeronicaJeanAnderson/mess ∨↯∧|mess] = ∨↯∧ = ∨ or ↯【いま】今 ∧【wedge】& ... ... ... ‸^‸ /(ˈkærɪt)/ ∩ intersection ∪ union == ↓ == ↯ 今【いま】 == ↑ == ∩ ∪ == ← == pernicious == → == grandfather paradox =🈁= 🚌🟨🟥🟦🚍〇丁鼎 Royal_We : have work flows; will train! 🚂 ==🚌== ==🚍== ==🚂== = 〇丁鼎 Royal_We Ventur= no ads no silent e ==〇== ==丁== ==鼎== {| |- |style="font-size: 22px; color: pink; background-color: #333; padding: 11px"| 0Royal•:⋮\日Week |style="font-size: 22px; color: salmon; background-color: #333; padding: 11px"| 1wiki |style="font-size: 22px; color: powderblue; background-color: #333; padding: 11px"| 2ver |style="font-size: 22px; color: cadetblue; background-color: #333; padding: 11px"| 3s |style="font-size: 22px; color: #fff; background-color: #000; padding: 11px"| 4ity |style="font-size: 22px; color: #fff; background-color: #111; padding: 11px"| 5North |style="font-size: 22px; color: #fff; background-color: #222; padding: 11px"| 6West |style="font-size: 22px; color: #fff; background-color: #333; padding: 11px"| 7[https://en.wikipedia.org/wiki/Human_taxonomy#Subspecies ^] superfamily: hominoidea |style="font-size: 22px; color: #fff; background-color: #444; padding: 11px"| 8hominidae |style="font-size: 22px; color: #fff; background-color: #555; padding: 11px"| 9homininae |style="font-size: 22px; color: #fff; background-color: #666; padding: 11px"| +hominini |style="font-size: 22px; color: #fff; background-color: #777; padding: 11px"| 11Homo |style="font-size: 22px; color: #fff; background-color: #888; padding: 11px"| 12Homo |style="font-size: 22px; color: #fff; background-color: #999; padding: 11px"| 13Homo |style="font-size: 22px; color: #fff; background-color: #aaa; padding: 11px"| 14Homo |style="font-size: 22px; color: #fff; background-color: #bbb; padding: 11px"| 15Homo |style="font-size: 22px; color: #fff; background-color: #ccc; padding: 11px"| 16Homo |style="font-size: 22px; color: #fff; background-color: #ddd; padding: 11px"| 17Homo |style="font-size: 22px; color: #fff; background-color: #eee; padding: 11px"| 18Homo |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 19Homo |} bii8chg9bd839pswm05bt71f45nonwp 2408049 2408043 2022-07-19T20:43:57Z Archie97305 2915204 wikitext text/x-wiki https://www.roland.com/global/support/by_product/sp-404mk2/owners_manuals/ yessiree bob in the wave mohammed agbadi youtube https://www.youtube.com/watch?v=4TCYjw88JSY http://kaomoji.ru/en/ https://period.co/collections/all ∨↯∧|序 https://www.freepik.com/ [http://themetawiki.clu ⚟十⚞][https://www.deviantart.com/team/art/Draw-a-Tiger-with-JoJoesArt-921502228 🐯][https://en.wikiversity.org/wiki/Embracing_Ambiguity ⸎][https://sharkonline.org/index.php/take-action/rodeo-video-tips 🦈][https://en.wikiversity.org/wiki/Wikiversity:Main_Page ⚞⸰⸰⸰△] https://tailwindcss.com/docs/dark-mode [https://play.tailwindcss.com/ tailwind][https://www.youtube.com/watch?v=lG5dNhabwBk&list=PLa1F2ddGya_87HJ72v_IgKUTNLIXSMfvB blender weekly][https://www.youtube.com/c/BlenderFoundation bf] [https://www.youtube.com/watch?v=3Sqm_v49zno acai] #https://momentjs.com/ #https://innocenceproject.org/ ⍱⍲⍑⍢⍐⎀⏀⌰⏢∨↯∧|序 [https://en.wikiversity.org/wiki/User:VeronicaJeanAnderson/Abe ⚞Abe⚟] [http://themetawiki.clu/w/index.php/Abe ⚟Abe⚞] [https://old.reddit.com/ ∞ꖉ∞⚟a⚞b⚟e⚞∞ꖉ∞] = ∞ꖉ⚞A⚟ꖉ∞ = https://www.youtube.com/watch?v=EtoZOqbwH9E :: success measured by how many car alarms go off ;) :: discord.gg/onlyinjapan instagram.com/onlyinjapantv twitter.com/onlyinjapantv facebook.com/onlyinjapantv https://www.youtube.com/watch?v=pE5h2kk0NTI == Color keywords == == Basic Colors == <table class="colortable"> <tr> <th>Named </th><th>Numeric </th><th>Color&nbsp;name </th><th>Hex&nbsp;rgb </th><th>Decimal </th></tr><tr> <td class="c" style="background-color:black;">&nbsp; </td><td class="c" style="background-color:rgb(0, 0, 0);">&nbsp; </td><td>black </td><td class="c" style="background-color:silver;">#000000 </td><td class="c" style="background-color:silver;">0,0,0 </td></tr><tr> <td class="c" style="background-color:silver;">&nbsp; </td><td class="c" style="background-color:rgb(192, 192, 192);">&nbsp; </td><td>silver </td><td class="c" style="background-color:silver;">#C0C0C0 </td><td class="c" style="background-color:silver;">192,192,192 </td></tr><tr> <td class="c" style="background-color:gray;">&nbsp; </td><td class="c" style="background-color:rgb(128, 128, 128);">&nbsp; </td><td>gray </td><td class="c" style="background-color:silver;">#808080 </td><td class="c" style="background-color:silver;">128,128,128 </td></tr><tr> <td class="c" style="background-color:white;">&nbsp; </td><td class="c" style="background-color:rgb(255, 255, 255);">&nbsp; </td><td>white </td><td class="c" style="background-color:silver;">#FFFFFF </td><td class="c" style="background-color:silver;">255,255,255 </td></tr><tr> <td class="c" style="background-color:maroon;">&nbsp; </td><td class="c" style="background-color:rgb(128, 0, 0);">&nbsp; </td><td>maroon </td><td class="c" style="background-color:silver;">#800000 </td><td class="c" style="background-color:silver;">128,0,0 </td></tr><tr> <td class="c" style="background-color:red;">&nbsp; </td><td class="c" style="background-color:rgb(255, 0, 0);">&nbsp; </td><td>red </td><td class="c" style="background-color:silver;">#FF0000 </td><td class="c" style="background-color:silver;">255,0,0 </td></tr><tr> <td class="c" style="background-color:purple;">&nbsp; </td><td class="c" style="background-color:rgb(128, 0, 128);">&nbsp; </td><td>purple </td><td class="c" style="background-color:silver;">#800080 </td><td class="c" style="background-color:silver;">128,0,128 </td></tr><tr> <td class="c" style="background-color:fuchsia;">&nbsp; </td><td class="c" style="background-color:rgb(255, 0, 255);">&nbsp; </td><td>fuchsia </td><td class="c" style="background-color:silver;">#FF00FF </td><td class="c" style="background-color:silver;">255,0,255 </td></tr><tr> <td class="c" style="background-color:green;">&nbsp; </td><td class="c" style="background-color:rgb(0, 128, 0);">&nbsp; </td><td>green </td><td class="c" style="background-color:silver;">#008000 </td><td class="c" style="background-color:silver;">0,128,0 </td></tr><tr> <td class="c" style="background-color:lime;">&nbsp; </td><td class="c" style="background-color:rgb(0, 255, 0);">&nbsp; </td><td>lime </td><td class="c" style="background-color:silver;">#00FF00 </td><td class="c" style="background-color:silver;">0,255,0 </td></tr><tr> <td class="c" style="background-color:olive;">&nbsp; </td><td class="c" style="background-color:rgb(128, 128, 0);">&nbsp; </td><td>olive </td><td class="c" style="background-color:silver;">#808000 </td><td class="c" style="background-color:silver;">128,128,0 </td></tr><tr> <td class="c" style="background-color:yellow;">&nbsp; </td><td class="c" style="background-color:rgb(255, 255, 0);">&nbsp; </td><td>yellow </td><td class="c" style="background-color:silver;">#FFFF00 </td><td class="c" style="background-color:silver;">255,255,0 </td></tr><tr> <td class="c" style="background-color:navy;">&nbsp; </td><td class="c" style="background-color:rgb(0, 0, 128);">&nbsp; </td><td>navy </td><td class="c" style="background-color:silver;">#000080 </td><td class="c" style="background-color:silver;">0,0,128 </td></tr><tr> <td class="c" style="background-color:blue;">&nbsp; </td><td class="c" style="background-color:rgb(0, 0, 255);">&nbsp; </td><td>blue </td><td class="c" style="background-color:silver;">#0000FF </td><td class="c" style="background-color:silver;">0,0,255 </td></tr><tr> <td class="c" style="background-color:teal;">&nbsp; </td><td class="c" style="background-color:rgb(0, 128, 128);">&nbsp; </td><td>teal </td><td class="c" style="background-color:silver;">#008080 </td><td class="c" style="background-color:silver;">0,128,128 </td></tr><tr> <td class="c" style="background-color:aqua;">&nbsp; </td><td class="c" style="background-color:rgb(0, 255, 255);">&nbsp; </td><td>aqua </td><td class="c" style="background-color:silver;">#00FFFF </td><td class="c" style="background-color:silver;">0,255,255 </td></tr></table> == Extended colors == <table> <tr> <th>Named </th><th>Numeric </th><th>Color&nbsp;name </th><th>Hex&nbsp;rgb </th><th>Decimal </th></tr><tr> <td class="c" style="background-color:aliceblue;">&nbsp; </td><td class="c" style="background-color:rgb(240, 248, 255);">&nbsp; </td><td>aliceblue </td><td class="c" style="background-color:silver;">#f0f8ff </td><td class="c" style="background-color:silver;">240,248,255 </td></tr><tr> <td class="c" style="background-color:antiquewhite;">&nbsp; </td><td class="c" style="background-color:rgb(250, 235, 215);">&nbsp; </td><td>antiquewhite </td><td class="c" style="background-color:silver;">#faebd7 </td><td class="c" style="background-color:silver;">250,235,215 </td></tr><tr> <td class="c" style="background-color:aqua;">&nbsp; </td><td class="c" style="background-color:rgb(0, 255, 255);">&nbsp; </td><td>aqua </td><td class="c" style="background-color:silver;">#00ffff </td><td class="c" style="background-color:silver;">0,255,255 </td></tr><tr> <td class="c" style="background-color:aquamarine;">&nbsp; </td><td class="c" style="background-color:rgb(127, 255, 212);">&nbsp; </td><td>aquamarine </td><td class="c" style="background-color:silver;">#7fffd4 </td><td class="c" style="background-color:silver;">127,255,212 </td></tr><tr> <td class="c" style="background-color:azure;">&nbsp; </td><td class="c" style="background-color:rgb(240, 255, 255);">&nbsp; </td><td>azure </td><td class="c" style="background-color:silver;">#f0ffff </td><td class="c" style="background-color:silver;">240,255,255 </td></tr><tr> <td class="c" style="background-color:beige;">&nbsp; </td><td class="c" style="background-color:rgb(245, 245, 220);">&nbsp; </td><td>beige </td><td class="c" style="background-color:silver;">#f5f5dc </td><td class="c" style="background-color:silver;">245,245,220 </td></tr><tr> <td class="c" style="background-color:bisque;">&nbsp; </td><td class="c" style="background-color:rgb(255, 228, 196);">&nbsp; </td><td>bisque </td><td class="c" style="background-color:silver;">#ffe4c4 </td><td class="c" style="background-color:silver;">255,228,196 </td></tr><tr> <td class="c" style="background-color:black;">&nbsp; </td><td class="c" style="background-color:rgb(0, 0, 0);">&nbsp; </td><td>black </td><td class="c" style="background-color:silver;">#000000 </td><td class="c" style="background-color:silver;">0,0,0 </td></tr><tr> <td class="c" style="background-color:blanchedalmond;">&nbsp; </td><td class="c" style="background-color:rgb(255, 235, 205);">&nbsp; </td><td>blanchedalmond </td><td class="c" style="background-color:silver;">#ffebcd </td><td class="c" style="background-color:silver;">255,235,205 </td></tr><tr> <td class="c" style="background-color:blue;">&nbsp; </td><td class="c" style="background-color:rgb(0, 0, 255);">&nbsp; </td><td>blue </td><td class="c" style="background-color:silver;">#0000ff </td><td class="c" style="background-color:silver;">0,0,255 </td></tr><tr> <td class="c" style="background-color:blueviolet;">&nbsp; </td><td class="c" style="background-color:rgb(138, 43, 226);">&nbsp; </td><td>blueviolet </td><td class="c" style="background-color:silver;">#8a2be2 </td><td class="c" style="background-color:silver;">138,43,226 </td></tr><tr> <td class="c" style="background-color:brown;">&nbsp; </td><td class="c" style="background-color:rgb(165, 42, 42);">&nbsp; </td><td>brown </td><td class="c" style="background-color:silver;">#a52a2a </td><td class="c" style="background-color:silver;">165,42,42 </td></tr><tr> <td class="c" style="background-color:burlywood;">&nbsp; </td><td class="c" style="background-color:rgb(222, 184, 135);">&nbsp; </td><td>burlywood </td><td class="c" style="background-color:silver;">#deb887 </td><td class="c" style="background-color:silver;">222,184,135 </td></tr><tr> <td class="c" style="background-color:cadetblue;">&nbsp; </td><td class="c" style="background-color:rgb(95, 158, 160);">&nbsp; </td><td>cadetblue </td><td class="c" style="background-color:silver;">#5f9ea0 </td><td class="c" style="background-color:silver;">95,158,160 </td></tr><tr> <td class="c" style="background-color:chartreuse;">&nbsp; </td><td class="c" style="background-color:rgb(127, 255, 0);">&nbsp; </td><td>chartreuse </td><td class="c" style="background-color:silver;">#7fff00 </td><td class="c" style="background-color:silver;">127,255,0 </td></tr><tr> <td class="c" style="background-color:chocolate;">&nbsp; </td><td class="c" style="background-color:rgb(210, 105, 30);">&nbsp; </td><td>chocolate </td><td class="c" style="background-color:silver;">#d2691e </td><td class="c" style="background-color:silver;">210,105,30 </td></tr><tr> <td class="c" style="background-color:coral;">&nbsp; </td><td class="c" style="background-color:rgb(255, 127, 80);">&nbsp; </td><td>coral </td><td class="c" style="background-color:silver;">#ff7f50 </td><td class="c" style="background-color:silver;">255,127,80 </td></tr><tr> <td class="c" style="background-color:cornflowerblue;">&nbsp; </td><td class="c" style="background-color:rgb(100, 149, 237);">&nbsp; </td><td>cornflowerblue </td><td class="c" style="background-color:silver;">#6495ed </td><td class="c" style="background-color:silver;">100,149,237 </td></tr><tr> <td class="c" style="background-color:cornsilk;">&nbsp; </td><td class="c" style="background-color:rgb(255, 248, 220);">&nbsp; </td><td>cornsilk </td><td class="c" style="background-color:silver;">#fff8dc </td><td class="c" style="background-color:silver;">255,248,220 </td></tr><tr> <td class="c" style="background-color:crimson;">&nbsp; </td><td class="c" style="background-color:rgb(220, 20, 60);">&nbsp; </td><td>crimson </td><td class="c" style="background-color:silver;">#dc143c </td><td class="c" style="background-color:silver;">220,20,60 </td></tr><tr> <td class="c" style="background-color:cyan;">&nbsp; </td><td class="c" style="background-color:rgb(0, 255, 255);">&nbsp; </td><td>cyan </td><td class="c" style="background-color:silver;">#00ffff </td><td class="c" style="background-color:silver;">0,255,255 </td></tr><tr> <td class="c" style="background-color:darkblue;">&nbsp; </td><td class="c" style="background-color:rgb(0, 0, 139);">&nbsp; </td><td>darkblue </td><td class="c" style="background-color:silver;">#00008b </td><td class="c" style="background-color:silver;">0,0,139 </td></tr><tr> <td class="c" style="background-color:darkcyan;">&nbsp; </td><td class="c" style="background-color:rgb(0, 139, 139);">&nbsp; </td><td>darkcyan </td><td class="c" style="background-color:silver;">#008b8b </td><td class="c" style="background-color:silver;">0,139,139 </td></tr><tr> <td class="c" style="background-color:darkgoldenrod;">&nbsp; </td><td class="c" style="background-color:rgb(184, 134, 11);">&nbsp; </td><td>darkgoldenrod </td><td class="c" style="background-color:silver;">#b8860b </td><td class="c" style="background-color:silver;">184,134,11 </td></tr><tr> <td class="c" style="background-color:darkgray;">&nbsp; </td><td class="c" style="background-color:rgb(169, 169, 169);">&nbsp; </td><td>darkgray </td><td class="c" style="background-color:silver;">#a9a9a9 </td><td class="c" style="background-color:silver;">169,169,169 </td></tr><tr> <td class="c" style="background-color:darkgreen;">&nbsp; </td><td class="c" style="background-color:rgb(0, 100, 0);">&nbsp; </td><td>darkgreen </td><td class="c" style="background-color:silver;">#006400 </td><td class="c" style="background-color:silver;">0,100,0 </td></tr><tr> <td class="c" style="background-color:darkgrey;">&nbsp; </td><td class="c" style="background-color:rgb(169, 169, 169);">&nbsp; </td><td>darkgrey </td><td class="c" style="background-color:silver;">#a9a9a9 </td><td class="c" style="background-color:silver;">169,169,169 </td></tr><tr> <td class="c" style="background-color:darkkhaki;">&nbsp; </td><td class="c" style="background-color:rgb(189, 183, 107);">&nbsp; </td><td>darkkhaki </td><td class="c" style="background-color:silver;">#bdb76b </td><td class="c" style="background-color:silver;">189,183,107 </td></tr><tr> <td class="c" style="background-color:darkmagenta;">&nbsp; </td><td class="c" style="background-color:rgb(139, 0, 139);">&nbsp; </td><td>darkmagenta </td><td class="c" style="background-color:silver;">#8b008b </td><td class="c" style="background-color:silver;">139,0,139 </td></tr><tr> <td class="c" style="background-color:darkolivegreen;">&nbsp; </td><td class="c" style="background-color:rgb(85, 107, 47);">&nbsp; </td><td>darkolivegreen </td><td class="c" style="background-color:silver;">#556b2f </td><td class="c" style="background-color:silver;">85,107,47 </td></tr><tr> <td class="c" style="background-color:darkorange;">&nbsp; </td><td class="c" style="background-color:rgb(255, 140, 0);">&nbsp; </td><td>darkorange </td><td class="c" style="background-color:silver;">#ff8c00 </td><td class="c" style="background-color:silver;">255,140,0 </td></tr><tr> <td class="c" style="background-color:darkorchid;">&nbsp; </td><td class="c" style="background-color:rgb(153, 50, 204);">&nbsp; </td><td>darkorchid </td><td class="c" style="background-color:silver;">#9932cc </td><td class="c" style="background-color:silver;">153,50,204 </td></tr><tr> <td class="c" style="background-color:darkred;">&nbsp; </td><td class="c" style="background-color:rgb(139, 0, 0);">&nbsp; </td><td>darkred </td><td class="c" style="background-color:silver;">#8b0000 </td><td class="c" style="background-color:silver;">139,0,0 </td></tr><tr> <td class="c" style="background-color:darksalmon;">&nbsp; </td><td class="c" style="background-color:rgb(233, 150, 122);">&nbsp; </td><td>darksalmon </td><td class="c" style="background-color:silver;">#e9967a </td><td class="c" style="background-color:silver;">233,150,122 </td></tr><tr> <td class="c" style="background-color:darkseagreen;">&nbsp; </td><td class="c" style="background-color:rgb(143, 188, 143);">&nbsp; </td><td>darkseagreen </td><td class="c" style="background-color:silver;">#8fbc8f </td><td class="c" style="background-color:silver;">143,188,143 </td></tr><tr> <td class="c" style="background-color:darkslateblue;">&nbsp; </td><td class="c" style="background-color:rgb(72, 61, 139);">&nbsp; </td><td>darkslateblue </td><td class="c" style="background-color:silver;">#483d8b </td><td class="c" style="background-color:silver;">72,61,139 </td></tr><tr> <td class="c" style="background-color:darkslategray;">&nbsp; </td><td class="c" style="background-color:rgb(47, 79, 79);">&nbsp; </td><td>darkslategray </td><td class="c" style="background-color:silver;">#2f4f4f </td><td class="c" style="background-color:silver;">47,79,79 </td></tr><tr> <td class="c" style="background-color:darkslategrey;">&nbsp; </td><td class="c" style="background-color:rgb(47, 79, 79);">&nbsp; </td><td>darkslategrey </td><td class="c" style="background-color:silver;">#2f4f4f </td><td class="c" style="background-color:silver;">47,79,79 </td></tr><tr> <td class="c" style="background-color:darkturquoise;">&nbsp; </td><td class="c" style="background-color:rgb(0, 206, 209);">&nbsp; </td><td>darkturquoise </td><td class="c" style="background-color:silver;">#00ced1 </td><td class="c" style="background-color:silver;">0,206,209 </td></tr><tr> <td class="c" style="background-color:darkviolet;">&nbsp; </td><td class="c" style="background-color:rgb(148, 0, 211);">&nbsp; </td><td>darkviolet </td><td class="c" style="background-color:silver;">#9400d3 </td><td class="c" style="background-color:silver;">148,0,211 </td></tr><tr> <td class="c" style="background-color:deeppink;">&nbsp; </td><td class="c" style="background-color:rgb(255, 20, 147);">&nbsp; </td><td>deeppink </td><td class="c" style="background-color:silver;">#ff1493 </td><td class="c" style="background-color:silver;">255,20,147 </td></tr><tr> <td class="c" style="background-color:deepskyblue;">&nbsp; </td><td class="c" style="background-color:rgb(0, 191, 255);">&nbsp; </td><td>deepskyblue </td><td class="c" style="background-color:silver;">#00bfff </td><td class="c" style="background-color:silver;">0,191,255 </td></tr><tr> <td class="c" style="background-color:dimgray;">&nbsp; </td><td class="c" style="background-color:rgb(105, 105, 105);">&nbsp; </td><td>dimgray </td><td class="c" style="background-color:silver;">#696969 </td><td class="c" style="background-color:silver;">105,105,105 </td></tr><tr> <td class="c" style="background-color:dimgrey;">&nbsp; </td><td class="c" style="background-color:rgb(105, 105, 105);">&nbsp; </td><td>dimgrey </td><td class="c" style="background-color:silver;">#696969 </td><td class="c" style="background-color:silver;">105,105,105 </td></tr><tr> <td class="c" style="background-color:dodgerblue;">&nbsp; </td><td class="c" style="background-color:rgb(30, 144, 255);">&nbsp; </td><td>dodgerblue </td><td class="c" style="background-color:silver;">#1e90ff </td><td class="c" style="background-color:silver;">30,144,255 </td></tr><tr> <td class="c" style="background-color:firebrick;">&nbsp; </td><td class="c" style="background-color:rgb(178, 34, 34);">&nbsp; </td><td>firebrick </td><td class="c" style="background-color:silver;">#b22222 </td><td class="c" style="background-color:silver;">178,34,34 </td></tr><tr> <td class="c" style="background-color:floralwhite;">&nbsp; </td><td class="c" style="background-color:rgb(255, 250, 240);">&nbsp; </td><td>floralwhite </td><td class="c" style="background-color:silver;">#fffaf0 </td><td class="c" style="background-color:silver;">255,250,240 </td></tr><tr> <td class="c" style="background-color:forestgreen;">&nbsp; </td><td class="c" style="background-color:rgb(34, 139, 34);">&nbsp; </td><td>forestgreen </td><td class="c" style="background-color:silver;">#228b22 </td><td class="c" style="background-color:silver;">34,139,34 </td></tr><tr> <td class="c" style="background-color:fuchsia;">&nbsp; </td><td class="c" style="background-color:rgb(255, 0, 255);">&nbsp; </td><td>fuchsia </td><td class="c" style="background-color:silver;">#ff00ff </td><td class="c" style="background-color:silver;">255,0,255 </td></tr><tr> <td class="c" style="background-color:gainsboro;">&nbsp; </td><td class="c" style="background-color:rgb(220, 220, 220);">&nbsp; </td><td>gainsboro </td><td class="c" style="background-color:silver;">#dcdcdc </td><td class="c" style="background-color:silver;">220,220,220 </td></tr><tr> <td class="c" style="background-color:ghostwhite;">&nbsp; </td><td class="c" style="background-color:rgb(248, 248, 255);">&nbsp; </td><td>ghostwhite </td><td class="c" style="background-color:silver;">#f8f8ff </td><td class="c" style="background-color:silver;">248,248,255 </td></tr><tr> <td class="c" style="background-color:gold;">&nbsp; </td><td class="c" style="background-color:rgb(255, 215, 0);">&nbsp; </td><td>gold </td><td class="c" style="background-color:silver;">#ffd700 </td><td class="c" style="background-color:silver;">255,215,0 </td></tr><tr> <td class="c" style="background-color:goldenrod;">&nbsp; </td><td class="c" style="background-color:rgb(218, 165, 32);">&nbsp; </td><td>goldenrod </td><td class="c" style="background-color:silver;">#daa520 </td><td class="c" style="background-color:silver;">218,165,32 </td></tr><tr> <td class="c" style="background-color:gray;">&nbsp; </td><td class="c" style="background-color:rgb(128, 128, 128);">&nbsp; </td><td>gray </td><td class="c" style="background-color:silver;">#808080 </td><td class="c" style="background-color:silver;">128,128,128 </td></tr><tr> <td class="c" style="background-color:green;">&nbsp; </td><td class="c" style="background-color:rgb(0, 128, 0);">&nbsp; </td><td>green </td><td class="c" style="background-color:silver;">#008000 </td><td class="c" style="background-color:silver;">0,128,0 </td></tr><tr> <td class="c" style="background-color:greenyellow;">&nbsp; </td><td class="c" style="background-color:rgb(173, 255, 47);">&nbsp; </td><td>greenyellow </td><td class="c" style="background-color:silver;">#adff2f </td><td class="c" style="background-color:silver;">173,255,47 </td></tr><tr> <td class="c" style="background-color:grey;">&nbsp; </td><td class="c" style="background-color:rgb(128, 128, 128);">&nbsp; </td><td>grey </td><td class="c" style="background-color:silver;">#808080 </td><td class="c" style="background-color:silver;">128,128,128 </td></tr><tr> <td class="c" style="background-color:honeydew;">&nbsp; </td><td class="c" style="background-color:rgb(240, 255, 240);">&nbsp; </td><td>honeydew </td><td class="c" style="background-color:silver;">#f0fff0 </td><td class="c" style="background-color:silver;">240,255,240 </td></tr><tr> <td class="c" style="background-color:hotpink;">&nbsp; </td><td class="c" style="background-color:rgb(255, 105, 180);">&nbsp; </td><td>hotpink </td><td class="c" style="background-color:silver;">#ff69b4 </td><td class="c" style="background-color:silver;">255,105,180 </td></tr><tr> <td class="c" style="background-color:indianred;">&nbsp; </td><td class="c" style="background-color:rgb(205, 92, 92);">&nbsp; </td><td>indianred </td><td class="c" style="background-color:silver;">#cd5c5c </td><td class="c" style="background-color:silver;">205,92,92 </td></tr><tr> <td class="c" style="background-color:indigo;">&nbsp; </td><td class="c" style="background-color:rgb(75, 0, 130);">&nbsp; </td><td>indigo </td><td class="c" style="background-color:silver;">#4b0082 </td><td class="c" style="background-color:silver;">75,0,130 </td></tr><tr> <td class="c" style="background-color:ivory;">&nbsp; </td><td class="c" style="background-color:rgb(255, 255, 240);">&nbsp; </td><td>ivory </td><td class="c" style="background-color:silver;">#fffff0 </td><td class="c" style="background-color:silver;">255,255,240 </td></tr><tr> <td class="c" style="background-color:khaki;">&nbsp; </td><td class="c" style="background-color:rgb(240, 230, 140);">&nbsp; </td><td>khaki </td><td class="c" style="background-color:silver;">#f0e68c </td><td class="c" style="background-color:silver;">240,230,140 </td></tr><tr> <td class="c" style="background-color:lavender;">&nbsp; </td><td class="c" style="background-color:rgb(230, 230, 250);">&nbsp; </td><td>lavender </td><td class="c" style="background-color:silver;">#e6e6fa </td><td class="c" style="background-color:silver;">230,230,250 </td></tr><tr> <td class="c" style="background-color:lavenderblush;">&nbsp; </td><td class="c" style="background-color:rgb(255, 240, 245);">&nbsp; </td><td>lavenderblush </td><td class="c" style="background-color:silver;">#fff0f5 </td><td class="c" style="background-color:silver;">255,240,245 </td></tr><tr> <td class="c" style="background-color:lawngreen;">&nbsp; </td><td class="c" style="background-color:rgb(124, 252, 0);">&nbsp; </td><td>lawngreen </td><td class="c" style="background-color:silver;">#7cfc00 </td><td class="c" style="background-color:silver;">124,252,0 </td></tr><tr> <td class="c" style="background-color:lemonchiffon;">&nbsp; </td><td class="c" style="background-color:rgb(255, 250, 205);">&nbsp; </td><td>lemonchiffon </td><td class="c" style="background-color:silver;">#fffacd </td><td class="c" style="background-color:silver;">255,250,205 </td></tr><tr> <td class="c" style="background-color:lightblue;">&nbsp; </td><td class="c" style="background-color:rgb(173, 216, 230);">&nbsp; </td><td>lightblue </td><td class="c" style="background-color:silver;">#add8e6 </td><td class="c" style="background-color:silver;">173,216,230 </td></tr><tr> <td class="c" style="background-color:lightcoral;">&nbsp; </td><td class="c" style="background-color:rgb(240, 128, 128);">&nbsp; </td><td>lightcoral </td><td class="c" style="background-color:silver;">#f08080 </td><td class="c" style="background-color:silver;">240,128,128 </td></tr><tr> <td class="c" style="background-color:lightcyan;">&nbsp; </td><td class="c" style="background-color:rgb(224, 255, 255);">&nbsp; </td><td>lightcyan </td><td class="c" style="background-color:silver;">#e0ffff </td><td class="c" style="background-color:silver;">224,255,255 </td></tr><tr> <td class="c" style="background-color:lightgoldenrodyellow;">&nbsp; </td><td class="c" style="background-color:rgb(250, 250, 210);">&nbsp; </td><td>lightgoldenrodyellow </td><td class="c" style="background-color:silver;">#fafad2 </td><td class="c" style="background-color:silver;">250,250,210 </td></tr><tr> <td class="c" style="background-color:lightgray;">&nbsp; </td><td class="c" style="background-color:rgb(211, 211, 211);">&nbsp; </td><td>lightgray </td><td class="c" style="background-color:silver;">#d3d3d3 </td><td class="c" style="background-color:silver;">211,211,211 </td></tr><tr> <td class="c" style="background-color:lightgreen;">&nbsp; </td><td class="c" style="background-color:rgb(144, 238, 144);">&nbsp; </td><td>lightgreen </td><td class="c" style="background-color:silver;">#90ee90 </td><td class="c" style="background-color:silver;">144,238,144 </td></tr><tr> <td class="c" style="background-color:lightgrey;">&nbsp; </td><td class="c" style="background-color:rgb(211, 211, 211);">&nbsp; </td><td>lightgrey </td><td class="c" style="background-color:silver;">#d3d3d3 </td><td class="c" style="background-color:silver;">211,211,211 </td></tr><tr> <td class="c" style="background-color:lightpink;">&nbsp; </td><td class="c" style="background-color:rgb(255, 182, 193);">&nbsp; </td><td>lightpink </td><td class="c" style="background-color:silver;">#ffb6c1 </td><td class="c" style="background-color:silver;">255,182,193 </td></tr><tr> <td class="c" style="background-color:lightsalmon;">&nbsp; </td><td class="c" style="background-color:rgb(255, 160, 122);">&nbsp; </td><td>lightsalmon </td><td class="c" style="background-color:silver;">#ffa07a </td><td class="c" style="background-color:silver;">255,160,122 </td></tr><tr> <td class="c" style="background-color:lightseagreen;">&nbsp; </td><td class="c" style="background-color:rgb(32, 178, 170);">&nbsp; </td><td>lightseagreen </td><td class="c" style="background-color:silver;">#20b2aa </td><td class="c" style="background-color:silver;">32,178,170 </td></tr><tr> <td class="c" style="background-color:lightskyblue;">&nbsp; </td><td class="c" style="background-color:rgb(135, 206, 250);">&nbsp; </td><td>lightskyblue </td><td class="c" style="background-color:silver;">#87cefa </td><td class="c" style="background-color:silver;">135,206,250 </td></tr><tr> <td class="c" style="background-color:lightslategray;">&nbsp; </td><td class="c" style="background-color:rgb(119, 136, 153);">&nbsp; </td><td>lightslategray </td><td class="c" style="background-color:silver;">#778899 </td><td class="c" style="background-color:silver;">119,136,153 </td></tr><tr> <td class="c" style="background-color:lightslategrey;">&nbsp; </td><td class="c" style="background-color:rgb(119, 136, 153);">&nbsp; </td><td>lightslategrey </td><td class="c" style="background-color:silver;">#778899 </td><td class="c" style="background-color:silver;">119,136,153 </td></tr><tr> <td class="c" style="background-color:lightsteelblue;">&nbsp; </td><td class="c" style="background-color:rgb(176, 196, 222);">&nbsp; </td><td>lightsteelblue </td><td class="c" style="background-color:silver;">#b0c4de </td><td class="c" style="background-color:silver;">176,196,222 </td></tr><tr> <td class="c" style="background-color:lightyellow;">&nbsp; </td><td class="c" style="background-color:rgb(255, 255, 224);">&nbsp; </td><td>lightyellow </td><td class="c" style="background-color:silver;">#ffffe0 </td><td class="c" style="background-color:silver;">255,255,224 </td></tr><tr> <td class="c" style="background-color:lime;">&nbsp; </td><td class="c" style="background-color:rgb(0, 255, 0);">&nbsp; </td><td>lime </td><td class="c" style="background-color:silver;">#00ff00 </td><td class="c" style="background-color:silver;">0,255,0 </td></tr><tr> <td class="c" style="background-color:limegreen;">&nbsp; </td><td class="c" style="background-color:rgb(50, 205, 50);">&nbsp; </td><td>limegreen </td><td class="c" style="background-color:silver;">#32cd32 </td><td class="c" style="background-color:silver;">50,205,50 </td></tr><tr> <td class="c" style="background-color:linen;">&nbsp; </td><td class="c" style="background-color:rgb(250, 240, 230);">&nbsp; </td><td>linen </td><td class="c" style="background-color:silver;">#faf0e6 </td><td class="c" style="background-color:silver;">250,240,230 </td></tr><tr> <td class="c" style="background-color:magenta;">&nbsp; </td><td class="c" style="background-color:rgb(255, 0, 255);">&nbsp; </td><td>magenta </td><td class="c" style="background-color:silver;">#ff00ff </td><td class="c" style="background-color:silver;">255,0,255 </td></tr><tr> <td class="c" style="background-color:maroon;">&nbsp; </td><td class="c" style="background-color:rgb(128, 0, 0);">&nbsp; </td><td>maroon </td><td class="c" style="background-color:silver;">#800000 </td><td class="c" style="background-color:silver;">128,0,0 </td></tr><tr> <td class="c" style="background-color:mediumaquamarine;">&nbsp; </td><td class="c" style="background-color:rgb(102, 205, 170);">&nbsp; </td><td>mediumaquamarine </td><td class="c" style="background-color:silver;">#66cdaa </td><td class="c" style="background-color:silver;">102,205,170 </td></tr><tr> <td class="c" style="background-color:mediumblue;">&nbsp; </td><td class="c" style="background-color:rgb(0, 0, 205);">&nbsp; </td><td>mediumblue </td><td class="c" style="background-color:silver;">#0000cd </td><td class="c" style="background-color:silver;">0,0,205 </td></tr><tr> <td class="c" style="background-color:mediumorchid;">&nbsp; </td><td class="c" style="background-color:rgb(186, 85, 211);">&nbsp; </td><td>mediumorchid </td><td class="c" style="background-color:silver;">#ba55d3 </td><td class="c" style="background-color:silver;">186,85,211 </td></tr><tr> <td class="c" style="background-color:mediumpurple;">&nbsp; </td><td class="c" style="background-color:rgb(147, 112, 219);">&nbsp; </td><td>mediumpurple </td><td class="c" style="background-color:silver;">#9370db </td><td class="c" style="background-color:silver;">147,112,219 </td></tr><tr> <td class="c" style="background-color:mediumseagreen;">&nbsp; </td><td class="c" style="background-color:rgb(60, 179, 113);">&nbsp; </td><td>mediumseagreen </td><td class="c" style="background-color:silver;">#3cb371 </td><td class="c" style="background-color:silver;">60,179,113 </td></tr><tr> <td class="c" style="background-color:mediumslateblue;">&nbsp; </td><td class="c" style="background-color:rgb(123, 104, 238);">&nbsp; </td><td>mediumslateblue </td><td class="c" style="background-color:silver;">#7b68ee </td><td class="c" style="background-color:silver;">123,104,238 </td></tr><tr> <td class="c" style="background-color:mediumspringgreen;">&nbsp; </td><td class="c" style="background-color:rgb(0, 250, 154);">&nbsp; </td><td>mediumspringgreen </td><td class="c" style="background-color:silver;">#00fa9a </td><td class="c" style="background-color:silver;">0,250,154 </td></tr><tr> <td class="c" style="background-color:mediumturquoise;">&nbsp; </td><td class="c" style="background-color:rgb(72, 209, 204);">&nbsp; </td><td>mediumturquoise </td><td class="c" style="background-color:silver;">#48d1cc </td><td class="c" style="background-color:silver;">72,209,204 </td></tr><tr> <td class="c" style="background-color:mediumvioletred;">&nbsp; </td><td class="c" style="background-color:rgb(199, 21, 133);">&nbsp; </td><td>mediumvioletred </td><td class="c" style="background-color:silver;">#c71585 </td><td class="c" style="background-color:silver;">199,21,133 </td></tr><tr> <td class="c" style="background-color:midnightblue;">&nbsp; </td><td class="c" style="background-color:rgb(25, 25, 112);">&nbsp; </td><td>midnightblue </td><td class="c" style="background-color:silver;">#191970 </td><td class="c" style="background-color:silver;">25,25,112 </td></tr><tr> <td class="c" style="background-color:mintcream;">&nbsp; </td><td class="c" style="background-color:rgb(245, 255, 250);">&nbsp; </td><td>mintcream </td><td class="c" style="background-color:silver;">#f5fffa </td><td class="c" style="background-color:silver;">245,255,250 </td></tr><tr> <td class="c" style="background-color:mistyrose;">&nbsp; </td><td class="c" style="background-color:rgb(255, 228, 225);">&nbsp; </td><td>mistyrose </td><td class="c" style="background-color:silver;">#ffe4e1 </td><td class="c" style="background-color:silver;">255,228,225 </td></tr><tr> <td class="c" style="background-color:moccasin;">&nbsp; </td><td class="c" style="background-color:rgb(255, 228, 181);">&nbsp; </td><td>moccasin </td><td class="c" style="background-color:silver;">#ffe4b5 </td><td class="c" style="background-color:silver;">255,228,181 </td></tr><tr> <td class="c" style="background-color:navajowhite;">&nbsp; </td><td class="c" style="background-color:rgb(255, 222, 173);">&nbsp; </td><td>navajowhite </td><td class="c" style="background-color:silver;">#ffdead </td><td class="c" style="background-color:silver;">255,222,173 </td></tr><tr> <td class="c" style="background-color:navy;">&nbsp; </td><td class="c" style="background-color:rgb(0, 0, 128);">&nbsp; </td><td>navy </td><td class="c" style="background-color:silver;">#000080 </td><td class="c" style="background-color:silver;">0,0,128 </td></tr><tr> <td class="c" style="background-color:oldlace;">&nbsp; </td><td class="c" style="background-color:rgb(253, 245, 230);">&nbsp; </td><td>oldlace </td><td class="c" style="background-color:silver;">#fdf5e6 </td><td class="c" style="background-color:silver;">253,245,230 </td></tr><tr> <td class="c" style="background-color:olive;">&nbsp; </td><td class="c" style="background-color:rgb(128, 128, 0);">&nbsp; </td><td>olive </td><td class="c" style="background-color:silver;">#808000 </td><td class="c" style="background-color:silver;">128,128,0 </td></tr><tr> <td class="c" style="background-color:olivedrab;">&nbsp; </td><td class="c" style="background-color:rgb(107, 142, 35);">&nbsp; </td><td>olivedrab </td><td class="c" style="background-color:silver;">#6b8e23 </td><td class="c" style="background-color:silver;">107,142,35 </td></tr><tr> <td class="c" style="background-color:orange;">&nbsp; </td><td class="c" style="background-color:rgb(255, 165, 0);">&nbsp; </td><td>orange </td><td class="c" style="background-color:silver;">#ffa500 </td><td class="c" style="background-color:silver;">255,165,0 </td></tr><tr> <td class="c" style="background-color:orangered;">&nbsp; </td><td class="c" style="background-color:rgb(255, 69, 0);">&nbsp; </td><td>orangered </td><td class="c" style="background-color:silver;">#ff4500 </td><td class="c" style="background-color:silver;">255,69,0 </td></tr><tr> <td class="c" style="background-color:orchid;">&nbsp; </td><td class="c" style="background-color:rgb(218, 112, 214);">&nbsp; </td><td>orchid </td><td class="c" style="background-color:silver;">#da70d6 </td><td class="c" style="background-color:silver;">218,112,214 </td></tr><tr> <td class="c" style="background-color:palegoldenrod;">&nbsp; </td><td class="c" style="background-color:rgb(238, 232, 170);">&nbsp; </td><td>palegoldenrod </td><td class="c" style="background-color:silver;">#eee8aa </td><td class="c" style="background-color:silver;">238,232,170 </td></tr><tr> <td class="c" style="background-color:palegreen;">&nbsp; </td><td class="c" style="background-color:rgb(152, 251, 152);">&nbsp; </td><td>palegreen </td><td class="c" style="background-color:silver;">#98fb98 </td><td class="c" style="background-color:silver;">152,251,152 </td></tr><tr> <td class="c" style="background-color:paleturquoise;">&nbsp; </td><td class="c" style="background-color:rgb(175, 238, 238);">&nbsp; </td><td>paleturquoise </td><td class="c" style="background-color:silver;">#afeeee </td><td class="c" style="background-color:silver;">175,238,238 </td></tr><tr> <td class="c" style="background-color:palevioletred;">&nbsp; </td><td class="c" style="background-color:rgb(219, 112, 147);">&nbsp; </td><td>palevioletred </td><td class="c" style="background-color:silver;">#db7093 </td><td class="c" style="background-color:silver;">219,112,147 </td></tr><tr> <td class="c" style="background-color:papayawhip;">&nbsp; </td><td class="c" style="background-color:rgb(255, 239, 213);">&nbsp; </td><td>papayawhip </td><td class="c" style="background-color:silver;">#ffefd5 </td><td class="c" style="background-color:silver;">255,239,213 </td></tr><tr> <td class="c" style="background-color:peachpuff;">&nbsp; </td><td class="c" style="background-color:rgb(255, 218, 185);">&nbsp; </td><td>peachpuff </td><td class="c" style="background-color:silver;">#ffdab9 </td><td class="c" style="background-color:silver;">255,218,185 </td></tr><tr> <td class="c" style="background-color:peru;">&nbsp; </td><td class="c" style="background-color:rgb(205, 133, 63);">&nbsp; </td><td>peru </td><td class="c" style="background-color:silver;">#cd853f </td><td class="c" style="background-color:silver;">205,133,63 </td></tr><tr> <td class="c" style="background-color:pink;">&nbsp; </td><td class="c" style="background-color:rgb(255, 192, 203);">&nbsp; </td><td>pink </td><td class="c" style="background-color:silver;">#ffc0cb </td><td class="c" style="background-color:silver;">255,192,203 </td></tr><tr> <td class="c" style="background-color:plum;">&nbsp; </td><td class="c" style="background-color:rgb(221, 160, 221);">&nbsp; </td><td>plum </td><td class="c" style="background-color:silver;">#dda0dd </td><td class="c" style="background-color:silver;">221,160,221 </td></tr><tr> <td class="c" style="background-color:powderblue;">&nbsp; </td><td class="c" style="background-color:rgb(176, 224, 230);">&nbsp; </td><td>powderblue </td><td class="c" style="background-color:silver;">#b0e0e6 </td><td class="c" style="background-color:silver;">176,224,230 </td></tr><tr> <td class="c" style="background-color:purple;">&nbsp; </td><td class="c" style="background-color:rgb(128, 0, 128);">&nbsp; </td><td>purple </td><td class="c" style="background-color:silver;">#800080 </td><td class="c" style="background-color:silver;">128,0,128 </td></tr><tr> <td class="c" style="background-color:red;">&nbsp; </td><td class="c" style="background-color:rgb(255, 0, 0);">&nbsp; </td><td>red </td><td class="c" style="background-color:silver;">#ff0000 </td><td class="c" style="background-color:silver;">255,0,0 </td></tr><tr> <td class="c" style="background-color:rosybrown;">&nbsp; </td><td class="c" style="background-color:rgb(188, 143, 143);">&nbsp; </td><td>rosybrown </td><td class="c" style="background-color:silver;">#bc8f8f </td><td class="c" style="background-color:silver;">188,143,143 </td></tr><tr> <td class="c" style="background-color:royalblue;">&nbsp; </td><td class="c" style="background-color:rgb(65, 105, 225);">&nbsp; </td><td>royalblue </td><td class="c" style="background-color:silver;">#4169e1 </td><td class="c" style="background-color:silver;">65,105,225 </td></tr><tr> <td class="c" style="background-color:saddlebrown;">&nbsp; </td><td class="c" style="background-color:rgb(139, 69, 19);">&nbsp; </td><td>saddlebrown </td><td class="c" style="background-color:silver;">#8b4513 </td><td class="c" style="background-color:silver;">139,69,19 </td></tr><tr> <td class="c" style="background-color:salmon;">&nbsp; </td><td class="c" style="background-color:rgb(250, 128, 114);">&nbsp; </td><td>salmon </td><td class="c" style="background-color:silver;">#fa8072 </td><td class="c" style="background-color:silver;">250,128,114 </td></tr><tr> <td class="c" style="background-color:sandybrown;">&nbsp; </td><td class="c" style="background-color:rgb(244, 164, 96);">&nbsp; </td><td>sandybrown </td><td class="c" style="background-color:silver;">#f4a460 </td><td class="c" style="background-color:silver;">244,164,96 </td></tr><tr> <td class="c" style="background-color:seagreen;">&nbsp; </td><td class="c" style="background-color:rgb(46, 139, 87);">&nbsp; </td><td>seagreen </td><td class="c" style="background-color:silver;">#2e8b57 </td><td class="c" style="background-color:silver;">46,139,87 </td></tr><tr> <td class="c" style="background-color:seashell;">&nbsp; </td><td class="c" style="background-color:rgb(255, 245, 238);">&nbsp; </td><td>seashell </td><td class="c" style="background-color:silver;">#fff5ee </td><td class="c" style="background-color:silver;">255,245,238 </td></tr><tr> <td class="c" style="background-color:sienna;">&nbsp; </td><td class="c" style="background-color:rgb(160, 82, 45);">&nbsp; </td><td>sienna </td><td class="c" style="background-color:silver;">#a0522d </td><td class="c" style="background-color:silver;">160,82,45 </td></tr><tr> <td class="c" style="background-color:silver;">&nbsp; </td><td class="c" style="background-color:rgb(192, 192, 192);">&nbsp; </td><td>silver </td><td class="c" style="background-color:silver;">#c0c0c0 </td><td class="c" style="background-color:silver;">192,192,192 </td></tr><tr> <td class="c" style="background-color:skyblue;">&nbsp; </td><td class="c" style="background-color:rgb(135, 206, 235);">&nbsp; </td><td>skyblue </td><td class="c" style="background-color:silver;">#87ceeb </td><td class="c" style="background-color:silver;">135,206,235 </td></tr><tr> <td class="c" style="background-color:slateblue;">&nbsp; </td><td class="c" style="background-color:rgb(106, 90, 205);">&nbsp; </td><td>slateblue </td><td class="c" style="background-color:silver;">#6a5acd </td><td class="c" style="background-color:silver;">106,90,205 </td></tr><tr> <td class="c" style="background-color:slategray;">&nbsp; </td><td class="c" style="background-color:rgb(112, 128, 144);">&nbsp; </td><td>slategray </td><td class="c" style="background-color:silver;">#708090 </td><td class="c" style="background-color:silver;">112,128,144 </td></tr><tr> <td class="c" style="background-color:slategrey;">&nbsp; </td><td class="c" style="background-color:rgb(112, 128, 144);">&nbsp; </td><td>slategrey </td><td class="c" style="background-color:silver;">#708090 </td><td class="c" style="background-color:silver;">112,128,144 </td></tr><tr> <td class="c" style="background-color:snow;">&nbsp; </td><td class="c" style="background-color:rgb(255, 250, 250);">&nbsp; </td><td>snow </td><td class="c" style="background-color:silver;">#fffafa </td><td class="c" style="background-color:silver;">255,250,250 </td></tr><tr> <td class="c" style="background-color:springgreen;">&nbsp; </td><td class="c" style="background-color:rgb(0, 255, 127);">&nbsp; </td><td>springgreen </td><td class="c" style="background-color:silver;">#00ff7f </td><td class="c" style="background-color:silver;">0,255,127 </td></tr><tr> <td class="c" style="background-color:steelblue;">&nbsp; </td><td class="c" style="background-color:rgb(70, 130, 180);">&nbsp; </td><td>steelblue </td><td class="c" style="background-color:silver;">#4682b4 </td><td class="c" style="background-color:silver;">70,130,180 </td></tr><tr> <td class="c" style="background-color:tan;">&nbsp; </td><td class="c" style="background-color:rgb(210, 180, 140);">&nbsp; </td><td>tan </td><td class="c" style="background-color:silver;">#d2b48c </td><td class="c" style="background-color:silver;">210,180,140 </td></tr><tr> <td class="c" style="background-color:teal;">&nbsp; </td><td class="c" style="background-color:rgb(0, 128, 128);">&nbsp; </td><td>teal </td><td class="c" style="background-color:silver;">#008080 </td><td class="c" style="background-color:silver;">0,128,128 </td></tr><tr> <td class="c" style="background-color:thistle;">&nbsp; </td><td class="c" style="background-color:rgb(216, 191, 216);">&nbsp; </td><td>thistle </td><td class="c" style="background-color:silver;">#d8bfd8 </td><td class="c" style="background-color:silver;">216,191,216 </td></tr><tr> <td class="c" style="background-color:tomato;">&nbsp; </td><td class="c" style="background-color:rgb(255, 99, 71);">&nbsp; </td><td>tomato </td><td class="c" style="background-color:silver;">#ff6347 </td><td class="c" style="background-color:silver;">255,99,71 </td></tr><tr> <td class="c" style="background-color:turquoise;">&nbsp; </td><td class="c" style="background-color:rgb(64, 224, 208);">&nbsp; </td><td>turquoise </td><td class="c" style="background-color:silver;">#40e0d0 </td><td class="c" style="background-color:silver;">64,224,208 </td></tr><tr> <td class="c" style="background-color:violet;">&nbsp; </td><td class="c" style="background-color:rgb(238, 130, 238);">&nbsp; </td><td>violet </td><td class="c" style="background-color:silver;">#ee82ee </td><td class="c" style="background-color:silver;">238,130,238 </td></tr><tr> <td class="c" style="background-color:wheat;">&nbsp; </td><td class="c" style="background-color:rgb(245, 222, 179);">&nbsp; </td><td>wheat </td><td class="c" style="background-color:silver;">#f5deb3 </td><td class="c" style="background-color:silver;">245,222,179 </td></tr><tr> <td class="c" style="background-color:white;">&nbsp; </td><td class="c" style="background-color:rgb(255, 255, 255);">&nbsp; </td><td>white </td><td class="c" style="background-color:silver;">#ffffff </td><td class="c" style="background-color:silver;">255,255,255 </td></tr><tr> <td class="c" style="background-color:whitesmoke;">&nbsp; </td><td class="c" style="background-color:rgb(245, 245, 245);">&nbsp; </td><td>whitesmoke </td><td class="c" style="background-color:silver;">#f5f5f5 </td><td class="c" style="background-color:silver;">245,245,245 </td></tr><tr> <td class="c" style="background-color:yellow;">&nbsp; </td><td class="c" style="background-color:rgb(255, 255, 0);">&nbsp; </td><td>yellow </td><td class="c" style="background-color:silver;">#ffff00 </td><td class="c" style="background-color:silver;">255,255,0 </td></tr><tr> <td class="c" style="background-color:yellowgreen;">&nbsp; </td><td class="c" style="background-color:rgb(154, 205, 50);">&nbsp; </td><td>yellowgreen </td><td class="c" style="background-color:silver;">#9acd32 </td><td class="c" style="background-color:silver;">154,205,50 </td></tr></table> == System Colors == <b>Note:</b> As of [[http://www.w3.org/TR/css3-color/ CSS Color]], the CSS2 System Color values have been deprecated in favor of the CSS3 UI ‘[[http://www.w3.org/TR/css3-ui/#appearance appearance]]’ property. *<code>ActiveBorder</code><br />Active window border. * <code>ActiveCaption</code><br />Active window caption. * <code>AppWorkspace</code><br />Background color of multiple document interface. * <code>Background</code><br />Desktop background. * <code>ButtonFace</code><br />The face background color for 3-D elements that appear 3-D due to one layer of surrounding border. * <code>ButtonHighlight</code><br />The color of the border facing the light source for 3-D elements that appear 3-D due to one layer of surrounding border. * <code>ButtonShadow</code><br />The color of the border away from the light source for 3-D elements that appear 3-D due to one layer of surrounding border. * <code>ButtonText</code><br />Text on push buttons. * <code>CaptionText</code><br />Text in caption, size box, and scrollbar arrow box. * <code>GrayText</code><br />Grayed (disabled) text. This color is set to #000 if the current display driver does not support a solid gray color. * <code>Highlight</code><br />Item(s) selected in a control. * <code>HighlightText</code><br />Text of item(s) selected in a control. * <code>InactiveBorder</code><br />Inactive window border. * <code>InactiveCaption</code><br />Inactive window caption. * <code>InactiveCaptionText</code><br />Color of text in an inactive caption. * <code>InfoBackground</code><br />Background color for tooltip controls. * <code>InfoText</code><br />Text color for tooltip controls. * <code>Menu</code><br />Menu background. * <code>MenuText</code><br />Text in menus. * <code>Scrollbar</code><br />Scroll bar gray area. * <code>ThreeDDarkShadow</code><br />The color of the darker (generally outer) of the two borders away from the light source for 3-D elements that appear 3-D due to two concentric layers of surrounding border. * <code>ThreeDFace</code><br />The face background color for 3-D elements that appear 3-D due to two concentric layers of surrounding border. * <code>ThreeDHighlight</code><br />The color of the lighter (generally outer) of the two borders facing the light source for 3-D elements that appear 3-D due to two concentric layers of surrounding border. * <code>ThreeDLightShadow</code><br />The color of the darker (generally inner) of the two borders facing the light source for 3-D elements that appear 3-D due to two concentric layers of surrounding border. * <code>ThreeDShadow</code><br />The color of the lighter (generally inner) of the two borders away from the light source for 3-D elements that appear 3-D due to two concentric layers of surrounding border. * <code>Window</code><br />Window background. * <code>WindowFrame</code><br />Window frame. * <code>WindowText</code><br />Text in windows. hikikomori aged 40-64: 610, 000 https://www.deviantart.com/ryky/art/How-to-draw-hair-568446916 'concierge' following viral tweet https://www.dropbox.com/contact U+2218 ∘ RING OPERATOR ( &compfn;, &SmallCircle;); huuzah https://japaneseparticlesmaster.xyz/yaruki-in-japanese/ "Take Me To Your Leader" "Recognizance Scout" "Actively Amazing" TASK for implementation 7/18 - 7/24th :: J's Deliverable: V [https://www.youtube.com/watch?v=-sk9kXyfGvU "unmotivated wood"] https://www.youtube.com/results?search_query=YARUKI https://www.roland.com/global/support/by_product/sp-404mk2/owners_manuals/ todo: what does a day @ wikiversity look like? https://nazarene.quora.com/ https://www.twitch.tv/archie97305 https://anchor.fm/ providence Bus 48 arrives @ HTC @ 7:43 p/u @ 7:29 [1 earlier: arrives @ HTC @ 7:10 p/u @ 6:57] Max Blue 7:52 = "1 route early" 8:07 = "on time" fleet armada ruminate https://en.wikipedia.org/wiki/Streisand_effect jackie anderson s4e10 [https://en.wikipedia.org/wiki/Schadenfreude ^]Schadenfreude (/ˈʃɑːdənfrɔɪdə/; German: [ˈʃaːdn̩ˌfʁɔʏ̯də] (listen); lit. 'harm-joy') is the experience of pleasure, joy, or self-satisfaction that comes from learning of or witnessing the troubles, failures, or humiliation of another. It is a borrowed word from German, with no direct translation, that originated in the 18th century. Schadenfreude has been detected in children as young as 24 months and may be an important social emotion establishing "inequity aversion".[1] [https://util.unicode.org/UnicodeJsps/character.jsp?a=2219 `] [https://tex.stackexchange.com/questions/19180/which-dot-character-to-use-in-which-context ^] 00B7 · MIDDLE DOT = midpoint (in typography) = Georgian comma = Greek middle dot (ano teleia) → 0387 · greek ano teleia → 16EB ᛫ runic single punctuation → 2022 • bullet → 2024 . one dot leader → 2027 ‧ hyphenation point → 2219 ∙ bullet operator → 22C5 ⋅ dot operator → 2E31 ⸱ word separator middle dot → 2E33 ⸳ raised dot → 30FB ・ katakana middle dot Block “General Punctuation” 2022 • BULLET = black small circle → 00B7 · middle dot → 2024 . one dot leader → 2219 ∙ bullet operator → 25D8 ◘ inverse bullet → 25E6 ◦ white bullet Block “Mathematical Operators” 2219 ∙ BULLET OPERATOR → 00B7 · middle dot → 2022 • bullet → 2024 . one dot leader 22C5 ⋅ DOT OPERATOR → 00B7 · middle dot <h1>⸰⸰⸰△∙•･⋅·‧ᐧ᛫ꞏ⸱·・ⷵ ⷶ ⷷ ⷸ ⷹ ⷺ ⷻ ⷼ ⷽ ⷾ ⷿ ⸀ ⸁ · ⸂ ⸃ ⸄ ⸅ ⸆ ⸇ ⸈ ⸉ ⸊ ⸋ ⸌ ⸍ ⸎ · ⸏ ⸐ ⸑ ⸒ ⸓ ⸔ ⸕ ⸖ ⸗ ⸘ ⸙ ⸚ ⸛.ᘛ⁐̤ᕐᐷ ⸱៰ ͘ ࣭⸰</h1> ·[U+00B7 MIDDLE DOT],★ 。⸰ 日 {| |- |style="font-size: 22px; color: pink; background-color: #333; padding: 11px"| Royal•週We |style="font-size: 22px; color: salmon; background-color: #333; padding: 11px"| 1wiki |style="font-size: 22px; color: powderblue; background-color: #333; padding: 11px"| 2ver |style="font-size: 22px; color: cadetblue; background-color: #333; padding: 11px"| 3s |style="font-size: 22px; color: #fff; background-color: #000; padding: 11px"| 4ity |style="font-size: 22px; color: #fff; background-color: #111; padding: 11px"| 5North |style="font-size: 22px; color: #fff; background-color: #222; padding: 11px"| 6West |style="font-size: 22px; color: #fff; background-color: #333; padding: 11px"| 7[https://en.wikipedia.org/wiki/Human_taxonomy#Subspecies ^] superfamily: hominoidea |style="font-size: 22px; color: #fff; background-color: #444; padding: 11px"| 8hominidae |style="font-size: 22px; color: #fff; background-color: #555; padding: 11px"| 9homininae |style="font-size: 22px; color: #fff; background-color: #666; padding: 11px"| +hominini |style="font-size: 22px; color: #fff; background-color: #777; padding: 11px"| 11 |style="font-size: 22px; color: #fff; background-color: #888; padding: 11px"| 12 |style="font-size: 22px; color: #fff; background-color: #999; padding: 11px"| 13 |style="font-size: 22px; color: #fff; background-color: #aaa; padding: 11px"| 14 |style="font-size: 22px; color: #fff; background-color: #bbb; padding: 11px"| 15 |style="font-size: 22px; color: #fff; background-color: #ccc; padding: 11px"| 16 |style="font-size: 22px; color: #fff; background-color: #ddd; padding: 11px"| 17 |style="font-size: 22px; color: #fff; background-color: #eee; padding: 11px"| 18 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 19 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 20 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 21 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 22 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 23 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 24 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 25 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 26 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 27 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 28 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 29 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 30 |style="font-size: 22px; color: #fff; background-color: #a020f0; padding: 11px"| 31 |- |style="font-size: 22px; color: pink; background-color: #333; padding: 11px"| 0Royal•:⋮\週Week |style="font-size: 22px; color: salmon; background-color: #333; padding: 11px"| 1wiki |style="font-size: 22px; color: powderblue; background-color: #333; padding: 11px"| 2ver |style="font-size: 22px; color: cadetblue; background-color: #333; padding: 11px"| 3s |style="font-size: 22px; color: #fff; background-color: #000; padding: 11px"| 4ity |style="font-size: 22px; color: #fff; background-color: #111; padding: 11px"| 5North |style="font-size: 22px; color: #fff; background-color: #222; padding: 11px"| 6West |style="font-size: 22px; color: #fff; background-color: #333; padding: 11px"| 7[https://en.wikipedia.org/wiki/Human_taxonomy#Subspecies ^] superfamily: hominoidea |style="font-size: 22px; color: #fff; background-color: #444; padding: 11px"| 8hominidae |style="font-size: 22px; color: #fff; background-color: #555; padding: 11px"| 9homininae |style="font-size: 22px; color: #fff; background-color: #666; padding: 11px"| +hominini |style="font-size: 22px; color: #fff; background-color: #777; padding: 11px"| 11 |style="font-size: 22px; color: #fff; background-color: #888; padding: 11px"| 12 |style="font-size: 22px; color: #fff; background-color: #999; padding: 11px"| 13 |style="font-size: 22px; color: #fff; background-color: #aaa; padding: 11px"| 14 |style="font-size: 22px; color: #fff; background-color: #bbb; padding: 11px"| 15 |style="font-size: 22px; color: #fff; background-color: #ccc; padding: 11px"| 16 |style="font-size: 22px; color: #fff; background-color: #ddd; padding: 11px"| 17 |style="font-size: 22px; color: #fff; background-color: #eee; padding: 11px"| 18 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 19 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 20 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 21 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 22 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 23 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 24 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 25 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 26 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 27 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 28 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 29 |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 30 |style="font-size: 22px; color: #fff; background-color: #a020f0; padding: 11px"| 31 |} https://www.vim.org/ https://www.uscis.gov/citizenship/learn-about-citizenship/the-naturalization-interview-and-test/naturalization-oath-of-allegiance-to-the-united-states-of-america https://en.wikipedia.org/wiki/Holding_Out_for_a_Hero {| |- || ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 ||𝄞𝄡𝄢 |- || A Major Scale || 1 || 2 || 3 || 4 || 5 || 6 || 7 || 8 || 9 || 十 || 11 || 12 || 1 |- || AM || A || ◯ || B || ◯ || C# || D || ◯ || E || ◯ || F# || ◯ || G# || A |- || F# minor || F# || ◯ || G# || A || ◯ || B || ◯ || C# || D || ◯ || E || ◯ || F# || F sharp minor is the Relative key to A Major |- || A minor || A || ◯ || B || C || ◯ || D || ◯ || E || F || ◯ || G || ◯ || A || A minor is the Parallel key to A Major |- || E Major || E || ◯ || F# || ◯ || G# || A || ◯ || B || ◯ || C# || D# || ◯ || E || E Major is the Dominant key to A major |- || D Major || D || ◯ || E || ◯ || F# || ◯ || G# || A || ◯ || B || ◯ || C# || D || D Major is the Subdominant key to A major || According to Paolo Pietropaolo, D major is Miss Congeniality: it is persistent, sunny, and energetic[https://en.wikipedia.org/wiki/D_major DM] |- || [https://en.wikipedia.org/wiki/A_major A major] |} A ◯ B ◯ C# ◠ D ◯ E ◯ F# ◯ G# ◠ A Major Scale 3⁄2 C D E F G A B C 1 +9⁄8 +5⁄4 +4⁄3 +3⁄2 +5⁄3 +15⁄8 2 {| |- || 0 || 1 || 2 || 3 || 4 || 5 || 6 || 7 || 8 || 9 || 十 || 11 || 12 |- || 0 || M || U || W || H || F || A || N |- || ▣ || 🟨 || 🟧 || 🟥 || 🟪 || 🟦 || 🟩 || ⬜ || ⬛ || ▤ || ▥ || ▦ || ▧ || ▨ || ▩ || ❏ || ❐ || ❑ |- ||a ||b ||c ||d ||e ||f ||g ||h ||i ||j ||k ||l ||m ||n ||o ||p ||q ||r ||s ||t ||u ||v ||w ||x ||y ||z |- ||🢄 ||🢁 ||🢅 ||🢀 ||⯐ ||🢂 ||🢇 ||🢃 ||🢆 |- ||🢀 ||⯐ ||🢂 |- ||🢇 ||🢃 ||🢆 |- ||𝄞 ||𝄡 ||𝄢 |} https://en.wikiversity.org/wiki/Portal:Music == Evens And Odds == West trends even East trends odd <h1> Hackers of the Whirled Unite </h1> "cultural de-real i zation" https://en.wikipedia.org/wiki/Arrow_(symbol) https://en.wikipedia.org/wiki/Amber_Ruffin hex #ffbf00 (also known as Amber, Fluorescent orange) is composed of 100% red, 74.9% green and 0% blue. == "I lost the game" == ==.slug:b**⋮:.== gma andy was a sister mon sig nor [https://en.wikipedia.org/wiki/Punch_buggy slug a bobby game per evil on paramount+&] =👀= ¼ task: properly document and opine re: Nazarene 👁 ½ task: properly document and opine re: univers-sity 👁👄 ¾ task: properly document and opine re: cross 👁👄👁 一 task: properly document and opine re: this real life ❌ generational event: https://www.instagram.com/p/CfO7fCwLn1Z/?utm_source=ig_embed&utm_campaign=loading ⭕️ ==¼👁.svg== ==½👁👄.ico== ==¾👁👄👁.png== ==一⭕️.html== ==❌index.== ==⭕️❌index.html== ==👀_cv-== =!👀= https://drive.google.com/drive/folders/1ku_XmbHOZ5ypgKCAjpzX6hlXaOJT7Uoq {||+ |- || 0 || 1 || 2 || 3 || 4 || 5 || 6 || 7 || 8 || 9 || 十 || 11 || 12 |- || 0 || M || U || W || H || F || A || N |- || ▣ || 🟨 || 🟧 || 🟥 || 🟪 || 🟦 || 🟩 || ⬜ || ⬛ || ▤ || ▥ || ▦ || ▧ || ▨ || ▩ || ❏ || ❐ || ❑ |} ◜+◝ = ◠ ◟+◞ = ◡ ◠+◡ = ◯ ◣+◥ or ◤+◢ = ◼ ◸+◿ or ◺+◹ = ◻ https://drive.google.com/drive/folders/1-sKzV5R8k_f8bOrGNtIf4CWuVL3LJJcL https://quaternius.com/packs/modularplatformer.html https://quaternius.com/tutorials.html 🈁🚌🟨🟥🟦🚍〇丁鼎 Royal_We : have work flows; will train! 🚂 = .:⋮ 🟨 🟥 🟦 = [https://en.wikiversity.org/wiki/User:VeronicaJeanAnderson/🟨 🟨] [https://en.wikiversity.org/wiki/User:VeronicaJeanAnderson/🟥 🟥] [https://en.wikiversity.org/wiki/User:VeronicaJeanAnderson/🟦 🟦] == 👤¹== [https://en.wikiversity.org/wiki/User:VeronicaJeanAnderson ∨↯∧|序] [http://themetawiki.clu/w/index.php/Main_Page 🈁] == 👥² == [https://en.wikiversity.org/wiki/User:VeronicaJeanAnderson/DAM ∨↯∧|DAM] == 👣³ == [https://en.wikiversity.org/wiki/User:VeronicaJeanAnderson/mess ∨↯∧|mess] = ∨↯∧ = ∨ or ↯【いま】今 ∧【wedge】& ... ... ... ‸^‸ /(ˈkærɪt)/ ∩ intersection ∪ union == ↓ == ↯ 今【いま】 == ↑ == ∩ ∪ == ← == pernicious == → == grandfather paradox =🈁= 🚌🟨🟥🟦🚍〇丁鼎 Royal_We : have work flows; will train! 🚂 ==🚌== ==🚍== ==🚂== = 〇丁鼎 Royal_We Ventur= no ads no silent e ==〇== ==丁== ==鼎== {| |- |style="font-size: 22px; color: pink; background-color: #333; padding: 11px"| 0Royal•:⋮\日Week |style="font-size: 22px; color: salmon; background-color: #333; padding: 11px"| 1wiki |style="font-size: 22px; color: powderblue; background-color: #333; padding: 11px"| 2ver |style="font-size: 22px; color: cadetblue; background-color: #333; padding: 11px"| 3s |style="font-size: 22px; color: #fff; background-color: #000; padding: 11px"| 4ity |style="font-size: 22px; color: #fff; background-color: #111; padding: 11px"| 5North |style="font-size: 22px; color: #fff; background-color: #222; padding: 11px"| 6West |style="font-size: 22px; color: #fff; background-color: #333; padding: 11px"| 7[https://en.wikipedia.org/wiki/Human_taxonomy#Subspecies ^] superfamily: hominoidea |style="font-size: 22px; color: #fff; background-color: #444; padding: 11px"| 8hominidae |style="font-size: 22px; color: #fff; background-color: #555; padding: 11px"| 9homininae |style="font-size: 22px; color: #fff; background-color: #666; padding: 11px"| +hominini |style="font-size: 22px; color: #fff; background-color: #777; padding: 11px"| 11Homo |style="font-size: 22px; color: #fff; background-color: #888; padding: 11px"| 12Homo |style="font-size: 22px; color: #fff; background-color: #999; padding: 11px"| 13Homo |style="font-size: 22px; color: #fff; background-color: #aaa; padding: 11px"| 14Homo |style="font-size: 22px; color: #fff; background-color: #bbb; padding: 11px"| 15Homo |style="font-size: 22px; color: #fff; background-color: #ccc; padding: 11px"| 16Homo |style="font-size: 22px; color: #fff; background-color: #ddd; padding: 11px"| 17Homo |style="font-size: 22px; color: #fff; background-color: #eee; padding: 11px"| 18Homo |style="font-size: 22px; color: #fff; background-color: #fff; padding: 11px"| 19Homo |} 81v7ksnspd38hx8t0v3g5gbfwikt6ac 0 269289 2407993 2407992 2022-07-19T12:10:51Z Maxim Masiutin 2902665 /* Backdoor Pathways to 5α-Dihydrotestosterone */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313" /><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == === Backdoor Pathways to 5α-Dihydrotestosterone === [[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows).<ref name="pmid30763313" /><ref name="pmid30943210" /> Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]]In canonical androgen steroidogenesis, the 5α-reductases type 2 and 3 catalyze the transformation of T to DHT in the terminal step. However, in the initial step into the androgen backdoor pathways to DHT, 5α-reductases type 1 and 2<ref name="pmid28774496"/> reduce a pregnane — 17-OHP or P4 — which is ultimately converted to DHT. Therefore, while 5α-reduction of a steroid is the last transformation in the canonical pathway, it is the first step in a backdoor pathway. These backdoor pathways are activated during normal prenatal development and lead to early male sexual differentiation in humans and other mammals.<ref name="pmid15249131" /><ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid23073980" /> ====5α-Reduction of 17α-Hydroxyprogesterone ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The pathway from 17-OHP to DHT may take place in steroidogenic tissues when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are simultaneously expressed.<ref name="pmid30763313" /><ref name="pmid25379460">{{cite journal |title=Steroid hormone synthetic pathways in prostate cancer |journal=Transl Androl Urol |volume=2 |issue=3 |pages=212–227 |date=September 2013 |pmid=25379460 |pmc=4219921 |doi=10.3978/j.issn.2223-4683.2013.09.16}}</ref> The pathway consists of five steps:{{ordered list |The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione catalyzed by 5α-reductase type 1 (SRD5A1) and 2 (SRD5A2).<ref name="pmid1527072">{{cite journal|last1=Normington|first1=K.|last2=Russell|first2=D. W.|title=Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions|journal=The Journal of Biological Chemistry|year=1992 |volume=267|issue=27|pages=19548–19554|doi=10.1016/S0021-9258(18)41809-1 |issn=0021-9258|pmid=1527072|doi-access=free }}</ref><ref name="pmid22170725"/><ref name="pmid14522586">{{cite journal |title=5alpha-reduced C21 steroids are substrates for human cytochrome P450c17 |journal=Arch Biochem Biophys |volume=418 |issue=2 |pages=151–60 |pmid=14522586 |doi=10.1016/j.abb.2003.07.003|last1=Gupta |first1=Manisha K. |last2=Guryev |first2=Oleg L. |last3=Auchus |first3=Richard J. |year=2003 }}</ref> Since 17-OHP is a poor substrate for CYP17A1,<ref name="pmid9452426"/><ref name="pmid32007561"/> the 5α-reductase conversion of 17-OHP by SRD5A1/SRD5A2<ref name="pmid28774496"/> will proceed efficiently to 17-OH-DHP via the backdoor pathway, rather than the 17,20-lyase conversion by CYP17A1 to A4 via the Δ⁴ pathway, resulting in negligible A4 being produced from 17-OHP.<ref name="pmid8325965">{{cite journal |title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase |journal=J Clin Endocrinol Metab |volume=77 |issue=1 |pages=98–102 |year=1993 |pmid=8325965 |doi=10.1210/jcem.77.1.8325965 |last1=Swart |first1=P. |last2=Swart |first2=A. C. |last3=Waterman |first3=M. R. |last4=Estabrook |first4=R. W. |last5=Mason |first5=J. I. }}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism |year=2003|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|year=2005 |volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> In a 2017 study by Barnard et al., 6 hours was enough for the full conversion of 17-OHP to 17-OH-DHP ''in vitro'', albeit the catalytic activity of SRD5A1 was higher than that of SRD5A2.<ref name="pmid28774496"/> Some authors<ref name="pmid23073980"/><ref name="pmid31611378"/> believe that 5α-reduction of 17-OHP appears to be primarily performed by SRD5A1 at least in the human fetus, citing a 1971 study by Frederiksen et al. of rat 5α-reductase activity ''in vitro''.<ref name="pmid4396507">{{cite journal |title=Partial characterization of the nuclear reduced nicotinamide adenine dinucleotide phosphate: delta 4-3-ketosteroid 5 alpha-oxidoreductase of rat prostate |journal=J Biol Chem |volume=246 |issue=8 |pages=2584–93|year=1971 |pmid=4396507|last1=Frederiksen |first1=D. W. |last2=Wilson |first2=J. D. |doi=10.1016/S0021-9258(18)62328-2 |doi-access=free }}</ref> However, these 1971 results were not confirmed by later studies, let alone in humans. Quite contrary, a 2017 study by Barnard et al. showed that both human isozymes were very efficient in converting 17-OHP to 17-OH-DHP.<ref name="pmid28774496" /> Both isozymes are expressed in the following fetal tissues of both sexes: adrenal gland, genital skin, and gonads.<ref name="pmid7488021">{{cite journal |title=Expression of the type 1 and 2 steroid 5 alpha-reductases in human fetal tissues |journal=Biochem Biophys Res Commun |year=1995 |volume=215 |issue=2 |pages=774–80 |pmid=7488021 |doi=10.1006/bbrc.1995.2530 |last1=Ellsworth |first1=K. |last2=Harris |first2=G. }}</ref><ref name="pmid17574609">{{cite journal |title=Fetal distribution of 5alpha-reductase 1 and 5alpha-reductase 2, and their input on human prostate development |journal=J Urol |volume=178 |issue=2 |pages=716–21 |year=2007 |pmid=17574609 |doi=10.1016/j.juro.2007.03.089 |last1=Lunacek |first1=A. |last2=Schwentner |first2=C. |last3=Oswald |first3=J. |last4=Fritsch |first4=H. |last5=Sergi |first5=C. |last6=Thomas |first6=L.N. |last7=Rittmaster |first7=R.S. |last8=Klocker |first8=H. |last9=Neuwirt |first9=H. |last10=Bartsch |first10=G. |last11=Radmayr |first11=C. }}</ref><ref name="pmid30763313"/><ref name="pmid31611378"/> Hence, it is not yet proven ''in vivo'' which of the isozymes takes part in 5α-reduction of 17-OHP in each and every case and condition.<ref name="pmid22170725"/><ref name="pmid28774496"/><ref name="pmid23073980"/> |17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4)<ref name="pmid30763313"/><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has the 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. |5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen).<ref name="pmid22170725"/><ref name="pmid30763313">{{cite journal | last1=O'Shaughnessy | first1=Peter J. | last2=Antignac | first2=Jean Philippe | last3=Le Bizec | first3=Bruno | last4=Morvan | first4=Marie-Line | last5=Svechnikov | first5=Konstantin | last6=Söder | first6=Olle | last7=Savchuk | first7=Iuliia | last8=Monteiro | first8=Ana | last9=Soffientini | first9=Ugo | last10=Johnston | first10=Zoe C. | last11=Bellingham | first11=Michelle | last12=Hough | first12=Denise | last13=Walker | first13=Natasha | last14=Filis | first14=Panagiotis | last15=Fowler | first15=Paul A. | editor-last1=Rawlins | editor-first1=Emma | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | year=2019 | volume = 17 | issue = 2 | pages = e3000002 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002}}</ref><ref name="pmid20613954">{{cite journal |last1=Auchus |first1=Richard J. |title=Management of the Adult with Congenital Adrenal Hyperplasia |journal=International Journal of Pediatric Endocrinology |year=2010 |volume=2010 |page=614107 |doi=10.1155/2010/614107 |pmid=20613954 |pmc=2896848 |doi-access=free }}</ref><ref name="pmid23073980">{{cite journal| title = Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development | journal = Developmental Dynamics | volume = 242 | issue = 4 | pages = 320–9 | pmid = 23073980 | doi = 10.1002/dvdy.23892| s2cid = 44702659 | last1 = Fukami | first1 = Maki | last2 = Homma | first2 = Keiko | last3 = Hasegawa | first3 = Tomonobu | last4 = Ogata | first4 = Tsutomu | year = 2013 }}</ref> |AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5. Type 3 (HSD17B3) is encoded by the ''HSD17B3'' gene in humans. The type 5 is actually an aldo-keto reductase family 1 member C3 (AKR1C3) encoded by the ''AKR1C3'' gene.<ref name="pmid31900912"/> |The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6 (also abbreviated as RL-HSD), HSD17B10, RDH16, RDH5, and DHRS9).<ref name="pmid15519890"/><ref name="pmid31900912"/><ref name="pmid31611378"/><ref name="pmid20613954"/> It is a reverse oxidative step not required in the canonical pathway.}} Therefore, the pathway can be outlined as follows:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21030877">{{cite journal| title = "Getting from here to there"--mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer | journal = Journal of Investigative Medicine : The Official Publication of the American Federation for Clinical Research | volume = 58 | issue = 8 | pages = 938–44 | doi = 10.2310/JIM.0b013e3181ff6bb8 | pmid = 21030877 | pmc = 5589138| last1 = Sharifi | first1 = Nima | last2 = McPhaul | first2 = Michael J. | last3 = Auchus | first3 = Richard J. | year = 2010 }}</ref><ref name="pmid23073980"/><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref><ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref>}} ====5α-reduction of Progesterone==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and has been confirmed first in mice<ref name="pmid15249131"/> and later in humans.<ref name="pmid30763313"/> Therefore, this pathway also essential for normal masculinization.<ref name="pmid21802064"/><ref name="pmid23073980"/> In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1, and, probably, SRD5A2.<ref name="pmid23073980"/><ref name="pmid28774496"/> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. Then this metabolic pathway proceeds to DHT the same way as the pathway that started with 17-OHP.<ref name="pmid30763313"/> Therefore, the pathway can be outlined as follows:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21802064"/><ref name="pmid23073980"/>}} === 5α-Dione Pathway === The pathway of A4 converted to androstanedione (5α-dione), and then to DHT (Figure 2) roundabout of T is unlikely to happen in sufficient quantities to have biological relevance in healthy humans. However, this pathway is relevant in CRPC.<ref name="pmid21795608"/> This pathway contains of two main steps: {{ordered list |The SRD5A1 enzyme 5α-reduces A4 to 5α-dione (also known as 5α-androstane-3,17-dione); |The HSD17B3 or AKR1C3 enzyme 17β-reduces 5α-dione to DHT.}} In this pathway, 5α-dione can also be interconverted with AST, which can also be converted to 3α-diol, which, in turn, can be converted to DHT by a number of dehydrogenases.<ref name="pmid11514561"/><ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> It should also be taken into consideration that the conversions of 5α-dione to AST and the conversion of DHT to 3α-diol are commonly considered inactivation reactions, but because these reactions are reversible, 3α-diol and AST may serve as a pool of inactive androgens and potential substrates for DHT. So, the alternative pathway that starts from A4 roundabout of T, called the "5α-dione" pathway, can be simplistically outlined as follows:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965"/><ref name="pmid12915666"/><ref name="pmid15774560"/><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. Instead, SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> In addition, 11-oxygenated androgens may also play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid31900912"/><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors to potent androgens,<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref> i.e., the conversion of circulating 11-oxygenated androgen precursors.<ref name="pmid33974560" /> In addition, 11KT levels are not affected by castration, thus making 11KT the most abundant active androgen in circulation. In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> The full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT are both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} r4m9whv94ed1rxtyosvlytntzmyp6ip 2407995 2407993 2022-07-19T12:44:56Z Maxim Masiutin 2902665 /* 5α-reduction of Progesterone */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313" /><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == === Backdoor Pathways to 5α-Dihydrotestosterone === [[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows).<ref name="pmid30763313" /><ref name="pmid30943210" /> Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]]In canonical androgen steroidogenesis, the 5α-reductases type 2 and 3 catalyze the transformation of T to DHT in the terminal step. However, in the initial step into the androgen backdoor pathways to DHT, 5α-reductases type 1 and 2<ref name="pmid28774496"/> reduce a pregnane — 17-OHP or P4 — which is ultimately converted to DHT. Therefore, while 5α-reduction of a steroid is the last transformation in the canonical pathway, it is the first step in a backdoor pathway. These backdoor pathways are activated during normal prenatal development and lead to early male sexual differentiation in humans and other mammals.<ref name="pmid15249131" /><ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid23073980" /> ====5α-Reduction of 17α-Hydroxyprogesterone ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The pathway from 17-OHP to DHT may take place in steroidogenic tissues when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are simultaneously expressed.<ref name="pmid30763313" /><ref name="pmid25379460">{{cite journal |title=Steroid hormone synthetic pathways in prostate cancer |journal=Transl Androl Urol |volume=2 |issue=3 |pages=212–227 |date=September 2013 |pmid=25379460 |pmc=4219921 |doi=10.3978/j.issn.2223-4683.2013.09.16}}</ref> The pathway consists of five steps:{{ordered list |The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione catalyzed by 5α-reductase type 1 (SRD5A1) and 2 (SRD5A2).<ref name="pmid1527072">{{cite journal|last1=Normington|first1=K.|last2=Russell|first2=D. W.|title=Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions|journal=The Journal of Biological Chemistry|year=1992 |volume=267|issue=27|pages=19548–19554|doi=10.1016/S0021-9258(18)41809-1 |issn=0021-9258|pmid=1527072|doi-access=free }}</ref><ref name="pmid22170725"/><ref name="pmid14522586">{{cite journal |title=5alpha-reduced C21 steroids are substrates for human cytochrome P450c17 |journal=Arch Biochem Biophys |volume=418 |issue=2 |pages=151–60 |pmid=14522586 |doi=10.1016/j.abb.2003.07.003|last1=Gupta |first1=Manisha K. |last2=Guryev |first2=Oleg L. |last3=Auchus |first3=Richard J. |year=2003 }}</ref> Since 17-OHP is a poor substrate for CYP17A1,<ref name="pmid9452426"/><ref name="pmid32007561"/> the 5α-reductase conversion of 17-OHP by SRD5A1/SRD5A2<ref name="pmid28774496"/> will proceed efficiently to 17-OH-DHP via the backdoor pathway, rather than the 17,20-lyase conversion by CYP17A1 to A4 via the Δ⁴ pathway, resulting in negligible A4 being produced from 17-OHP.<ref name="pmid8325965">{{cite journal |title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase |journal=J Clin Endocrinol Metab |volume=77 |issue=1 |pages=98–102 |year=1993 |pmid=8325965 |doi=10.1210/jcem.77.1.8325965 |last1=Swart |first1=P. |last2=Swart |first2=A. C. |last3=Waterman |first3=M. R. |last4=Estabrook |first4=R. W. |last5=Mason |first5=J. I. }}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism |year=2003|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|year=2005 |volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> In a 2017 study by Barnard et al., 6 hours was enough for the full conversion of 17-OHP to 17-OH-DHP ''in vitro'', albeit the catalytic activity of SRD5A1 was higher than that of SRD5A2.<ref name="pmid28774496"/> Some authors<ref name="pmid23073980"/><ref name="pmid31611378"/> believe that 5α-reduction of 17-OHP appears to be primarily performed by SRD5A1 at least in the human fetus, citing a 1971 study by Frederiksen et al. of rat 5α-reductase activity ''in vitro''.<ref name="pmid4396507">{{cite journal |title=Partial characterization of the nuclear reduced nicotinamide adenine dinucleotide phosphate: delta 4-3-ketosteroid 5 alpha-oxidoreductase of rat prostate |journal=J Biol Chem |volume=246 |issue=8 |pages=2584–93|year=1971 |pmid=4396507|last1=Frederiksen |first1=D. W. |last2=Wilson |first2=J. D. |doi=10.1016/S0021-9258(18)62328-2 |doi-access=free }}</ref> However, these 1971 results were not confirmed by later studies, let alone in humans. Quite contrary, a 2017 study by Barnard et al. showed that both human isozymes were very efficient in converting 17-OHP to 17-OH-DHP.<ref name="pmid28774496" /> Both isozymes are expressed in the following fetal tissues of both sexes: adrenal gland, genital skin, and gonads.<ref name="pmid7488021">{{cite journal |title=Expression of the type 1 and 2 steroid 5 alpha-reductases in human fetal tissues |journal=Biochem Biophys Res Commun |year=1995 |volume=215 |issue=2 |pages=774–80 |pmid=7488021 |doi=10.1006/bbrc.1995.2530 |last1=Ellsworth |first1=K. |last2=Harris |first2=G. }}</ref><ref name="pmid17574609">{{cite journal |title=Fetal distribution of 5alpha-reductase 1 and 5alpha-reductase 2, and their input on human prostate development |journal=J Urol |volume=178 |issue=2 |pages=716–21 |year=2007 |pmid=17574609 |doi=10.1016/j.juro.2007.03.089 |last1=Lunacek |first1=A. |last2=Schwentner |first2=C. |last3=Oswald |first3=J. |last4=Fritsch |first4=H. |last5=Sergi |first5=C. |last6=Thomas |first6=L.N. |last7=Rittmaster |first7=R.S. |last8=Klocker |first8=H. |last9=Neuwirt |first9=H. |last10=Bartsch |first10=G. |last11=Radmayr |first11=C. }}</ref><ref name="pmid30763313"/><ref name="pmid31611378"/> Hence, it is not yet proven ''in vivo'' which of the isozymes takes part in 5α-reduction of 17-OHP in each and every case and condition.<ref name="pmid22170725"/><ref name="pmid28774496"/><ref name="pmid23073980"/> |17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4)<ref name="pmid30763313"/><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has the 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. |5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen).<ref name="pmid22170725"/><ref name="pmid30763313">{{cite journal | last1=O'Shaughnessy | first1=Peter J. | last2=Antignac | first2=Jean Philippe | last3=Le Bizec | first3=Bruno | last4=Morvan | first4=Marie-Line | last5=Svechnikov | first5=Konstantin | last6=Söder | first6=Olle | last7=Savchuk | first7=Iuliia | last8=Monteiro | first8=Ana | last9=Soffientini | first9=Ugo | last10=Johnston | first10=Zoe C. | last11=Bellingham | first11=Michelle | last12=Hough | first12=Denise | last13=Walker | first13=Natasha | last14=Filis | first14=Panagiotis | last15=Fowler | first15=Paul A. | editor-last1=Rawlins | editor-first1=Emma | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | year=2019 | volume = 17 | issue = 2 | pages = e3000002 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002}}</ref><ref name="pmid20613954">{{cite journal |last1=Auchus |first1=Richard J. |title=Management of the Adult with Congenital Adrenal Hyperplasia |journal=International Journal of Pediatric Endocrinology |year=2010 |volume=2010 |page=614107 |doi=10.1155/2010/614107 |pmid=20613954 |pmc=2896848 |doi-access=free }}</ref><ref name="pmid23073980">{{cite journal| title = Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development | journal = Developmental Dynamics | volume = 242 | issue = 4 | pages = 320–9 | pmid = 23073980 | doi = 10.1002/dvdy.23892| s2cid = 44702659 | last1 = Fukami | first1 = Maki | last2 = Homma | first2 = Keiko | last3 = Hasegawa | first3 = Tomonobu | last4 = Ogata | first4 = Tsutomu | year = 2013 }}</ref> |AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5. Type 3 (HSD17B3) is encoded by the ''HSD17B3'' gene in humans. The type 5 is actually an aldo-keto reductase family 1 member C3 (AKR1C3) encoded by the ''AKR1C3'' gene.<ref name="pmid31900912"/> |The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6 (also abbreviated as RL-HSD), HSD17B10, RDH16, RDH5, and DHRS9).<ref name="pmid15519890"/><ref name="pmid31900912"/><ref name="pmid31611378"/><ref name="pmid20613954"/> It is a reverse oxidative step not required in the canonical pathway.}} Therefore, the pathway can be outlined as follows:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21030877">{{cite journal| title = "Getting from here to there"--mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer | journal = Journal of Investigative Medicine : The Official Publication of the American Federation for Clinical Research | volume = 58 | issue = 8 | pages = 938–44 | doi = 10.2310/JIM.0b013e3181ff6bb8 | pmid = 21030877 | pmc = 5589138| last1 = Sharifi | first1 = Nima | last2 = McPhaul | first2 = Michael J. | last3 = Auchus | first3 = Richard J. | year = 2010 }}</ref><ref name="pmid23073980"/><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref><ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref>}} ====5α-reduction of Progesterone==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and has been confirmed first in mice<ref name="pmid15249131"/> and later in humans.<ref name="pmid30763313"/> Therefore, this pathway also essential for normal masculinization.<ref name="pmid21802064"/><ref name="pmid23073980"/> In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1, and, probably, SRD5A2.<ref name="pmid23073980"/><ref name="pmid28774496"/><ref name="pmid32593151"/> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. Then this metabolic pathway proceeds to DHT the same way as the pathway that started with 17-OHP.<ref name="pmid30763313"/> Therefore, the pathway can be outlined as follows:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21802064"/><ref name="pmid23073980"/>}} === 5α-Dione Pathway === The pathway of A4 converted to androstanedione (5α-dione), and then to DHT (Figure 2) roundabout of T is unlikely to happen in sufficient quantities to have biological relevance in healthy humans. However, this pathway is relevant in CRPC.<ref name="pmid21795608"/> This pathway contains of two main steps: {{ordered list |The SRD5A1 enzyme 5α-reduces A4 to 5α-dione (also known as 5α-androstane-3,17-dione); |The HSD17B3 or AKR1C3 enzyme 17β-reduces 5α-dione to DHT.}} In this pathway, 5α-dione can also be interconverted with AST, which can also be converted to 3α-diol, which, in turn, can be converted to DHT by a number of dehydrogenases.<ref name="pmid11514561"/><ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> It should also be taken into consideration that the conversions of 5α-dione to AST and the conversion of DHT to 3α-diol are commonly considered inactivation reactions, but because these reactions are reversible, 3α-diol and AST may serve as a pool of inactive androgens and potential substrates for DHT. So, the alternative pathway that starts from A4 roundabout of T, called the "5α-dione" pathway, can be simplistically outlined as follows:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965"/><ref name="pmid12915666"/><ref name="pmid15774560"/><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. Instead, SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> In addition, 11-oxygenated androgens may also play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid31900912"/><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors to potent androgens,<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref> i.e., the conversion of circulating 11-oxygenated androgen precursors.<ref name="pmid33974560" /> In addition, 11KT levels are not affected by castration, thus making 11KT the most abundant active androgen in circulation. In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> The full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT are both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} mb4yoh731ns32q0i6e72ya4lh2rsv3v 2407996 2407995 2022-07-19T12:49:52Z Maxim Masiutin 2902665 /* Backdoor Pathways to 5α-Dihydrotestosterone */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313" /><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == === Backdoor Pathways to 5α-Dihydrotestosterone === [[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows).<ref name="pmid30763313" /><ref name="pmid30943210" /> Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]]In canonical androgen steroidogenesis, the 5α-reductases type 2 and 3 catalyze the transformation of T to DHT in the terminal step. However, in the initial step into the androgen backdoor pathways to DHT, 5α-reductases type 1 and 2<ref name="pmid28774496"/><ref name="pmid31626910"/> reduce a pregnane — 17-OHP or P4 — which is ultimately converted to DHT. Therefore, while 5α-reduction of a steroid is the last transformation in the canonical pathway, it is the first step in a backdoor pathway. These backdoor pathways are activated during normal prenatal development and lead to early male sexual differentiation in humans and other mammals.<ref name="pmid15249131" /><ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid23073980" /> ====5α-Reduction of 17α-Hydroxyprogesterone ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The pathway from 17-OHP to DHT may take place in steroidogenic tissues when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are simultaneously expressed.<ref name="pmid30763313" /><ref name="pmid25379460">{{cite journal |title=Steroid hormone synthetic pathways in prostate cancer |journal=Transl Androl Urol |volume=2 |issue=3 |pages=212–227 |date=September 2013 |pmid=25379460 |pmc=4219921 |doi=10.3978/j.issn.2223-4683.2013.09.16}}</ref> The pathway consists of five steps:{{ordered list |The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione catalyzed by 5α-reductase type 1 (SRD5A1) and 2 (SRD5A2).<ref name="pmid1527072">{{cite journal|last1=Normington|first1=K.|last2=Russell|first2=D. W.|title=Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions|journal=The Journal of Biological Chemistry|year=1992 |volume=267|issue=27|pages=19548–19554|doi=10.1016/S0021-9258(18)41809-1 |issn=0021-9258|pmid=1527072|doi-access=free }}</ref><ref name="pmid22170725"/><ref name="pmid14522586">{{cite journal |title=5alpha-reduced C21 steroids are substrates for human cytochrome P450c17 |journal=Arch Biochem Biophys |volume=418 |issue=2 |pages=151–60 |pmid=14522586 |doi=10.1016/j.abb.2003.07.003|last1=Gupta |first1=Manisha K. |last2=Guryev |first2=Oleg L. |last3=Auchus |first3=Richard J. |year=2003 }}</ref> Since 17-OHP is a poor substrate for CYP17A1,<ref name="pmid9452426"/><ref name="pmid32007561"/> the 5α-reductase conversion of 17-OHP by SRD5A1/SRD5A2<ref name="pmid28774496"/><ref name="pmid31626910"/> will proceed efficiently to 17-OH-DHP via the backdoor pathway, rather than the 17,20-lyase conversion by CYP17A1 to A4 via the Δ⁴ pathway, resulting in negligible A4 being produced from 17-OHP.<ref name="pmid8325965">{{cite journal |title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase |journal=J Clin Endocrinol Metab |volume=77 |issue=1 |pages=98–102 |year=1993 |pmid=8325965 |doi=10.1210/jcem.77.1.8325965 |last1=Swart |first1=P. |last2=Swart |first2=A. C. |last3=Waterman |first3=M. R. |last4=Estabrook |first4=R. W. |last5=Mason |first5=J. I. }}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism |year=2003|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|year=2005 |volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> In a 2017 study by Barnard et al., 6 hours was enough for the full conversion of 17-OHP to 17-OH-DHP ''in vitro'', albeit the catalytic activity of SRD5A1 was higher than that of SRD5A2.<ref name="pmid28774496"/> Some authors<ref name="pmid23073980"/><ref name="pmid31611378"/> believe that 5α-reduction of 17-OHP appears to be primarily performed by SRD5A1 at least in the human fetus, citing a 1971 study by Frederiksen et al. of rat 5α-reductase activity ''in vitro''.<ref name="pmid4396507">{{cite journal |title=Partial characterization of the nuclear reduced nicotinamide adenine dinucleotide phosphate: delta 4-3-ketosteroid 5 alpha-oxidoreductase of rat prostate |journal=J Biol Chem |volume=246 |issue=8 |pages=2584–93|year=1971 |pmid=4396507|last1=Frederiksen |first1=D. W. |last2=Wilson |first2=J. D. |doi=10.1016/S0021-9258(18)62328-2 |doi-access=free }}</ref> However, these 1971 results were not confirmed by later studies, let alone in humans. Quite contrary, a 2017 study by Barnard et al. showed that both human isozymes were very efficient in converting 17-OHP to 17-OH-DHP.<ref name="pmid28774496" /> Both isozymes are expressed in the following fetal tissues of both sexes: adrenal gland, genital skin, and gonads.<ref name="pmid7488021">{{cite journal |title=Expression of the type 1 and 2 steroid 5 alpha-reductases in human fetal tissues |journal=Biochem Biophys Res Commun |year=1995 |volume=215 |issue=2 |pages=774–80 |pmid=7488021 |doi=10.1006/bbrc.1995.2530 |last1=Ellsworth |first1=K. |last2=Harris |first2=G. }}</ref><ref name="pmid17574609">{{cite journal |title=Fetal distribution of 5alpha-reductase 1 and 5alpha-reductase 2, and their input on human prostate development |journal=J Urol |volume=178 |issue=2 |pages=716–21 |year=2007 |pmid=17574609 |doi=10.1016/j.juro.2007.03.089 |last1=Lunacek |first1=A. |last2=Schwentner |first2=C. |last3=Oswald |first3=J. |last4=Fritsch |first4=H. |last5=Sergi |first5=C. |last6=Thomas |first6=L.N. |last7=Rittmaster |first7=R.S. |last8=Klocker |first8=H. |last9=Neuwirt |first9=H. |last10=Bartsch |first10=G. |last11=Radmayr |first11=C. }}</ref><ref name="pmid30763313"/><ref name="pmid31611378"/> Hence, it is not yet proven ''in vivo'' which of the isozymes takes part in 5α-reduction of 17-OHP in each and every case and condition.<ref name="pmid22170725"/><ref name="pmid28774496"/><ref name="pmid23073980"/> |17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4)<ref name="pmid30763313"/><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has the 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. |5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen).<ref name="pmid22170725"/><ref name="pmid30763313">{{cite journal | last1=O'Shaughnessy | first1=Peter J. | last2=Antignac | first2=Jean Philippe | last3=Le Bizec | first3=Bruno | last4=Morvan | first4=Marie-Line | last5=Svechnikov | first5=Konstantin | last6=Söder | first6=Olle | last7=Savchuk | first7=Iuliia | last8=Monteiro | first8=Ana | last9=Soffientini | first9=Ugo | last10=Johnston | first10=Zoe C. | last11=Bellingham | first11=Michelle | last12=Hough | first12=Denise | last13=Walker | first13=Natasha | last14=Filis | first14=Panagiotis | last15=Fowler | first15=Paul A. | editor-last1=Rawlins | editor-first1=Emma | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | year=2019 | volume = 17 | issue = 2 | pages = e3000002 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002}}</ref><ref name="pmid20613954">{{cite journal |last1=Auchus |first1=Richard J. |title=Management of the Adult with Congenital Adrenal Hyperplasia |journal=International Journal of Pediatric Endocrinology |year=2010 |volume=2010 |page=614107 |doi=10.1155/2010/614107 |pmid=20613954 |pmc=2896848 |doi-access=free }}</ref><ref name="pmid23073980">{{cite journal| title = Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development | journal = Developmental Dynamics | volume = 242 | issue = 4 | pages = 320–9 | pmid = 23073980 | doi = 10.1002/dvdy.23892| s2cid = 44702659 | last1 = Fukami | first1 = Maki | last2 = Homma | first2 = Keiko | last3 = Hasegawa | first3 = Tomonobu | last4 = Ogata | first4 = Tsutomu | year = 2013 }}</ref> |AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5. Type 3 (HSD17B3) is encoded by the ''HSD17B3'' gene in humans. The type 5 is actually an aldo-keto reductase family 1 member C3 (AKR1C3) encoded by the ''AKR1C3'' gene.<ref name="pmid31900912"/> |The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6 (also abbreviated as RL-HSD), HSD17B10, RDH16, RDH5, and DHRS9).<ref name="pmid15519890"/><ref name="pmid31900912"/><ref name="pmid31611378"/><ref name="pmid20613954"/> It is a reverse oxidative step not required in the canonical pathway.}} Therefore, the pathway can be outlined as follows:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21030877">{{cite journal| title = "Getting from here to there"--mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer | journal = Journal of Investigative Medicine : The Official Publication of the American Federation for Clinical Research | volume = 58 | issue = 8 | pages = 938–44 | doi = 10.2310/JIM.0b013e3181ff6bb8 | pmid = 21030877 | pmc = 5589138| last1 = Sharifi | first1 = Nima | last2 = McPhaul | first2 = Michael J. | last3 = Auchus | first3 = Richard J. | year = 2010 }}</ref><ref name="pmid23073980"/><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref><ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref>}} ====5α-reduction of Progesterone==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and has been confirmed first in mice<ref name="pmid15249131"/> and later in humans.<ref name="pmid30763313"/> Therefore, this pathway also essential for normal masculinization.<ref name="pmid21802064"/><ref name="pmid23073980"/> In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1, and, probably, SRD5A2.<ref name="pmid23073980"/><ref name="pmid28774496"/><ref name="pmid32593151"/> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. Then this metabolic pathway proceeds to DHT the same way as the pathway that started with 17-OHP.<ref name="pmid30763313"/> Therefore, the pathway can be outlined as follows:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21802064"/><ref name="pmid23073980"/>}} === 5α-Dione Pathway === The pathway of A4 converted to androstanedione (5α-dione), and then to DHT (Figure 2) roundabout of T is unlikely to happen in sufficient quantities to have biological relevance in healthy humans. However, this pathway is relevant in CRPC.<ref name="pmid21795608"/> This pathway contains of two main steps: {{ordered list |The SRD5A1 enzyme 5α-reduces A4 to 5α-dione (also known as 5α-androstane-3,17-dione); |The HSD17B3 or AKR1C3 enzyme 17β-reduces 5α-dione to DHT.}} In this pathway, 5α-dione can also be interconverted with AST, which can also be converted to 3α-diol, which, in turn, can be converted to DHT by a number of dehydrogenases.<ref name="pmid11514561"/><ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> It should also be taken into consideration that the conversions of 5α-dione to AST and the conversion of DHT to 3α-diol are commonly considered inactivation reactions, but because these reactions are reversible, 3α-diol and AST may serve as a pool of inactive androgens and potential substrates for DHT. So, the alternative pathway that starts from A4 roundabout of T, called the "5α-dione" pathway, can be simplistically outlined as follows:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965"/><ref name="pmid12915666"/><ref name="pmid15774560"/><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. Instead, SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> In addition, 11-oxygenated androgens may also play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid31900912"/><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors to potent androgens,<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref> i.e., the conversion of circulating 11-oxygenated androgen precursors.<ref name="pmid33974560" /> In addition, 11KT levels are not affected by castration, thus making 11KT the most abundant active androgen in circulation. In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> The full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT are both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} l04434xidbiexqbgh3l0fpzu0kwfz10 2407997 2407996 2022-07-19T12:53:08Z Maxim Masiutin 2902665 removed references that are no longer relevant wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313" /><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == === Backdoor Pathways to 5α-Dihydrotestosterone === [[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]]In canonical androgen steroidogenesis, the 5α-reductases type 2 and 3 catalyze the transformation of T to DHT in the terminal step. However, in the initial step into the androgen backdoor pathways to DHT, 5α-reductases type 1 and 2<ref name="pmid28774496"/><ref name="pmid31626910"/> reduce a pregnane — 17-OHP or P4 — which is ultimately converted to DHT. Therefore, while 5α-reduction of a steroid is the last transformation in the canonical pathway, it is the first step in a backdoor pathway. These backdoor pathways are activated during normal prenatal development and lead to early male sexual differentiation in humans and other mammals.<ref name="pmid15249131" /><ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid23073980" /> ====5α-Reduction of 17α-Hydroxyprogesterone ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The pathway from 17-OHP to DHT may take place in steroidogenic tissues when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are simultaneously expressed.<ref name="pmid30763313" /><ref name="pmid25379460">{{cite journal |title=Steroid hormone synthetic pathways in prostate cancer |journal=Transl Androl Urol |volume=2 |issue=3 |pages=212–227 |date=September 2013 |pmid=25379460 |pmc=4219921 |doi=10.3978/j.issn.2223-4683.2013.09.16}}</ref> The pathway consists of five steps:{{ordered list |The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione catalyzed by 5α-reductase type 1 (SRD5A1) and 2 (SRD5A2).<ref name="pmid1527072">{{cite journal|last1=Normington|first1=K.|last2=Russell|first2=D. W.|title=Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions|journal=The Journal of Biological Chemistry|year=1992 |volume=267|issue=27|pages=19548–19554|doi=10.1016/S0021-9258(18)41809-1 |issn=0021-9258|pmid=1527072|doi-access=free }}</ref><ref name="pmid22170725"/><ref name="pmid14522586">{{cite journal |title=5alpha-reduced C21 steroids are substrates for human cytochrome P450c17 |journal=Arch Biochem Biophys |volume=418 |issue=2 |pages=151–60 |pmid=14522586 |doi=10.1016/j.abb.2003.07.003|last1=Gupta |first1=Manisha K. |last2=Guryev |first2=Oleg L. |last3=Auchus |first3=Richard J. |year=2003 }}</ref> Since 17-OHP is a poor substrate for CYP17A1,<ref name="pmid9452426"/><ref name="pmid32007561"/> the 5α-reductase conversion of 17-OHP by SRD5A1/SRD5A2<ref name="pmid28774496"/><ref name="pmid31626910"/> will proceed efficiently to 17-OH-DHP via the backdoor pathway, rather than the 17,20-lyase conversion by CYP17A1 to A4 via the Δ⁴ pathway, resulting in negligible A4 being produced from 17-OHP.<ref name="pmid8325965">{{cite journal |title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase |journal=J Clin Endocrinol Metab |volume=77 |issue=1 |pages=98–102 |year=1993 |pmid=8325965 |doi=10.1210/jcem.77.1.8325965 |last1=Swart |first1=P. |last2=Swart |first2=A. C. |last3=Waterman |first3=M. R. |last4=Estabrook |first4=R. W. |last5=Mason |first5=J. I. }}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism |year=2003|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|year=2005 |volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> In a 2017 study by Barnard et al., 6 hours was enough for the full conversion of 17-OHP to 17-OH-DHP ''in vitro'', albeit the catalytic activity of SRD5A1 was higher than that of SRD5A2.<ref name="pmid28774496"/> Some authors<ref name="pmid23073980"/><ref name="pmid31611378"/> believe that 5α-reduction of 17-OHP appears to be primarily performed by SRD5A1 at least in the human fetus, citing a 1971 study by Frederiksen et al. of rat 5α-reductase activity ''in vitro''.<ref name="pmid4396507">{{cite journal |title=Partial characterization of the nuclear reduced nicotinamide adenine dinucleotide phosphate: delta 4-3-ketosteroid 5 alpha-oxidoreductase of rat prostate |journal=J Biol Chem |volume=246 |issue=8 |pages=2584–93|year=1971 |pmid=4396507|last1=Frederiksen |first1=D. W. |last2=Wilson |first2=J. D. |doi=10.1016/S0021-9258(18)62328-2 |doi-access=free }}</ref> However, these 1971 results were not confirmed by later studies, let alone in humans. Quite contrary, a 2017 study by Barnard et al. showed that both human isozymes were very efficient in converting 17-OHP to 17-OH-DHP.<ref name="pmid28774496" /> Both isozymes are expressed in the following fetal tissues of both sexes: adrenal gland, genital skin, and gonads.<ref name="pmid7488021">{{cite journal |title=Expression of the type 1 and 2 steroid 5 alpha-reductases in human fetal tissues |journal=Biochem Biophys Res Commun |year=1995 |volume=215 |issue=2 |pages=774–80 |pmid=7488021 |doi=10.1006/bbrc.1995.2530 |last1=Ellsworth |first1=K. |last2=Harris |first2=G. }}</ref><ref name="pmid17574609">{{cite journal |title=Fetal distribution of 5alpha-reductase 1 and 5alpha-reductase 2, and their input on human prostate development |journal=J Urol |volume=178 |issue=2 |pages=716–21 |year=2007 |pmid=17574609 |doi=10.1016/j.juro.2007.03.089 |last1=Lunacek |first1=A. |last2=Schwentner |first2=C. |last3=Oswald |first3=J. |last4=Fritsch |first4=H. |last5=Sergi |first5=C. |last6=Thomas |first6=L.N. |last7=Rittmaster |first7=R.S. |last8=Klocker |first8=H. |last9=Neuwirt |first9=H. |last10=Bartsch |first10=G. |last11=Radmayr |first11=C. }}</ref><ref name="pmid30763313"/><ref name="pmid31611378"/> Hence, it is not yet proven ''in vivo'' which of the isozymes takes part in 5α-reduction of 17-OHP in each and every case and condition.<ref name="pmid22170725"/><ref name="pmid28774496"/><ref name="pmid23073980"/> |17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4)<ref name="pmid30763313"/><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has the 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. |5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen).<ref name="pmid22170725"/><ref name="pmid30763313">{{cite journal | last1=O'Shaughnessy | first1=Peter J. | last2=Antignac | first2=Jean Philippe | last3=Le Bizec | first3=Bruno | last4=Morvan | first4=Marie-Line | last5=Svechnikov | first5=Konstantin | last6=Söder | first6=Olle | last7=Savchuk | first7=Iuliia | last8=Monteiro | first8=Ana | last9=Soffientini | first9=Ugo | last10=Johnston | first10=Zoe C. | last11=Bellingham | first11=Michelle | last12=Hough | first12=Denise | last13=Walker | first13=Natasha | last14=Filis | first14=Panagiotis | last15=Fowler | first15=Paul A. | editor-last1=Rawlins | editor-first1=Emma | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | year=2019 | volume = 17 | issue = 2 | pages = e3000002 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002}}</ref><ref name="pmid20613954">{{cite journal |last1=Auchus |first1=Richard J. |title=Management of the Adult with Congenital Adrenal Hyperplasia |journal=International Journal of Pediatric Endocrinology |year=2010 |volume=2010 |page=614107 |doi=10.1155/2010/614107 |pmid=20613954 |pmc=2896848 |doi-access=free }}</ref><ref name="pmid23073980">{{cite journal| title = Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development | journal = Developmental Dynamics | volume = 242 | issue = 4 | pages = 320–9 | pmid = 23073980 | doi = 10.1002/dvdy.23892| s2cid = 44702659 | last1 = Fukami | first1 = Maki | last2 = Homma | first2 = Keiko | last3 = Hasegawa | first3 = Tomonobu | last4 = Ogata | first4 = Tsutomu | year = 2013 }}</ref> |AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5. Type 3 (HSD17B3) is encoded by the ''HSD17B3'' gene in humans. The type 5 is actually an aldo-keto reductase family 1 member C3 (AKR1C3) encoded by the ''AKR1C3'' gene.<ref name="pmid31900912"/> |The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6 (also abbreviated as RL-HSD), HSD17B10, RDH16, RDH5, and DHRS9).<ref name="pmid15519890"/><ref name="pmid31900912"/><ref name="pmid31611378"/><ref name="pmid20613954"/> It is a reverse oxidative step not required in the canonical pathway.}} Therefore, the pathway can be outlined as follows:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21030877">{{cite journal| title = "Getting from here to there"--mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer | journal = Journal of Investigative Medicine : The Official Publication of the American Federation for Clinical Research | volume = 58 | issue = 8 | pages = 938–44 | doi = 10.2310/JIM.0b013e3181ff6bb8 | pmid = 21030877 | pmc = 5589138| last1 = Sharifi | first1 = Nima | last2 = McPhaul | first2 = Michael J. | last3 = Auchus | first3 = Richard J. | year = 2010 }}</ref><ref name="pmid23073980"/><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref><ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref>}} ====5α-reduction of Progesterone==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and has been confirmed first in mice<ref name="pmid15249131"/> and later in humans.<ref name="pmid30763313"/> Therefore, this pathway also essential for normal masculinization.<ref name="pmid21802064"/><ref name="pmid23073980"/> In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1, and, probably, SRD5A2.<ref name="pmid23073980"/><ref name="pmid28774496"/><ref name="pmid32593151"/> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. Then this metabolic pathway proceeds to DHT the same way as the pathway that started with 17-OHP.<ref name="pmid30763313"/> Therefore, the pathway can be outlined as follows:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21802064"/><ref name="pmid23073980"/>}} === 5α-Dione Pathway === The pathway of A4 converted to androstanedione (5α-dione), and then to DHT (Figure 2) roundabout of T is unlikely to happen in sufficient quantities to have biological relevance in healthy humans. However, this pathway is relevant in CRPC.<ref name="pmid21795608"/> This pathway contains of two main steps: {{ordered list |The SRD5A1 enzyme 5α-reduces A4 to 5α-dione (also known as 5α-androstane-3,17-dione); |The HSD17B3 or AKR1C3 enzyme 17β-reduces 5α-dione to DHT.}} In this pathway, 5α-dione can also be interconverted with AST, which can also be converted to 3α-diol, which, in turn, can be converted to DHT by a number of dehydrogenases.<ref name="pmid11514561"/><ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> It should also be taken into consideration that the conversions of 5α-dione to AST and the conversion of DHT to 3α-diol are commonly considered inactivation reactions, but because these reactions are reversible, 3α-diol and AST may serve as a pool of inactive androgens and potential substrates for DHT. So, the alternative pathway that starts from A4 roundabout of T, called the "5α-dione" pathway, can be simplistically outlined as follows:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965"/><ref name="pmid12915666"/><ref name="pmid15774560"/><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. Instead, SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> In addition, 11-oxygenated androgens may also play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid31900912"/><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors to potent androgens,<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref> i.e., the conversion of circulating 11-oxygenated androgen precursors.<ref name="pmid33974560" /> In addition, 11KT levels are not affected by castration, thus making 11KT the most abundant active androgen in circulation. In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> The full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT are both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} 24ujf3241hanirdu0ds0vnpylqksp9p 2408000 2407997 2022-07-19T13:31:08Z Maxim Masiutin 2902665 wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313" /><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == === Backdoor Pathways to 5α-Dihydrotestosterone === [[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]]In canonical androgen steroidogenesis, the 5α-reductases type 2 and 3 catalyze the transformation of T to DHT in the terminal step. However, in the initial step into the androgen backdoor pathways to DHT, 5α-reductases type 1 and 2<ref name="pmid28774496"/><ref name="pmid31626910"/> reduce a pregnane — 17-OHP or P4 — which is ultimately converted to DHT. Therefore, while 5α-reduction of a steroid is the last transformation in the canonical pathway, it is the first step in a backdoor pathway. These backdoor pathways are activated during normal prenatal development and lead to early male sexual differentiation in humans and other mammals.<ref name="pmid15249131" /><ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid23073980" /> ====5α-Reduction of 17α-Hydroxyprogesterone ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The pathway from 17-OHP to DHT may take place in steroidogenic tissues when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are simultaneously expressed.<ref name="pmid30763313" /><ref name="pmid25379460">{{cite journal |title=Steroid hormone synthetic pathways in prostate cancer |journal=Transl Androl Urol |volume=2 |issue=3 |pages=212–227 |date=September 2013 |pmid=25379460 |pmc=4219921 |doi=10.3978/j.issn.2223-4683.2013.09.16}}</ref> The pathway consists of five steps:{{ordered list |The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione catalyzed by 5α-reductase type 1 (SRD5A1) and 2 (SRD5A2).<ref name="pmid1527072">{{cite journal|last1=Normington|first1=K.|last2=Russell|first2=D. W.|title=Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions|journal=The Journal of Biological Chemistry|year=1992 |volume=267|issue=27|pages=19548–19554|doi=10.1016/S0021-9258(18)41809-1 |issn=0021-9258|pmid=1527072|doi-access=free }}</ref><ref name="pmid22170725"/><ref name="pmid14522586">{{cite journal |title=5alpha-reduced C21 steroids are substrates for human cytochrome P450c17 |journal=Arch Biochem Biophys |volume=418 |issue=2 |pages=151–60 |pmid=14522586 |doi=10.1016/j.abb.2003.07.003|last1=Gupta |first1=Manisha K. |last2=Guryev |first2=Oleg L. |last3=Auchus |first3=Richard J. |year=2003 }}</ref> Since 17-OHP is a poor substrate for CYP17A1,<ref name="pmid9452426"/><ref name="pmid32007561"/> the 5α-reductase conversion of 17-OHP by SRD5A1/SRD5A2<ref name="pmid28774496"/><ref name="pmid31626910"/> will proceed efficiently to 17-OH-DHP via the backdoor pathway, rather than the 17,20-lyase conversion by CYP17A1 to A4 via the Δ⁴ pathway, resulting in negligible A4 being produced from 17-OHP.<ref name="pmid8325965">{{cite journal |title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase |journal=J Clin Endocrinol Metab |volume=77 |issue=1 |pages=98–102 |year=1993 |pmid=8325965 |doi=10.1210/jcem.77.1.8325965 |last1=Swart |first1=P. |last2=Swart |first2=A. C. |last3=Waterman |first3=M. R. |last4=Estabrook |first4=R. W. |last5=Mason |first5=J. I. }}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism |year=2003|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|year=2005 |volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> In a 2017 study by Barnard et al., 6 hours was enough for the full conversion of 17-OHP to 17-OH-DHP ''in vitro'', albeit the catalytic activity of SRD5A1 was higher than that of SRD5A2.<ref name="pmid28774496"/> Some authors<ref name="pmid23073980"/><ref name="pmid31611378"/> believe that 5α-reduction of 17-OHP appears to be primarily performed by SRD5A1 at least in the human fetus, citing a 1971 study by Frederiksen et al. of rat 5α-reductase activity ''in vitro''.<ref name="pmid4396507">{{cite journal |title=Partial characterization of the nuclear reduced nicotinamide adenine dinucleotide phosphate: delta 4-3-ketosteroid 5 alpha-oxidoreductase of rat prostate |journal=J Biol Chem |volume=246 |issue=8 |pages=2584–93|year=1971 |pmid=4396507|last1=Frederiksen |first1=D. W. |last2=Wilson |first2=J. D. |doi=10.1016/S0021-9258(18)62328-2 |doi-access=free }}</ref> However, these 1971 results were not confirmed by later studies, let alone in humans. Quite contrary, a 2017 study by Barnard et al. showed that both human isozymes were very efficient in converting 17-OHP to 17-OH-DHP.<ref name="pmid28774496" /> Both isozymes are expressed in the following fetal tissues of both sexes: adrenal gland, genital skin, and gonads.<ref name="pmid7488021">{{cite journal |title=Expression of the type 1 and 2 steroid 5 alpha-reductases in human fetal tissues |journal=Biochem Biophys Res Commun |year=1995 |volume=215 |issue=2 |pages=774–80 |pmid=7488021 |doi=10.1006/bbrc.1995.2530 |last1=Ellsworth |first1=K. |last2=Harris |first2=G. }}</ref><ref name="pmid17574609">{{cite journal |title=Fetal distribution of 5alpha-reductase 1 and 5alpha-reductase 2, and their input on human prostate development |journal=J Urol |volume=178 |issue=2 |pages=716–21 |year=2007 |pmid=17574609 |doi=10.1016/j.juro.2007.03.089 |last1=Lunacek |first1=A. |last2=Schwentner |first2=C. |last3=Oswald |first3=J. |last4=Fritsch |first4=H. |last5=Sergi |first5=C. |last6=Thomas |first6=L.N. |last7=Rittmaster |first7=R.S. |last8=Klocker |first8=H. |last9=Neuwirt |first9=H. |last10=Bartsch |first10=G. |last11=Radmayr |first11=C. }}</ref><ref name="pmid30763313"/><ref name="pmid31611378"/> Hence, it is not yet proven ''in vivo'' which of the isozymes takes part in 5α-reduction of 17-OHP in each and every case and condition.<ref name="pmid22170725"/><ref name="pmid28774496"/><ref name="pmid23073980"/> |17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4)<ref name="pmid30763313"/><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has the 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. |5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen).<ref name="pmid22170725"/><ref name="pmid30763313">{{cite journal | last1=O'Shaughnessy | first1=Peter J. | last2=Antignac | first2=Jean Philippe | last3=Le Bizec | first3=Bruno | last4=Morvan | first4=Marie-Line | last5=Svechnikov | first5=Konstantin | last6=Söder | first6=Olle | last7=Savchuk | first7=Iuliia | last8=Monteiro | first8=Ana | last9=Soffientini | first9=Ugo | last10=Johnston | first10=Zoe C. | last11=Bellingham | first11=Michelle | last12=Hough | first12=Denise | last13=Walker | first13=Natasha | last14=Filis | first14=Panagiotis | last15=Fowler | first15=Paul A. | editor-last1=Rawlins | editor-first1=Emma | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | year=2019 | volume = 17 | issue = 2 | pages = e3000002 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002}}</ref><ref name="pmid20613954">{{cite journal |last1=Auchus |first1=Richard J. |title=Management of the Adult with Congenital Adrenal Hyperplasia |journal=International Journal of Pediatric Endocrinology |year=2010 |volume=2010 |page=614107 |doi=10.1155/2010/614107 |pmid=20613954 |pmc=2896848 |doi-access=free }}</ref><ref name="pmid23073980">{{cite journal| title = Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development | journal = Developmental Dynamics | volume = 242 | issue = 4 | pages = 320–9 | pmid = 23073980 | doi = 10.1002/dvdy.23892| s2cid = 44702659 | last1 = Fukami | first1 = Maki | last2 = Homma | first2 = Keiko | last3 = Hasegawa | first3 = Tomonobu | last4 = Ogata | first4 = Tsutomu | year = 2013 }}</ref> |AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5. Type 3 (HSD17B3) is encoded by the ''HSD17B3'' gene in humans. The type 5 is actually an aldo-keto reductase family 1 member C3 (AKR1C3) encoded by the ''AKR1C3'' gene.<ref name="pmid31900912"/> |The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6 (also abbreviated as RL-HSD), HSD17B10, RDH16, RDH5, and DHRS9).<ref name="pmid15519890"/><ref name="pmid31900912"/><ref name="pmid31611378"/><ref name="pmid20613954"/> It is a reverse oxidative step not required in the canonical pathway.}} Therefore, the pathway can be outlined as follows:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21030877">{{cite journal| title = "Getting from here to there"--mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer | journal = Journal of Investigative Medicine : The Official Publication of the American Federation for Clinical Research | volume = 58 | issue = 8 | pages = 938–44 | doi = 10.2310/JIM.0b013e3181ff6bb8 | pmid = 21030877 | pmc = 5589138| last1 = Sharifi | first1 = Nima | last2 = McPhaul | first2 = Michael J. | last3 = Auchus | first3 = Richard J. | year = 2010 }}</ref><ref name="pmid23073980"/><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref><ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref>}} ====5α-reduction of Progesterone==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and has been confirmed first in mice<ref name="pmid15249131"/> and later in humans.<ref name="pmid30763313"/> Therefore, this pathway also essential for normal masculinization.<ref name="pmid21802064"/><ref name="pmid23073980"/> In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1, and, probably, SRD5A2.<ref name="pmid23073980"/><ref name="pmid28774496"/><ref name="pmid32593151">{{cite journal |vauthors=du Toit T, van Rooyen D, Stander MA, Atkin SL, Swart AC |title=Analysis of 52 C19 and C21 steroids by UPC2-MS/MS: Characterising the C11-oxy steroid metabolome in serum |journal=J Chromatogr B Analyt Technol Biomed Life Sci |volume=1152 |issue= |pages=122243 |date=September 2020 |pmid=32593151 |doi=10.1016/j.jchromb.2020.122243 |url=}}</ref> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. Then this metabolic pathway proceeds to DHT the same way as the pathway that started with 17-OHP.<ref name="pmid30763313"/> Therefore, the pathway can be outlined as follows:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21802064"/><ref name="pmid23073980"/>}} === 5α-Dione Pathway === The pathway of A4 converted to androstanedione (5α-dione), and then to DHT (Figure 2) roundabout of T is unlikely to happen in sufficient quantities to have biological relevance in healthy humans. However, this pathway is relevant in CRPC.<ref name="pmid21795608"/> This pathway contains of two main steps: {{ordered list |The SRD5A1 enzyme 5α-reduces A4 to 5α-dione (also known as 5α-androstane-3,17-dione); |The HSD17B3 or AKR1C3 enzyme 17β-reduces 5α-dione to DHT.}} In this pathway, 5α-dione can also be interconverted with AST, which can also be converted to 3α-diol, which, in turn, can be converted to DHT by a number of dehydrogenases.<ref name="pmid11514561"/><ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> It should also be taken into consideration that the conversions of 5α-dione to AST and the conversion of DHT to 3α-diol are commonly considered inactivation reactions, but because these reactions are reversible, 3α-diol and AST may serve as a pool of inactive androgens and potential substrates for DHT. So, the alternative pathway that starts from A4 roundabout of T, called the "5α-dione" pathway, can be simplistically outlined as follows:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965"/><ref name="pmid12915666"/><ref name="pmid15774560"/><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. Instead, SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> In addition, 11-oxygenated androgens may also play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid31900912"/><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors to potent androgens,<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref> i.e., the conversion of circulating 11-oxygenated androgen precursors.<ref name="pmid33974560" /> In addition, 11KT levels are not affected by castration, thus making 11KT the most abundant active androgen in circulation. In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> The full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT are both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} jlpm7k6t7uo13hrtp4h41x9zxlmbbd9 2408024 2408000 2022-07-19T15:12:21Z Maxim Masiutin 2902665 /* Castration-Resistant Prostate Cancer */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313" /><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == === Backdoor Pathways to 5α-Dihydrotestosterone === [[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]]In canonical androgen steroidogenesis, the 5α-reductases type 2 and 3 catalyze the transformation of T to DHT in the terminal step. However, in the initial step into the androgen backdoor pathways to DHT, 5α-reductases type 1 and 2<ref name="pmid28774496"/><ref name="pmid31626910"/> reduce a pregnane — 17-OHP or P4 — which is ultimately converted to DHT. Therefore, while 5α-reduction of a steroid is the last transformation in the canonical pathway, it is the first step in a backdoor pathway. These backdoor pathways are activated during normal prenatal development and lead to early male sexual differentiation in humans and other mammals.<ref name="pmid15249131" /><ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid23073980" /> ====5α-Reduction of 17α-Hydroxyprogesterone ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The pathway from 17-OHP to DHT may take place in steroidogenic tissues when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are simultaneously expressed.<ref name="pmid30763313" /><ref name="pmid25379460">{{cite journal |title=Steroid hormone synthetic pathways in prostate cancer |journal=Transl Androl Urol |volume=2 |issue=3 |pages=212–227 |date=September 2013 |pmid=25379460 |pmc=4219921 |doi=10.3978/j.issn.2223-4683.2013.09.16}}</ref> The pathway consists of five steps:{{ordered list |The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione catalyzed by 5α-reductase type 1 (SRD5A1) and 2 (SRD5A2).<ref name="pmid1527072">{{cite journal|last1=Normington|first1=K.|last2=Russell|first2=D. W.|title=Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions|journal=The Journal of Biological Chemistry|year=1992 |volume=267|issue=27|pages=19548–19554|doi=10.1016/S0021-9258(18)41809-1 |issn=0021-9258|pmid=1527072|doi-access=free }}</ref><ref name="pmid22170725"/><ref name="pmid14522586">{{cite journal |title=5alpha-reduced C21 steroids are substrates for human cytochrome P450c17 |journal=Arch Biochem Biophys |volume=418 |issue=2 |pages=151–60 |pmid=14522586 |doi=10.1016/j.abb.2003.07.003|last1=Gupta |first1=Manisha K. |last2=Guryev |first2=Oleg L. |last3=Auchus |first3=Richard J. |year=2003 }}</ref> Since 17-OHP is a poor substrate for CYP17A1,<ref name="pmid9452426"/><ref name="pmid32007561"/> the 5α-reductase conversion of 17-OHP by SRD5A1/SRD5A2<ref name="pmid28774496"/><ref name="pmid31626910"/> will proceed efficiently to 17-OH-DHP via the backdoor pathway, rather than the 17,20-lyase conversion by CYP17A1 to A4 via the Δ⁴ pathway, resulting in negligible A4 being produced from 17-OHP.<ref name="pmid8325965">{{cite journal |title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase |journal=J Clin Endocrinol Metab |volume=77 |issue=1 |pages=98–102 |year=1993 |pmid=8325965 |doi=10.1210/jcem.77.1.8325965 |last1=Swart |first1=P. |last2=Swart |first2=A. C. |last3=Waterman |first3=M. R. |last4=Estabrook |first4=R. W. |last5=Mason |first5=J. I. }}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism |year=2003|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|year=2005 |volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> In a 2017 study by Barnard et al., 6 hours was enough for the full conversion of 17-OHP to 17-OH-DHP ''in vitro'', albeit the catalytic activity of SRD5A1 was higher than that of SRD5A2.<ref name="pmid28774496"/> Some authors<ref name="pmid23073980"/><ref name="pmid31611378"/> believe that 5α-reduction of 17-OHP appears to be primarily performed by SRD5A1 at least in the human fetus, citing a 1971 study by Frederiksen et al. of rat 5α-reductase activity ''in vitro''.<ref name="pmid4396507">{{cite journal |title=Partial characterization of the nuclear reduced nicotinamide adenine dinucleotide phosphate: delta 4-3-ketosteroid 5 alpha-oxidoreductase of rat prostate |journal=J Biol Chem |volume=246 |issue=8 |pages=2584–93|year=1971 |pmid=4396507|last1=Frederiksen |first1=D. W. |last2=Wilson |first2=J. D. |doi=10.1016/S0021-9258(18)62328-2 |doi-access=free }}</ref> However, these 1971 results were not confirmed by later studies, let alone in humans. Quite contrary, a 2017 study by Barnard et al. showed that both human isozymes were very efficient in converting 17-OHP to 17-OH-DHP.<ref name="pmid28774496" /> Both isozymes are expressed in the following fetal tissues of both sexes: adrenal gland, genital skin, and gonads.<ref name="pmid7488021">{{cite journal |title=Expression of the type 1 and 2 steroid 5 alpha-reductases in human fetal tissues |journal=Biochem Biophys Res Commun |year=1995 |volume=215 |issue=2 |pages=774–80 |pmid=7488021 |doi=10.1006/bbrc.1995.2530 |last1=Ellsworth |first1=K. |last2=Harris |first2=G. }}</ref><ref name="pmid17574609">{{cite journal |title=Fetal distribution of 5alpha-reductase 1 and 5alpha-reductase 2, and their input on human prostate development |journal=J Urol |volume=178 |issue=2 |pages=716–21 |year=2007 |pmid=17574609 |doi=10.1016/j.juro.2007.03.089 |last1=Lunacek |first1=A. |last2=Schwentner |first2=C. |last3=Oswald |first3=J. |last4=Fritsch |first4=H. |last5=Sergi |first5=C. |last6=Thomas |first6=L.N. |last7=Rittmaster |first7=R.S. |last8=Klocker |first8=H. |last9=Neuwirt |first9=H. |last10=Bartsch |first10=G. |last11=Radmayr |first11=C. }}</ref><ref name="pmid30763313"/><ref name="pmid31611378"/> Hence, it is not yet proven ''in vivo'' which of the isozymes takes part in 5α-reduction of 17-OHP in each and every case and condition.<ref name="pmid22170725"/><ref name="pmid28774496"/><ref name="pmid23073980"/> |17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4)<ref name="pmid30763313"/><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has the 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. |5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen).<ref name="pmid22170725"/><ref name="pmid30763313">{{cite journal | last1=O'Shaughnessy | first1=Peter J. | last2=Antignac | first2=Jean Philippe | last3=Le Bizec | first3=Bruno | last4=Morvan | first4=Marie-Line | last5=Svechnikov | first5=Konstantin | last6=Söder | first6=Olle | last7=Savchuk | first7=Iuliia | last8=Monteiro | first8=Ana | last9=Soffientini | first9=Ugo | last10=Johnston | first10=Zoe C. | last11=Bellingham | first11=Michelle | last12=Hough | first12=Denise | last13=Walker | first13=Natasha | last14=Filis | first14=Panagiotis | last15=Fowler | first15=Paul A. | editor-last1=Rawlins | editor-first1=Emma | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | year=2019 | volume = 17 | issue = 2 | pages = e3000002 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002}}</ref><ref name="pmid20613954">{{cite journal |last1=Auchus |first1=Richard J. |title=Management of the Adult with Congenital Adrenal Hyperplasia |journal=International Journal of Pediatric Endocrinology |year=2010 |volume=2010 |page=614107 |doi=10.1155/2010/614107 |pmid=20613954 |pmc=2896848 |doi-access=free }}</ref><ref name="pmid23073980">{{cite journal| title = Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development | journal = Developmental Dynamics | volume = 242 | issue = 4 | pages = 320–9 | pmid = 23073980 | doi = 10.1002/dvdy.23892| s2cid = 44702659 | last1 = Fukami | first1 = Maki | last2 = Homma | first2 = Keiko | last3 = Hasegawa | first3 = Tomonobu | last4 = Ogata | first4 = Tsutomu | year = 2013 }}</ref> |AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5. Type 3 (HSD17B3) is encoded by the ''HSD17B3'' gene in humans. The type 5 is actually an aldo-keto reductase family 1 member C3 (AKR1C3) encoded by the ''AKR1C3'' gene.<ref name="pmid31900912"/> |The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6 (also abbreviated as RL-HSD), HSD17B10, RDH16, RDH5, and DHRS9).<ref name="pmid15519890"/><ref name="pmid31900912"/><ref name="pmid31611378"/><ref name="pmid20613954"/> It is a reverse oxidative step not required in the canonical pathway.}} Therefore, the pathway can be outlined as follows:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21030877">{{cite journal| title = "Getting from here to there"--mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer | journal = Journal of Investigative Medicine : The Official Publication of the American Federation for Clinical Research | volume = 58 | issue = 8 | pages = 938–44 | doi = 10.2310/JIM.0b013e3181ff6bb8 | pmid = 21030877 | pmc = 5589138| last1 = Sharifi | first1 = Nima | last2 = McPhaul | first2 = Michael J. | last3 = Auchus | first3 = Richard J. | year = 2010 }}</ref><ref name="pmid23073980"/><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref><ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref>}} ====5α-reduction of Progesterone==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and has been confirmed first in mice<ref name="pmid15249131"/> and later in humans.<ref name="pmid30763313"/> Therefore, this pathway also essential for normal masculinization.<ref name="pmid21802064"/><ref name="pmid23073980"/> In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1, and, probably, SRD5A2.<ref name="pmid23073980"/><ref name="pmid28774496"/><ref name="pmid32593151">{{cite journal |vauthors=du Toit T, van Rooyen D, Stander MA, Atkin SL, Swart AC |title=Analysis of 52 C19 and C21 steroids by UPC2-MS/MS: Characterising the C11-oxy steroid metabolome in serum |journal=J Chromatogr B Analyt Technol Biomed Life Sci |volume=1152 |issue= |pages=122243 |date=September 2020 |pmid=32593151 |doi=10.1016/j.jchromb.2020.122243 |url=}}</ref> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. Then this metabolic pathway proceeds to DHT the same way as the pathway that started with 17-OHP.<ref name="pmid30763313"/> Therefore, the pathway can be outlined as follows:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21802064"/><ref name="pmid23073980"/>}} === 5α-Dione Pathway === The pathway of A4 converted to androstanedione (5α-dione), and then to DHT (Figure 2) roundabout of T is unlikely to happen in sufficient quantities to have biological relevance in healthy humans. However, this pathway is relevant in CRPC.<ref name="pmid21795608"/> This pathway contains of two main steps: {{ordered list |The SRD5A1 enzyme 5α-reduces A4 to 5α-dione (also known as 5α-androstane-3,17-dione); |The HSD17B3 or AKR1C3 enzyme 17β-reduces 5α-dione to DHT.}} In this pathway, 5α-dione can also be interconverted with AST, which can also be converted to 3α-diol, which, in turn, can be converted to DHT by a number of dehydrogenases.<ref name="pmid11514561"/><ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> It should also be taken into consideration that the conversions of 5α-dione to AST and the conversion of DHT to 3α-diol are commonly considered inactivation reactions, but because these reactions are reversible, 3α-diol and AST may serve as a pool of inactive androgens and potential substrates for DHT. So, the alternative pathway that starts from A4 roundabout of T, called the "5α-dione" pathway, can be simplistically outlined as follows:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965"/><ref name="pmid12915666"/><ref name="pmid15774560"/><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> In addition, 11-oxygenated androgens may also play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid31900912"/><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors to potent androgens,<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref> i.e., the conversion of circulating 11-oxygenated androgen precursors.<ref name="pmid33974560" /> In addition, 11KT levels are not affected by castration, thus making 11KT the most abundant active androgen in circulation. In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> The full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT are both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} f5f7tdrvi6tp0qbv7puv8y5q6x5rchc 2408025 2408024 2022-07-19T15:14:04Z Maxim Masiutin 2902665 /* Castration-Resistant Prostate Cancer */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313" /><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == === Backdoor Pathways to 5α-Dihydrotestosterone === [[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]]In canonical androgen steroidogenesis, the 5α-reductases type 2 and 3 catalyze the transformation of T to DHT in the terminal step. However, in the initial step into the androgen backdoor pathways to DHT, 5α-reductases type 1 and 2<ref name="pmid28774496"/><ref name="pmid31626910"/> reduce a pregnane — 17-OHP or P4 — which is ultimately converted to DHT. Therefore, while 5α-reduction of a steroid is the last transformation in the canonical pathway, it is the first step in a backdoor pathway. These backdoor pathways are activated during normal prenatal development and lead to early male sexual differentiation in humans and other mammals.<ref name="pmid15249131" /><ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid23073980" /> ====5α-Reduction of 17α-Hydroxyprogesterone ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The pathway from 17-OHP to DHT may take place in steroidogenic tissues when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are simultaneously expressed.<ref name="pmid30763313" /><ref name="pmid25379460">{{cite journal |title=Steroid hormone synthetic pathways in prostate cancer |journal=Transl Androl Urol |volume=2 |issue=3 |pages=212–227 |date=September 2013 |pmid=25379460 |pmc=4219921 |doi=10.3978/j.issn.2223-4683.2013.09.16}}</ref> The pathway consists of five steps:{{ordered list |The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione catalyzed by 5α-reductase type 1 (SRD5A1) and 2 (SRD5A2).<ref name="pmid1527072">{{cite journal|last1=Normington|first1=K.|last2=Russell|first2=D. W.|title=Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions|journal=The Journal of Biological Chemistry|year=1992 |volume=267|issue=27|pages=19548–19554|doi=10.1016/S0021-9258(18)41809-1 |issn=0021-9258|pmid=1527072|doi-access=free }}</ref><ref name="pmid22170725"/><ref name="pmid14522586">{{cite journal |title=5alpha-reduced C21 steroids are substrates for human cytochrome P450c17 |journal=Arch Biochem Biophys |volume=418 |issue=2 |pages=151–60 |pmid=14522586 |doi=10.1016/j.abb.2003.07.003|last1=Gupta |first1=Manisha K. |last2=Guryev |first2=Oleg L. |last3=Auchus |first3=Richard J. |year=2003 }}</ref> Since 17-OHP is a poor substrate for CYP17A1,<ref name="pmid9452426"/><ref name="pmid32007561"/> the 5α-reductase conversion of 17-OHP by SRD5A1/SRD5A2<ref name="pmid28774496"/><ref name="pmid31626910"/> will proceed efficiently to 17-OH-DHP via the backdoor pathway, rather than the 17,20-lyase conversion by CYP17A1 to A4 via the Δ⁴ pathway, resulting in negligible A4 being produced from 17-OHP.<ref name="pmid8325965">{{cite journal |title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase |journal=J Clin Endocrinol Metab |volume=77 |issue=1 |pages=98–102 |year=1993 |pmid=8325965 |doi=10.1210/jcem.77.1.8325965 |last1=Swart |first1=P. |last2=Swart |first2=A. C. |last3=Waterman |first3=M. R. |last4=Estabrook |first4=R. W. |last5=Mason |first5=J. I. }}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism |year=2003|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|year=2005 |volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> In a 2017 study by Barnard et al., 6 hours was enough for the full conversion of 17-OHP to 17-OH-DHP ''in vitro'', albeit the catalytic activity of SRD5A1 was higher than that of SRD5A2.<ref name="pmid28774496"/> Some authors<ref name="pmid23073980"/><ref name="pmid31611378"/> believe that 5α-reduction of 17-OHP appears to be primarily performed by SRD5A1 at least in the human fetus, citing a 1971 study by Frederiksen et al. of rat 5α-reductase activity ''in vitro''.<ref name="pmid4396507">{{cite journal |title=Partial characterization of the nuclear reduced nicotinamide adenine dinucleotide phosphate: delta 4-3-ketosteroid 5 alpha-oxidoreductase of rat prostate |journal=J Biol Chem |volume=246 |issue=8 |pages=2584–93|year=1971 |pmid=4396507|last1=Frederiksen |first1=D. W. |last2=Wilson |first2=J. D. |doi=10.1016/S0021-9258(18)62328-2 |doi-access=free }}</ref> However, these 1971 results were not confirmed by later studies, let alone in humans. Quite contrary, a 2017 study by Barnard et al. showed that both human isozymes were very efficient in converting 17-OHP to 17-OH-DHP.<ref name="pmid28774496" /> Both isozymes are expressed in the following fetal tissues of both sexes: adrenal gland, genital skin, and gonads.<ref name="pmid7488021">{{cite journal |title=Expression of the type 1 and 2 steroid 5 alpha-reductases in human fetal tissues |journal=Biochem Biophys Res Commun |year=1995 |volume=215 |issue=2 |pages=774–80 |pmid=7488021 |doi=10.1006/bbrc.1995.2530 |last1=Ellsworth |first1=K. |last2=Harris |first2=G. }}</ref><ref name="pmid17574609">{{cite journal |title=Fetal distribution of 5alpha-reductase 1 and 5alpha-reductase 2, and their input on human prostate development |journal=J Urol |volume=178 |issue=2 |pages=716–21 |year=2007 |pmid=17574609 |doi=10.1016/j.juro.2007.03.089 |last1=Lunacek |first1=A. |last2=Schwentner |first2=C. |last3=Oswald |first3=J. |last4=Fritsch |first4=H. |last5=Sergi |first5=C. |last6=Thomas |first6=L.N. |last7=Rittmaster |first7=R.S. |last8=Klocker |first8=H. |last9=Neuwirt |first9=H. |last10=Bartsch |first10=G. |last11=Radmayr |first11=C. }}</ref><ref name="pmid30763313"/><ref name="pmid31611378"/> Hence, it is not yet proven ''in vivo'' which of the isozymes takes part in 5α-reduction of 17-OHP in each and every case and condition.<ref name="pmid22170725"/><ref name="pmid28774496"/><ref name="pmid23073980"/> |17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4)<ref name="pmid30763313"/><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has the 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. |5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen).<ref name="pmid22170725"/><ref name="pmid30763313">{{cite journal | last1=O'Shaughnessy | first1=Peter J. | last2=Antignac | first2=Jean Philippe | last3=Le Bizec | first3=Bruno | last4=Morvan | first4=Marie-Line | last5=Svechnikov | first5=Konstantin | last6=Söder | first6=Olle | last7=Savchuk | first7=Iuliia | last8=Monteiro | first8=Ana | last9=Soffientini | first9=Ugo | last10=Johnston | first10=Zoe C. | last11=Bellingham | first11=Michelle | last12=Hough | first12=Denise | last13=Walker | first13=Natasha | last14=Filis | first14=Panagiotis | last15=Fowler | first15=Paul A. | editor-last1=Rawlins | editor-first1=Emma | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | year=2019 | volume = 17 | issue = 2 | pages = e3000002 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002}}</ref><ref name="pmid20613954">{{cite journal |last1=Auchus |first1=Richard J. |title=Management of the Adult with Congenital Adrenal Hyperplasia |journal=International Journal of Pediatric Endocrinology |year=2010 |volume=2010 |page=614107 |doi=10.1155/2010/614107 |pmid=20613954 |pmc=2896848 |doi-access=free }}</ref><ref name="pmid23073980">{{cite journal| title = Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development | journal = Developmental Dynamics | volume = 242 | issue = 4 | pages = 320–9 | pmid = 23073980 | doi = 10.1002/dvdy.23892| s2cid = 44702659 | last1 = Fukami | first1 = Maki | last2 = Homma | first2 = Keiko | last3 = Hasegawa | first3 = Tomonobu | last4 = Ogata | first4 = Tsutomu | year = 2013 }}</ref> |AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5. Type 3 (HSD17B3) is encoded by the ''HSD17B3'' gene in humans. The type 5 is actually an aldo-keto reductase family 1 member C3 (AKR1C3) encoded by the ''AKR1C3'' gene.<ref name="pmid31900912"/> |The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6 (also abbreviated as RL-HSD), HSD17B10, RDH16, RDH5, and DHRS9).<ref name="pmid15519890"/><ref name="pmid31900912"/><ref name="pmid31611378"/><ref name="pmid20613954"/> It is a reverse oxidative step not required in the canonical pathway.}} Therefore, the pathway can be outlined as follows:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21030877">{{cite journal| title = "Getting from here to there"--mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer | journal = Journal of Investigative Medicine : The Official Publication of the American Federation for Clinical Research | volume = 58 | issue = 8 | pages = 938–44 | doi = 10.2310/JIM.0b013e3181ff6bb8 | pmid = 21030877 | pmc = 5589138| last1 = Sharifi | first1 = Nima | last2 = McPhaul | first2 = Michael J. | last3 = Auchus | first3 = Richard J. | year = 2010 }}</ref><ref name="pmid23073980"/><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref><ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref>}} ====5α-reduction of Progesterone==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and has been confirmed first in mice<ref name="pmid15249131"/> and later in humans.<ref name="pmid30763313"/> Therefore, this pathway also essential for normal masculinization.<ref name="pmid21802064"/><ref name="pmid23073980"/> In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1, and, probably, SRD5A2.<ref name="pmid23073980"/><ref name="pmid28774496"/><ref name="pmid32593151">{{cite journal |vauthors=du Toit T, van Rooyen D, Stander MA, Atkin SL, Swart AC |title=Analysis of 52 C19 and C21 steroids by UPC2-MS/MS: Characterising the C11-oxy steroid metabolome in serum |journal=J Chromatogr B Analyt Technol Biomed Life Sci |volume=1152 |issue= |pages=122243 |date=September 2020 |pmid=32593151 |doi=10.1016/j.jchromb.2020.122243 |url=}}</ref> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. Then this metabolic pathway proceeds to DHT the same way as the pathway that started with 17-OHP.<ref name="pmid30763313"/> Therefore, the pathway can be outlined as follows:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21802064"/><ref name="pmid23073980"/>}} === 5α-Dione Pathway === The pathway of A4 converted to androstanedione (5α-dione), and then to DHT (Figure 2) roundabout of T is unlikely to happen in sufficient quantities to have biological relevance in healthy humans. However, this pathway is relevant in CRPC.<ref name="pmid21795608"/> This pathway contains of two main steps: {{ordered list |The SRD5A1 enzyme 5α-reduces A4 to 5α-dione (also known as 5α-androstane-3,17-dione); |The HSD17B3 or AKR1C3 enzyme 17β-reduces 5α-dione to DHT.}} In this pathway, 5α-dione can also be interconverted with AST, which can also be converted to 3α-diol, which, in turn, can be converted to DHT by a number of dehydrogenases.<ref name="pmid11514561"/><ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> It should also be taken into consideration that the conversions of 5α-dione to AST and the conversion of DHT to 3α-diol are commonly considered inactivation reactions, but because these reactions are reversible, 3α-diol and AST may serve as a pool of inactive androgens and potential substrates for DHT. So, the alternative pathway that starts from A4 roundabout of T, called the "5α-dione" pathway, can be simplistically outlined as follows:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965"/><ref name="pmid12915666"/><ref name="pmid15774560"/><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens may also play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid31900912"/><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors to potent androgens,<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref> i.e., the conversion of circulating 11-oxygenated androgen precursors.<ref name="pmid33974560" /> In addition, 11KT levels are not affected by castration, thus making 11KT the most abundant active androgen in circulation. In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> The full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT are both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} lnc3tsmx6qs2cxgt7zw8pcy0tm40wx4 2408026 2408025 2022-07-19T15:14:47Z Maxim Masiutin 2902665 /* Castration-Resistant Prostate Cancer */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313" /><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == === Backdoor Pathways to 5α-Dihydrotestosterone === [[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]]In canonical androgen steroidogenesis, the 5α-reductases type 2 and 3 catalyze the transformation of T to DHT in the terminal step. However, in the initial step into the androgen backdoor pathways to DHT, 5α-reductases type 1 and 2<ref name="pmid28774496"/><ref name="pmid31626910"/> reduce a pregnane — 17-OHP or P4 — which is ultimately converted to DHT. Therefore, while 5α-reduction of a steroid is the last transformation in the canonical pathway, it is the first step in a backdoor pathway. These backdoor pathways are activated during normal prenatal development and lead to early male sexual differentiation in humans and other mammals.<ref name="pmid15249131" /><ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid23073980" /> ====5α-Reduction of 17α-Hydroxyprogesterone ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The pathway from 17-OHP to DHT may take place in steroidogenic tissues when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are simultaneously expressed.<ref name="pmid30763313" /><ref name="pmid25379460">{{cite journal |title=Steroid hormone synthetic pathways in prostate cancer |journal=Transl Androl Urol |volume=2 |issue=3 |pages=212–227 |date=September 2013 |pmid=25379460 |pmc=4219921 |doi=10.3978/j.issn.2223-4683.2013.09.16}}</ref> The pathway consists of five steps:{{ordered list |The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione catalyzed by 5α-reductase type 1 (SRD5A1) and 2 (SRD5A2).<ref name="pmid1527072">{{cite journal|last1=Normington|first1=K.|last2=Russell|first2=D. W.|title=Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions|journal=The Journal of Biological Chemistry|year=1992 |volume=267|issue=27|pages=19548–19554|doi=10.1016/S0021-9258(18)41809-1 |issn=0021-9258|pmid=1527072|doi-access=free }}</ref><ref name="pmid22170725"/><ref name="pmid14522586">{{cite journal |title=5alpha-reduced C21 steroids are substrates for human cytochrome P450c17 |journal=Arch Biochem Biophys |volume=418 |issue=2 |pages=151–60 |pmid=14522586 |doi=10.1016/j.abb.2003.07.003|last1=Gupta |first1=Manisha K. |last2=Guryev |first2=Oleg L. |last3=Auchus |first3=Richard J. |year=2003 }}</ref> Since 17-OHP is a poor substrate for CYP17A1,<ref name="pmid9452426"/><ref name="pmid32007561"/> the 5α-reductase conversion of 17-OHP by SRD5A1/SRD5A2<ref name="pmid28774496"/><ref name="pmid31626910"/> will proceed efficiently to 17-OH-DHP via the backdoor pathway, rather than the 17,20-lyase conversion by CYP17A1 to A4 via the Δ⁴ pathway, resulting in negligible A4 being produced from 17-OHP.<ref name="pmid8325965">{{cite journal |title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase |journal=J Clin Endocrinol Metab |volume=77 |issue=1 |pages=98–102 |year=1993 |pmid=8325965 |doi=10.1210/jcem.77.1.8325965 |last1=Swart |first1=P. |last2=Swart |first2=A. C. |last3=Waterman |first3=M. R. |last4=Estabrook |first4=R. W. |last5=Mason |first5=J. I. }}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism |year=2003|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|year=2005 |volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> In a 2017 study by Barnard et al., 6 hours was enough for the full conversion of 17-OHP to 17-OH-DHP ''in vitro'', albeit the catalytic activity of SRD5A1 was higher than that of SRD5A2.<ref name="pmid28774496"/> Some authors<ref name="pmid23073980"/><ref name="pmid31611378"/> believe that 5α-reduction of 17-OHP appears to be primarily performed by SRD5A1 at least in the human fetus, citing a 1971 study by Frederiksen et al. of rat 5α-reductase activity ''in vitro''.<ref name="pmid4396507">{{cite journal |title=Partial characterization of the nuclear reduced nicotinamide adenine dinucleotide phosphate: delta 4-3-ketosteroid 5 alpha-oxidoreductase of rat prostate |journal=J Biol Chem |volume=246 |issue=8 |pages=2584–93|year=1971 |pmid=4396507|last1=Frederiksen |first1=D. W. |last2=Wilson |first2=J. D. |doi=10.1016/S0021-9258(18)62328-2 |doi-access=free }}</ref> However, these 1971 results were not confirmed by later studies, let alone in humans. Quite contrary, a 2017 study by Barnard et al. showed that both human isozymes were very efficient in converting 17-OHP to 17-OH-DHP.<ref name="pmid28774496" /> Both isozymes are expressed in the following fetal tissues of both sexes: adrenal gland, genital skin, and gonads.<ref name="pmid7488021">{{cite journal |title=Expression of the type 1 and 2 steroid 5 alpha-reductases in human fetal tissues |journal=Biochem Biophys Res Commun |year=1995 |volume=215 |issue=2 |pages=774–80 |pmid=7488021 |doi=10.1006/bbrc.1995.2530 |last1=Ellsworth |first1=K. |last2=Harris |first2=G. }}</ref><ref name="pmid17574609">{{cite journal |title=Fetal distribution of 5alpha-reductase 1 and 5alpha-reductase 2, and their input on human prostate development |journal=J Urol |volume=178 |issue=2 |pages=716–21 |year=2007 |pmid=17574609 |doi=10.1016/j.juro.2007.03.089 |last1=Lunacek |first1=A. |last2=Schwentner |first2=C. |last3=Oswald |first3=J. |last4=Fritsch |first4=H. |last5=Sergi |first5=C. |last6=Thomas |first6=L.N. |last7=Rittmaster |first7=R.S. |last8=Klocker |first8=H. |last9=Neuwirt |first9=H. |last10=Bartsch |first10=G. |last11=Radmayr |first11=C. }}</ref><ref name="pmid30763313"/><ref name="pmid31611378"/> Hence, it is not yet proven ''in vivo'' which of the isozymes takes part in 5α-reduction of 17-OHP in each and every case and condition.<ref name="pmid22170725"/><ref name="pmid28774496"/><ref name="pmid23073980"/> |17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4)<ref name="pmid30763313"/><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has the 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. |5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen).<ref name="pmid22170725"/><ref name="pmid30763313">{{cite journal | last1=O'Shaughnessy | first1=Peter J. | last2=Antignac | first2=Jean Philippe | last3=Le Bizec | first3=Bruno | last4=Morvan | first4=Marie-Line | last5=Svechnikov | first5=Konstantin | last6=Söder | first6=Olle | last7=Savchuk | first7=Iuliia | last8=Monteiro | first8=Ana | last9=Soffientini | first9=Ugo | last10=Johnston | first10=Zoe C. | last11=Bellingham | first11=Michelle | last12=Hough | first12=Denise | last13=Walker | first13=Natasha | last14=Filis | first14=Panagiotis | last15=Fowler | first15=Paul A. | editor-last1=Rawlins | editor-first1=Emma | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | year=2019 | volume = 17 | issue = 2 | pages = e3000002 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002}}</ref><ref name="pmid20613954">{{cite journal |last1=Auchus |first1=Richard J. |title=Management of the Adult with Congenital Adrenal Hyperplasia |journal=International Journal of Pediatric Endocrinology |year=2010 |volume=2010 |page=614107 |doi=10.1155/2010/614107 |pmid=20613954 |pmc=2896848 |doi-access=free }}</ref><ref name="pmid23073980">{{cite journal| title = Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development | journal = Developmental Dynamics | volume = 242 | issue = 4 | pages = 320–9 | pmid = 23073980 | doi = 10.1002/dvdy.23892| s2cid = 44702659 | last1 = Fukami | first1 = Maki | last2 = Homma | first2 = Keiko | last3 = Hasegawa | first3 = Tomonobu | last4 = Ogata | first4 = Tsutomu | year = 2013 }}</ref> |AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5. Type 3 (HSD17B3) is encoded by the ''HSD17B3'' gene in humans. The type 5 is actually an aldo-keto reductase family 1 member C3 (AKR1C3) encoded by the ''AKR1C3'' gene.<ref name="pmid31900912"/> |The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6 (also abbreviated as RL-HSD), HSD17B10, RDH16, RDH5, and DHRS9).<ref name="pmid15519890"/><ref name="pmid31900912"/><ref name="pmid31611378"/><ref name="pmid20613954"/> It is a reverse oxidative step not required in the canonical pathway.}} Therefore, the pathway can be outlined as follows:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21030877">{{cite journal| title = "Getting from here to there"--mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer | journal = Journal of Investigative Medicine : The Official Publication of the American Federation for Clinical Research | volume = 58 | issue = 8 | pages = 938–44 | doi = 10.2310/JIM.0b013e3181ff6bb8 | pmid = 21030877 | pmc = 5589138| last1 = Sharifi | first1 = Nima | last2 = McPhaul | first2 = Michael J. | last3 = Auchus | first3 = Richard J. | year = 2010 }}</ref><ref name="pmid23073980"/><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref><ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref>}} ====5α-reduction of Progesterone==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and has been confirmed first in mice<ref name="pmid15249131"/> and later in humans.<ref name="pmid30763313"/> Therefore, this pathway also essential for normal masculinization.<ref name="pmid21802064"/><ref name="pmid23073980"/> In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1, and, probably, SRD5A2.<ref name="pmid23073980"/><ref name="pmid28774496"/><ref name="pmid32593151">{{cite journal |vauthors=du Toit T, van Rooyen D, Stander MA, Atkin SL, Swart AC |title=Analysis of 52 C19 and C21 steroids by UPC2-MS/MS: Characterising the C11-oxy steroid metabolome in serum |journal=J Chromatogr B Analyt Technol Biomed Life Sci |volume=1152 |issue= |pages=122243 |date=September 2020 |pmid=32593151 |doi=10.1016/j.jchromb.2020.122243 |url=}}</ref> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. Then this metabolic pathway proceeds to DHT the same way as the pathway that started with 17-OHP.<ref name="pmid30763313"/> Therefore, the pathway can be outlined as follows:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21802064"/><ref name="pmid23073980"/>}} === 5α-Dione Pathway === The pathway of A4 converted to androstanedione (5α-dione), and then to DHT (Figure 2) roundabout of T is unlikely to happen in sufficient quantities to have biological relevance in healthy humans. However, this pathway is relevant in CRPC.<ref name="pmid21795608"/> This pathway contains of two main steps: {{ordered list |The SRD5A1 enzyme 5α-reduces A4 to 5α-dione (also known as 5α-androstane-3,17-dione); |The HSD17B3 or AKR1C3 enzyme 17β-reduces 5α-dione to DHT.}} In this pathway, 5α-dione can also be interconverted with AST, which can also be converted to 3α-diol, which, in turn, can be converted to DHT by a number of dehydrogenases.<ref name="pmid11514561"/><ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> It should also be taken into consideration that the conversions of 5α-dione to AST and the conversion of DHT to 3α-diol are commonly considered inactivation reactions, but because these reactions are reversible, 3α-diol and AST may serve as a pool of inactive androgens and potential substrates for DHT. So, the alternative pathway that starts from A4 roundabout of T, called the "5α-dione" pathway, can be simplistically outlined as follows:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965"/><ref name="pmid12915666"/><ref name="pmid15774560"/><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid31900912"/><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors to potent androgens,<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref> i.e., the conversion of circulating 11-oxygenated androgen precursors.<ref name="pmid33974560" /> In addition, 11KT levels are not affected by castration, thus making 11KT the most abundant active androgen in circulation. In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> The full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT are both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} 011xvibd0epyumavftt3edhd3qxtxk9 2408028 2408026 2022-07-19T15:25:48Z Maxim Masiutin 2902665 /* Castration-Resistant Prostate Cancer */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313" /><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == === Backdoor Pathways to 5α-Dihydrotestosterone === [[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]]In canonical androgen steroidogenesis, the 5α-reductases type 2 and 3 catalyze the transformation of T to DHT in the terminal step. However, in the initial step into the androgen backdoor pathways to DHT, 5α-reductases type 1 and 2<ref name="pmid28774496"/><ref name="pmid31626910"/> reduce a pregnane — 17-OHP or P4 — which is ultimately converted to DHT. Therefore, while 5α-reduction of a steroid is the last transformation in the canonical pathway, it is the first step in a backdoor pathway. These backdoor pathways are activated during normal prenatal development and lead to early male sexual differentiation in humans and other mammals.<ref name="pmid15249131" /><ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid23073980" /> ====5α-Reduction of 17α-Hydroxyprogesterone ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The pathway from 17-OHP to DHT may take place in steroidogenic tissues when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are simultaneously expressed.<ref name="pmid30763313" /><ref name="pmid25379460">{{cite journal |title=Steroid hormone synthetic pathways in prostate cancer |journal=Transl Androl Urol |volume=2 |issue=3 |pages=212–227 |date=September 2013 |pmid=25379460 |pmc=4219921 |doi=10.3978/j.issn.2223-4683.2013.09.16}}</ref> The pathway consists of five steps:{{ordered list |The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione catalyzed by 5α-reductase type 1 (SRD5A1) and 2 (SRD5A2).<ref name="pmid1527072">{{cite journal|last1=Normington|first1=K.|last2=Russell|first2=D. W.|title=Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions|journal=The Journal of Biological Chemistry|year=1992 |volume=267|issue=27|pages=19548–19554|doi=10.1016/S0021-9258(18)41809-1 |issn=0021-9258|pmid=1527072|doi-access=free }}</ref><ref name="pmid22170725"/><ref name="pmid14522586">{{cite journal |title=5alpha-reduced C21 steroids are substrates for human cytochrome P450c17 |journal=Arch Biochem Biophys |volume=418 |issue=2 |pages=151–60 |pmid=14522586 |doi=10.1016/j.abb.2003.07.003|last1=Gupta |first1=Manisha K. |last2=Guryev |first2=Oleg L. |last3=Auchus |first3=Richard J. |year=2003 }}</ref> Since 17-OHP is a poor substrate for CYP17A1,<ref name="pmid9452426"/><ref name="pmid32007561"/> the 5α-reductase conversion of 17-OHP by SRD5A1/SRD5A2<ref name="pmid28774496"/><ref name="pmid31626910"/> will proceed efficiently to 17-OH-DHP via the backdoor pathway, rather than the 17,20-lyase conversion by CYP17A1 to A4 via the Δ⁴ pathway, resulting in negligible A4 being produced from 17-OHP.<ref name="pmid8325965">{{cite journal |title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase |journal=J Clin Endocrinol Metab |volume=77 |issue=1 |pages=98–102 |year=1993 |pmid=8325965 |doi=10.1210/jcem.77.1.8325965 |last1=Swart |first1=P. |last2=Swart |first2=A. C. |last3=Waterman |first3=M. R. |last4=Estabrook |first4=R. W. |last5=Mason |first5=J. I. }}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism |year=2003|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|year=2005 |volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> In a 2017 study by Barnard et al., 6 hours was enough for the full conversion of 17-OHP to 17-OH-DHP ''in vitro'', albeit the catalytic activity of SRD5A1 was higher than that of SRD5A2.<ref name="pmid28774496"/> Some authors<ref name="pmid23073980"/><ref name="pmid31611378"/> believe that 5α-reduction of 17-OHP appears to be primarily performed by SRD5A1 at least in the human fetus, citing a 1971 study by Frederiksen et al. of rat 5α-reductase activity ''in vitro''.<ref name="pmid4396507">{{cite journal |title=Partial characterization of the nuclear reduced nicotinamide adenine dinucleotide phosphate: delta 4-3-ketosteroid 5 alpha-oxidoreductase of rat prostate |journal=J Biol Chem |volume=246 |issue=8 |pages=2584–93|year=1971 |pmid=4396507|last1=Frederiksen |first1=D. W. |last2=Wilson |first2=J. D. |doi=10.1016/S0021-9258(18)62328-2 |doi-access=free }}</ref> However, these 1971 results were not confirmed by later studies, let alone in humans. Quite contrary, a 2017 study by Barnard et al. showed that both human isozymes were very efficient in converting 17-OHP to 17-OH-DHP.<ref name="pmid28774496" /> Both isozymes are expressed in the following fetal tissues of both sexes: adrenal gland, genital skin, and gonads.<ref name="pmid7488021">{{cite journal |title=Expression of the type 1 and 2 steroid 5 alpha-reductases in human fetal tissues |journal=Biochem Biophys Res Commun |year=1995 |volume=215 |issue=2 |pages=774–80 |pmid=7488021 |doi=10.1006/bbrc.1995.2530 |last1=Ellsworth |first1=K. |last2=Harris |first2=G. }}</ref><ref name="pmid17574609">{{cite journal |title=Fetal distribution of 5alpha-reductase 1 and 5alpha-reductase 2, and their input on human prostate development |journal=J Urol |volume=178 |issue=2 |pages=716–21 |year=2007 |pmid=17574609 |doi=10.1016/j.juro.2007.03.089 |last1=Lunacek |first1=A. |last2=Schwentner |first2=C. |last3=Oswald |first3=J. |last4=Fritsch |first4=H. |last5=Sergi |first5=C. |last6=Thomas |first6=L.N. |last7=Rittmaster |first7=R.S. |last8=Klocker |first8=H. |last9=Neuwirt |first9=H. |last10=Bartsch |first10=G. |last11=Radmayr |first11=C. }}</ref><ref name="pmid30763313"/><ref name="pmid31611378"/> Hence, it is not yet proven ''in vivo'' which of the isozymes takes part in 5α-reduction of 17-OHP in each and every case and condition.<ref name="pmid22170725"/><ref name="pmid28774496"/><ref name="pmid23073980"/> |17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4)<ref name="pmid30763313"/><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has the 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. |5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen).<ref name="pmid22170725"/><ref name="pmid30763313">{{cite journal | last1=O'Shaughnessy | first1=Peter J. | last2=Antignac | first2=Jean Philippe | last3=Le Bizec | first3=Bruno | last4=Morvan | first4=Marie-Line | last5=Svechnikov | first5=Konstantin | last6=Söder | first6=Olle | last7=Savchuk | first7=Iuliia | last8=Monteiro | first8=Ana | last9=Soffientini | first9=Ugo | last10=Johnston | first10=Zoe C. | last11=Bellingham | first11=Michelle | last12=Hough | first12=Denise | last13=Walker | first13=Natasha | last14=Filis | first14=Panagiotis | last15=Fowler | first15=Paul A. | editor-last1=Rawlins | editor-first1=Emma | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | year=2019 | volume = 17 | issue = 2 | pages = e3000002 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002}}</ref><ref name="pmid20613954">{{cite journal |last1=Auchus |first1=Richard J. |title=Management of the Adult with Congenital Adrenal Hyperplasia |journal=International Journal of Pediatric Endocrinology |year=2010 |volume=2010 |page=614107 |doi=10.1155/2010/614107 |pmid=20613954 |pmc=2896848 |doi-access=free }}</ref><ref name="pmid23073980">{{cite journal| title = Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development | journal = Developmental Dynamics | volume = 242 | issue = 4 | pages = 320–9 | pmid = 23073980 | doi = 10.1002/dvdy.23892| s2cid = 44702659 | last1 = Fukami | first1 = Maki | last2 = Homma | first2 = Keiko | last3 = Hasegawa | first3 = Tomonobu | last4 = Ogata | first4 = Tsutomu | year = 2013 }}</ref> |AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5. Type 3 (HSD17B3) is encoded by the ''HSD17B3'' gene in humans. The type 5 is actually an aldo-keto reductase family 1 member C3 (AKR1C3) encoded by the ''AKR1C3'' gene.<ref name="pmid31900912"/> |The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6 (also abbreviated as RL-HSD), HSD17B10, RDH16, RDH5, and DHRS9).<ref name="pmid15519890"/><ref name="pmid31900912"/><ref name="pmid31611378"/><ref name="pmid20613954"/> It is a reverse oxidative step not required in the canonical pathway.}} Therefore, the pathway can be outlined as follows:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21030877">{{cite journal| title = "Getting from here to there"--mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer | journal = Journal of Investigative Medicine : The Official Publication of the American Federation for Clinical Research | volume = 58 | issue = 8 | pages = 938–44 | doi = 10.2310/JIM.0b013e3181ff6bb8 | pmid = 21030877 | pmc = 5589138| last1 = Sharifi | first1 = Nima | last2 = McPhaul | first2 = Michael J. | last3 = Auchus | first3 = Richard J. | year = 2010 }}</ref><ref name="pmid23073980"/><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref><ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref>}} ====5α-reduction of Progesterone==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and has been confirmed first in mice<ref name="pmid15249131"/> and later in humans.<ref name="pmid30763313"/> Therefore, this pathway also essential for normal masculinization.<ref name="pmid21802064"/><ref name="pmid23073980"/> In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1, and, probably, SRD5A2.<ref name="pmid23073980"/><ref name="pmid28774496"/><ref name="pmid32593151">{{cite journal |vauthors=du Toit T, van Rooyen D, Stander MA, Atkin SL, Swart AC |title=Analysis of 52 C19 and C21 steroids by UPC2-MS/MS: Characterising the C11-oxy steroid metabolome in serum |journal=J Chromatogr B Analyt Technol Biomed Life Sci |volume=1152 |issue= |pages=122243 |date=September 2020 |pmid=32593151 |doi=10.1016/j.jchromb.2020.122243 |url=}}</ref> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. Then this metabolic pathway proceeds to DHT the same way as the pathway that started with 17-OHP.<ref name="pmid30763313"/> Therefore, the pathway can be outlined as follows:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21802064"/><ref name="pmid23073980"/>}} === 5α-Dione Pathway === The pathway of A4 converted to androstanedione (5α-dione), and then to DHT (Figure 2) roundabout of T is unlikely to happen in sufficient quantities to have biological relevance in healthy humans. However, this pathway is relevant in CRPC.<ref name="pmid21795608"/> This pathway contains of two main steps: {{ordered list |The SRD5A1 enzyme 5α-reduces A4 to 5α-dione (also known as 5α-androstane-3,17-dione); |The HSD17B3 or AKR1C3 enzyme 17β-reduces 5α-dione to DHT.}} In this pathway, 5α-dione can also be interconverted with AST, which can also be converted to 3α-diol, which, in turn, can be converted to DHT by a number of dehydrogenases.<ref name="pmid11514561"/><ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> It should also be taken into consideration that the conversions of 5α-dione to AST and the conversion of DHT to 3α-diol are commonly considered inactivation reactions, but because these reactions are reversible, 3α-diol and AST may serve as a pool of inactive androgens and potential substrates for DHT. So, the alternative pathway that starts from A4 roundabout of T, called the "5α-dione" pathway, can be simplistically outlined as follows:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965"/><ref name="pmid12915666"/><ref name="pmid15774560"/><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid31900912"/><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> The full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT are both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} cdllwyxv1in49858225y2csvojlei0a 2408029 2408028 2022-07-19T15:30:16Z Maxim Masiutin 2902665 /* Castration-Resistant Prostate Cancer */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313" /><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == === Backdoor Pathways to 5α-Dihydrotestosterone === [[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]]In canonical androgen steroidogenesis, the 5α-reductases type 2 and 3 catalyze the transformation of T to DHT in the terminal step. However, in the initial step into the androgen backdoor pathways to DHT, 5α-reductases type 1 and 2<ref name="pmid28774496"/><ref name="pmid31626910"/> reduce a pregnane — 17-OHP or P4 — which is ultimately converted to DHT. Therefore, while 5α-reduction of a steroid is the last transformation in the canonical pathway, it is the first step in a backdoor pathway. These backdoor pathways are activated during normal prenatal development and lead to early male sexual differentiation in humans and other mammals.<ref name="pmid15249131" /><ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid23073980" /> ====5α-Reduction of 17α-Hydroxyprogesterone ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The pathway from 17-OHP to DHT may take place in steroidogenic tissues when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are simultaneously expressed.<ref name="pmid30763313" /><ref name="pmid25379460">{{cite journal |title=Steroid hormone synthetic pathways in prostate cancer |journal=Transl Androl Urol |volume=2 |issue=3 |pages=212–227 |date=September 2013 |pmid=25379460 |pmc=4219921 |doi=10.3978/j.issn.2223-4683.2013.09.16}}</ref> The pathway consists of five steps:{{ordered list |The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione catalyzed by 5α-reductase type 1 (SRD5A1) and 2 (SRD5A2).<ref name="pmid1527072">{{cite journal|last1=Normington|first1=K.|last2=Russell|first2=D. W.|title=Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions|journal=The Journal of Biological Chemistry|year=1992 |volume=267|issue=27|pages=19548–19554|doi=10.1016/S0021-9258(18)41809-1 |issn=0021-9258|pmid=1527072|doi-access=free }}</ref><ref name="pmid22170725"/><ref name="pmid14522586">{{cite journal |title=5alpha-reduced C21 steroids are substrates for human cytochrome P450c17 |journal=Arch Biochem Biophys |volume=418 |issue=2 |pages=151–60 |pmid=14522586 |doi=10.1016/j.abb.2003.07.003|last1=Gupta |first1=Manisha K. |last2=Guryev |first2=Oleg L. |last3=Auchus |first3=Richard J. |year=2003 }}</ref> Since 17-OHP is a poor substrate for CYP17A1,<ref name="pmid9452426"/><ref name="pmid32007561"/> the 5α-reductase conversion of 17-OHP by SRD5A1/SRD5A2<ref name="pmid28774496"/><ref name="pmid31626910"/> will proceed efficiently to 17-OH-DHP via the backdoor pathway, rather than the 17,20-lyase conversion by CYP17A1 to A4 via the Δ⁴ pathway, resulting in negligible A4 being produced from 17-OHP.<ref name="pmid8325965">{{cite journal |title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase |journal=J Clin Endocrinol Metab |volume=77 |issue=1 |pages=98–102 |year=1993 |pmid=8325965 |doi=10.1210/jcem.77.1.8325965 |last1=Swart |first1=P. |last2=Swart |first2=A. C. |last3=Waterman |first3=M. R. |last4=Estabrook |first4=R. W. |last5=Mason |first5=J. I. }}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism |year=2003|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|year=2005 |volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> In a 2017 study by Barnard et al., 6 hours was enough for the full conversion of 17-OHP to 17-OH-DHP ''in vitro'', albeit the catalytic activity of SRD5A1 was higher than that of SRD5A2.<ref name="pmid28774496"/> Some authors<ref name="pmid23073980"/><ref name="pmid31611378"/> believe that 5α-reduction of 17-OHP appears to be primarily performed by SRD5A1 at least in the human fetus, citing a 1971 study by Frederiksen et al. of rat 5α-reductase activity ''in vitro''.<ref name="pmid4396507">{{cite journal |title=Partial characterization of the nuclear reduced nicotinamide adenine dinucleotide phosphate: delta 4-3-ketosteroid 5 alpha-oxidoreductase of rat prostate |journal=J Biol Chem |volume=246 |issue=8 |pages=2584–93|year=1971 |pmid=4396507|last1=Frederiksen |first1=D. W. |last2=Wilson |first2=J. D. |doi=10.1016/S0021-9258(18)62328-2 |doi-access=free }}</ref> However, these 1971 results were not confirmed by later studies, let alone in humans. Quite contrary, a 2017 study by Barnard et al. showed that both human isozymes were very efficient in converting 17-OHP to 17-OH-DHP.<ref name="pmid28774496" /> Both isozymes are expressed in the following fetal tissues of both sexes: adrenal gland, genital skin, and gonads.<ref name="pmid7488021">{{cite journal |title=Expression of the type 1 and 2 steroid 5 alpha-reductases in human fetal tissues |journal=Biochem Biophys Res Commun |year=1995 |volume=215 |issue=2 |pages=774–80 |pmid=7488021 |doi=10.1006/bbrc.1995.2530 |last1=Ellsworth |first1=K. |last2=Harris |first2=G. }}</ref><ref name="pmid17574609">{{cite journal |title=Fetal distribution of 5alpha-reductase 1 and 5alpha-reductase 2, and their input on human prostate development |journal=J Urol |volume=178 |issue=2 |pages=716–21 |year=2007 |pmid=17574609 |doi=10.1016/j.juro.2007.03.089 |last1=Lunacek |first1=A. |last2=Schwentner |first2=C. |last3=Oswald |first3=J. |last4=Fritsch |first4=H. |last5=Sergi |first5=C. |last6=Thomas |first6=L.N. |last7=Rittmaster |first7=R.S. |last8=Klocker |first8=H. |last9=Neuwirt |first9=H. |last10=Bartsch |first10=G. |last11=Radmayr |first11=C. }}</ref><ref name="pmid30763313"/><ref name="pmid31611378"/> Hence, it is not yet proven ''in vivo'' which of the isozymes takes part in 5α-reduction of 17-OHP in each and every case and condition.<ref name="pmid22170725"/><ref name="pmid28774496"/><ref name="pmid23073980"/> |17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4)<ref name="pmid30763313"/><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has the 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. |5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen).<ref name="pmid22170725"/><ref name="pmid30763313">{{cite journal | last1=O'Shaughnessy | first1=Peter J. | last2=Antignac | first2=Jean Philippe | last3=Le Bizec | first3=Bruno | last4=Morvan | first4=Marie-Line | last5=Svechnikov | first5=Konstantin | last6=Söder | first6=Olle | last7=Savchuk | first7=Iuliia | last8=Monteiro | first8=Ana | last9=Soffientini | first9=Ugo | last10=Johnston | first10=Zoe C. | last11=Bellingham | first11=Michelle | last12=Hough | first12=Denise | last13=Walker | first13=Natasha | last14=Filis | first14=Panagiotis | last15=Fowler | first15=Paul A. | editor-last1=Rawlins | editor-first1=Emma | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | year=2019 | volume = 17 | issue = 2 | pages = e3000002 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002}}</ref><ref name="pmid20613954">{{cite journal |last1=Auchus |first1=Richard J. |title=Management of the Adult with Congenital Adrenal Hyperplasia |journal=International Journal of Pediatric Endocrinology |year=2010 |volume=2010 |page=614107 |doi=10.1155/2010/614107 |pmid=20613954 |pmc=2896848 |doi-access=free }}</ref><ref name="pmid23073980">{{cite journal| title = Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development | journal = Developmental Dynamics | volume = 242 | issue = 4 | pages = 320–9 | pmid = 23073980 | doi = 10.1002/dvdy.23892| s2cid = 44702659 | last1 = Fukami | first1 = Maki | last2 = Homma | first2 = Keiko | last3 = Hasegawa | first3 = Tomonobu | last4 = Ogata | first4 = Tsutomu | year = 2013 }}</ref> |AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5. Type 3 (HSD17B3) is encoded by the ''HSD17B3'' gene in humans. The type 5 is actually an aldo-keto reductase family 1 member C3 (AKR1C3) encoded by the ''AKR1C3'' gene.<ref name="pmid31900912"/> |The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6 (also abbreviated as RL-HSD), HSD17B10, RDH16, RDH5, and DHRS9).<ref name="pmid15519890"/><ref name="pmid31900912"/><ref name="pmid31611378"/><ref name="pmid20613954"/> It is a reverse oxidative step not required in the canonical pathway.}} Therefore, the pathway can be outlined as follows:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21030877">{{cite journal| title = "Getting from here to there"--mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer | journal = Journal of Investigative Medicine : The Official Publication of the American Federation for Clinical Research | volume = 58 | issue = 8 | pages = 938–44 | doi = 10.2310/JIM.0b013e3181ff6bb8 | pmid = 21030877 | pmc = 5589138| last1 = Sharifi | first1 = Nima | last2 = McPhaul | first2 = Michael J. | last3 = Auchus | first3 = Richard J. | year = 2010 }}</ref><ref name="pmid23073980"/><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref><ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref>}} ====5α-reduction of Progesterone==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and has been confirmed first in mice<ref name="pmid15249131"/> and later in humans.<ref name="pmid30763313"/> Therefore, this pathway also essential for normal masculinization.<ref name="pmid21802064"/><ref name="pmid23073980"/> In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1, and, probably, SRD5A2.<ref name="pmid23073980"/><ref name="pmid28774496"/><ref name="pmid32593151">{{cite journal |vauthors=du Toit T, van Rooyen D, Stander MA, Atkin SL, Swart AC |title=Analysis of 52 C19 and C21 steroids by UPC2-MS/MS: Characterising the C11-oxy steroid metabolome in serum |journal=J Chromatogr B Analyt Technol Biomed Life Sci |volume=1152 |issue= |pages=122243 |date=September 2020 |pmid=32593151 |doi=10.1016/j.jchromb.2020.122243 |url=}}</ref> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. Then this metabolic pathway proceeds to DHT the same way as the pathway that started with 17-OHP.<ref name="pmid30763313"/> Therefore, the pathway can be outlined as follows:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21802064"/><ref name="pmid23073980"/>}} === 5α-Dione Pathway === The pathway of A4 converted to androstanedione (5α-dione), and then to DHT (Figure 2) roundabout of T is unlikely to happen in sufficient quantities to have biological relevance in healthy humans. However, this pathway is relevant in CRPC.<ref name="pmid21795608"/> This pathway contains of two main steps: {{ordered list |The SRD5A1 enzyme 5α-reduces A4 to 5α-dione (also known as 5α-androstane-3,17-dione); |The HSD17B3 or AKR1C3 enzyme 17β-reduces 5α-dione to DHT.}} In this pathway, 5α-dione can also be interconverted with AST, which can also be converted to 3α-diol, which, in turn, can be converted to DHT by a number of dehydrogenases.<ref name="pmid11514561"/><ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> It should also be taken into consideration that the conversions of 5α-dione to AST and the conversion of DHT to 3α-diol are commonly considered inactivation reactions, but because these reactions are reversible, 3α-diol and AST may serve as a pool of inactive androgens and potential substrates for DHT. So, the alternative pathway that starts from A4 roundabout of T, called the "5α-dione" pathway, can be simplistically outlined as follows:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965"/><ref name="pmid12915666"/><ref name="pmid15774560"/><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid31900912"/><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} k6skja15yvx6pqhjgnveh1kuq8pjtdd 2408030 2408029 2022-07-19T15:35:46Z Maxim Masiutin 2902665 /* Castration-Resistant Prostate Cancer */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313" /><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == === Backdoor Pathways to 5α-Dihydrotestosterone === [[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]]In canonical androgen steroidogenesis, the 5α-reductases type 2 and 3 catalyze the transformation of T to DHT in the terminal step. However, in the initial step into the androgen backdoor pathways to DHT, 5α-reductases type 1 and 2<ref name="pmid28774496"/><ref name="pmid31626910"/> reduce a pregnane — 17-OHP or P4 — which is ultimately converted to DHT. Therefore, while 5α-reduction of a steroid is the last transformation in the canonical pathway, it is the first step in a backdoor pathway. These backdoor pathways are activated during normal prenatal development and lead to early male sexual differentiation in humans and other mammals.<ref name="pmid15249131" /><ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid23073980" /> ====5α-Reduction of 17α-Hydroxyprogesterone ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The pathway from 17-OHP to DHT may take place in steroidogenic tissues when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are simultaneously expressed.<ref name="pmid30763313" /><ref name="pmid25379460">{{cite journal |title=Steroid hormone synthetic pathways in prostate cancer |journal=Transl Androl Urol |volume=2 |issue=3 |pages=212–227 |date=September 2013 |pmid=25379460 |pmc=4219921 |doi=10.3978/j.issn.2223-4683.2013.09.16}}</ref> The pathway consists of five steps:{{ordered list |The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione catalyzed by 5α-reductase type 1 (SRD5A1) and 2 (SRD5A2).<ref name="pmid1527072">{{cite journal|last1=Normington|first1=K.|last2=Russell|first2=D. W.|title=Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions|journal=The Journal of Biological Chemistry|year=1992 |volume=267|issue=27|pages=19548–19554|doi=10.1016/S0021-9258(18)41809-1 |issn=0021-9258|pmid=1527072|doi-access=free }}</ref><ref name="pmid22170725"/><ref name="pmid14522586">{{cite journal |title=5alpha-reduced C21 steroids are substrates for human cytochrome P450c17 |journal=Arch Biochem Biophys |volume=418 |issue=2 |pages=151–60 |pmid=14522586 |doi=10.1016/j.abb.2003.07.003|last1=Gupta |first1=Manisha K. |last2=Guryev |first2=Oleg L. |last3=Auchus |first3=Richard J. |year=2003 }}</ref> Since 17-OHP is a poor substrate for CYP17A1,<ref name="pmid9452426"/><ref name="pmid32007561"/> the 5α-reductase conversion of 17-OHP by SRD5A1/SRD5A2<ref name="pmid28774496"/><ref name="pmid31626910"/> will proceed efficiently to 17-OH-DHP via the backdoor pathway, rather than the 17,20-lyase conversion by CYP17A1 to A4 via the Δ⁴ pathway, resulting in negligible A4 being produced from 17-OHP.<ref name="pmid8325965">{{cite journal |title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase |journal=J Clin Endocrinol Metab |volume=77 |issue=1 |pages=98–102 |year=1993 |pmid=8325965 |doi=10.1210/jcem.77.1.8325965 |last1=Swart |first1=P. |last2=Swart |first2=A. C. |last3=Waterman |first3=M. R. |last4=Estabrook |first4=R. W. |last5=Mason |first5=J. I. }}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism |year=2003|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|year=2005 |volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> In a 2017 study by Barnard et al., 6 hours was enough for the full conversion of 17-OHP to 17-OH-DHP ''in vitro'', albeit the catalytic activity of SRD5A1 was higher than that of SRD5A2.<ref name="pmid28774496"/> Some authors<ref name="pmid23073980"/><ref name="pmid31611378"/> believe that 5α-reduction of 17-OHP appears to be primarily performed by SRD5A1 at least in the human fetus, citing a 1971 study by Frederiksen et al. of rat 5α-reductase activity ''in vitro''.<ref name="pmid4396507">{{cite journal |title=Partial characterization of the nuclear reduced nicotinamide adenine dinucleotide phosphate: delta 4-3-ketosteroid 5 alpha-oxidoreductase of rat prostate |journal=J Biol Chem |volume=246 |issue=8 |pages=2584–93|year=1971 |pmid=4396507|last1=Frederiksen |first1=D. W. |last2=Wilson |first2=J. D. |doi=10.1016/S0021-9258(18)62328-2 |doi-access=free }}</ref> However, these 1971 results were not confirmed by later studies, let alone in humans. Quite contrary, a 2017 study by Barnard et al. showed that both human isozymes were very efficient in converting 17-OHP to 17-OH-DHP.<ref name="pmid28774496" /> Both isozymes are expressed in the following fetal tissues of both sexes: adrenal gland, genital skin, and gonads.<ref name="pmid7488021">{{cite journal |title=Expression of the type 1 and 2 steroid 5 alpha-reductases in human fetal tissues |journal=Biochem Biophys Res Commun |year=1995 |volume=215 |issue=2 |pages=774–80 |pmid=7488021 |doi=10.1006/bbrc.1995.2530 |last1=Ellsworth |first1=K. |last2=Harris |first2=G. }}</ref><ref name="pmid17574609">{{cite journal |title=Fetal distribution of 5alpha-reductase 1 and 5alpha-reductase 2, and their input on human prostate development |journal=J Urol |volume=178 |issue=2 |pages=716–21 |year=2007 |pmid=17574609 |doi=10.1016/j.juro.2007.03.089 |last1=Lunacek |first1=A. |last2=Schwentner |first2=C. |last3=Oswald |first3=J. |last4=Fritsch |first4=H. |last5=Sergi |first5=C. |last6=Thomas |first6=L.N. |last7=Rittmaster |first7=R.S. |last8=Klocker |first8=H. |last9=Neuwirt |first9=H. |last10=Bartsch |first10=G. |last11=Radmayr |first11=C. }}</ref><ref name="pmid30763313"/><ref name="pmid31611378"/> Hence, it is not yet proven ''in vivo'' which of the isozymes takes part in 5α-reduction of 17-OHP in each and every case and condition.<ref name="pmid22170725"/><ref name="pmid28774496"/><ref name="pmid23073980"/> |17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4)<ref name="pmid30763313"/><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has the 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. |5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen).<ref name="pmid22170725"/><ref name="pmid30763313">{{cite journal | last1=O'Shaughnessy | first1=Peter J. | last2=Antignac | first2=Jean Philippe | last3=Le Bizec | first3=Bruno | last4=Morvan | first4=Marie-Line | last5=Svechnikov | first5=Konstantin | last6=Söder | first6=Olle | last7=Savchuk | first7=Iuliia | last8=Monteiro | first8=Ana | last9=Soffientini | first9=Ugo | last10=Johnston | first10=Zoe C. | last11=Bellingham | first11=Michelle | last12=Hough | first12=Denise | last13=Walker | first13=Natasha | last14=Filis | first14=Panagiotis | last15=Fowler | first15=Paul A. | editor-last1=Rawlins | editor-first1=Emma | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | year=2019 | volume = 17 | issue = 2 | pages = e3000002 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002}}</ref><ref name="pmid20613954">{{cite journal |last1=Auchus |first1=Richard J. |title=Management of the Adult with Congenital Adrenal Hyperplasia |journal=International Journal of Pediatric Endocrinology |year=2010 |volume=2010 |page=614107 |doi=10.1155/2010/614107 |pmid=20613954 |pmc=2896848 |doi-access=free }}</ref><ref name="pmid23073980">{{cite journal| title = Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development | journal = Developmental Dynamics | volume = 242 | issue = 4 | pages = 320–9 | pmid = 23073980 | doi = 10.1002/dvdy.23892| s2cid = 44702659 | last1 = Fukami | first1 = Maki | last2 = Homma | first2 = Keiko | last3 = Hasegawa | first3 = Tomonobu | last4 = Ogata | first4 = Tsutomu | year = 2013 }}</ref> |AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5. Type 3 (HSD17B3) is encoded by the ''HSD17B3'' gene in humans. The type 5 is actually an aldo-keto reductase family 1 member C3 (AKR1C3) encoded by the ''AKR1C3'' gene.<ref name="pmid31900912"/> |The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6 (also abbreviated as RL-HSD), HSD17B10, RDH16, RDH5, and DHRS9).<ref name="pmid15519890"/><ref name="pmid31900912"/><ref name="pmid31611378"/><ref name="pmid20613954"/> It is a reverse oxidative step not required in the canonical pathway.}} Therefore, the pathway can be outlined as follows:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21030877">{{cite journal| title = "Getting from here to there"--mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer | journal = Journal of Investigative Medicine : The Official Publication of the American Federation for Clinical Research | volume = 58 | issue = 8 | pages = 938–44 | doi = 10.2310/JIM.0b013e3181ff6bb8 | pmid = 21030877 | pmc = 5589138| last1 = Sharifi | first1 = Nima | last2 = McPhaul | first2 = Michael J. | last3 = Auchus | first3 = Richard J. | year = 2010 }}</ref><ref name="pmid23073980"/><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref><ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref>}} ====5α-reduction of Progesterone==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and has been confirmed first in mice<ref name="pmid15249131"/> and later in humans.<ref name="pmid30763313"/> Therefore, this pathway also essential for normal masculinization.<ref name="pmid21802064"/><ref name="pmid23073980"/> In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1, and, probably, SRD5A2.<ref name="pmid23073980"/><ref name="pmid28774496"/><ref name="pmid32593151">{{cite journal |vauthors=du Toit T, van Rooyen D, Stander MA, Atkin SL, Swart AC |title=Analysis of 52 C19 and C21 steroids by UPC2-MS/MS: Characterising the C11-oxy steroid metabolome in serum |journal=J Chromatogr B Analyt Technol Biomed Life Sci |volume=1152 |issue= |pages=122243 |date=September 2020 |pmid=32593151 |doi=10.1016/j.jchromb.2020.122243 |url=}}</ref> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. Then this metabolic pathway proceeds to DHT the same way as the pathway that started with 17-OHP.<ref name="pmid30763313"/> Therefore, the pathway can be outlined as follows:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21802064"/><ref name="pmid23073980"/>}} === 5α-Dione Pathway === The pathway of A4 converted to androstanedione (5α-dione), and then to DHT (Figure 2) roundabout of T is unlikely to happen in sufficient quantities to have biological relevance in healthy humans. However, this pathway is relevant in CRPC.<ref name="pmid21795608"/> This pathway contains of two main steps: {{ordered list |The SRD5A1 enzyme 5α-reduces A4 to 5α-dione (also known as 5α-androstane-3,17-dione); |The HSD17B3 or AKR1C3 enzyme 17β-reduces 5α-dione to DHT.}} In this pathway, 5α-dione can also be interconverted with AST, which can also be converted to 3α-diol, which, in turn, can be converted to DHT by a number of dehydrogenases.<ref name="pmid11514561"/><ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> It should also be taken into consideration that the conversions of 5α-dione to AST and the conversion of DHT to 3α-diol are commonly considered inactivation reactions, but because these reactions are reversible, 3α-diol and AST may serve as a pool of inactive androgens and potential substrates for DHT. So, the alternative pathway that starts from A4 roundabout of T, called the "5α-dione" pathway, can be simplistically outlined as follows:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965"/><ref name="pmid12915666"/><ref name="pmid15774560"/><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} ahvv44xspe9xlefhkg9jz79b1inyjln 2408031 2408030 2022-07-19T15:46:26Z Maxim Masiutin 2902665 /* Castration-Resistant Prostate Cancer */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313" /><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == === Backdoor Pathways to 5α-Dihydrotestosterone === [[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]]In canonical androgen steroidogenesis, the 5α-reductases type 2 and 3 catalyze the transformation of T to DHT in the terminal step. However, in the initial step into the androgen backdoor pathways to DHT, 5α-reductases type 1 and 2<ref name="pmid28774496"/><ref name="pmid31626910"/> reduce a pregnane — 17-OHP or P4 — which is ultimately converted to DHT. Therefore, while 5α-reduction of a steroid is the last transformation in the canonical pathway, it is the first step in a backdoor pathway. These backdoor pathways are activated during normal prenatal development and lead to early male sexual differentiation in humans and other mammals.<ref name="pmid15249131" /><ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid23073980" /> ====5α-Reduction of 17α-Hydroxyprogesterone ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The pathway from 17-OHP to DHT may take place in steroidogenic tissues when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are simultaneously expressed.<ref name="pmid30763313" /><ref name="pmid25379460">{{cite journal |title=Steroid hormone synthetic pathways in prostate cancer |journal=Transl Androl Urol |volume=2 |issue=3 |pages=212–227 |date=September 2013 |pmid=25379460 |pmc=4219921 |doi=10.3978/j.issn.2223-4683.2013.09.16}}</ref> The pathway consists of five steps:{{ordered list |The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione catalyzed by 5α-reductase type 1 (SRD5A1) and 2 (SRD5A2).<ref name="pmid1527072">{{cite journal|last1=Normington|first1=K.|last2=Russell|first2=D. W.|title=Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions|journal=The Journal of Biological Chemistry|year=1992 |volume=267|issue=27|pages=19548–19554|doi=10.1016/S0021-9258(18)41809-1 |issn=0021-9258|pmid=1527072|doi-access=free }}</ref><ref name="pmid22170725"/><ref name="pmid14522586">{{cite journal |title=5alpha-reduced C21 steroids are substrates for human cytochrome P450c17 |journal=Arch Biochem Biophys |volume=418 |issue=2 |pages=151–60 |pmid=14522586 |doi=10.1016/j.abb.2003.07.003|last1=Gupta |first1=Manisha K. |last2=Guryev |first2=Oleg L. |last3=Auchus |first3=Richard J. |year=2003 }}</ref> Since 17-OHP is a poor substrate for CYP17A1,<ref name="pmid9452426"/><ref name="pmid32007561"/> the 5α-reductase conversion of 17-OHP by SRD5A1/SRD5A2<ref name="pmid28774496"/><ref name="pmid31626910"/> will proceed efficiently to 17-OH-DHP via the backdoor pathway, rather than the 17,20-lyase conversion by CYP17A1 to A4 via the Δ⁴ pathway, resulting in negligible A4 being produced from 17-OHP.<ref name="pmid8325965">{{cite journal |title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase |journal=J Clin Endocrinol Metab |volume=77 |issue=1 |pages=98–102 |year=1993 |pmid=8325965 |doi=10.1210/jcem.77.1.8325965 |last1=Swart |first1=P. |last2=Swart |first2=A. C. |last3=Waterman |first3=M. R. |last4=Estabrook |first4=R. W. |last5=Mason |first5=J. I. }}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism |year=2003|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|year=2005 |volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> In a 2017 study by Barnard et al., 6 hours was enough for the full conversion of 17-OHP to 17-OH-DHP ''in vitro'', albeit the catalytic activity of SRD5A1 was higher than that of SRD5A2.<ref name="pmid28774496"/> Some authors<ref name="pmid23073980"/><ref name="pmid31611378"/> believe that 5α-reduction of 17-OHP appears to be primarily performed by SRD5A1 at least in the human fetus, citing a 1971 study by Frederiksen et al. of rat 5α-reductase activity ''in vitro''.<ref name="pmid4396507">{{cite journal |title=Partial characterization of the nuclear reduced nicotinamide adenine dinucleotide phosphate: delta 4-3-ketosteroid 5 alpha-oxidoreductase of rat prostate |journal=J Biol Chem |volume=246 |issue=8 |pages=2584–93|year=1971 |pmid=4396507|last1=Frederiksen |first1=D. W. |last2=Wilson |first2=J. D. |doi=10.1016/S0021-9258(18)62328-2 |doi-access=free }}</ref> However, these 1971 results were not confirmed by later studies, let alone in humans. Quite contrary, a 2017 study by Barnard et al. showed that both human isozymes were very efficient in converting 17-OHP to 17-OH-DHP.<ref name="pmid28774496" /> Both isozymes are expressed in the following fetal tissues of both sexes: adrenal gland, genital skin, and gonads.<ref name="pmid7488021">{{cite journal |title=Expression of the type 1 and 2 steroid 5 alpha-reductases in human fetal tissues |journal=Biochem Biophys Res Commun |year=1995 |volume=215 |issue=2 |pages=774–80 |pmid=7488021 |doi=10.1006/bbrc.1995.2530 |last1=Ellsworth |first1=K. |last2=Harris |first2=G. }}</ref><ref name="pmid17574609">{{cite journal |title=Fetal distribution of 5alpha-reductase 1 and 5alpha-reductase 2, and their input on human prostate development |journal=J Urol |volume=178 |issue=2 |pages=716–21 |year=2007 |pmid=17574609 |doi=10.1016/j.juro.2007.03.089 |last1=Lunacek |first1=A. |last2=Schwentner |first2=C. |last3=Oswald |first3=J. |last4=Fritsch |first4=H. |last5=Sergi |first5=C. |last6=Thomas |first6=L.N. |last7=Rittmaster |first7=R.S. |last8=Klocker |first8=H. |last9=Neuwirt |first9=H. |last10=Bartsch |first10=G. |last11=Radmayr |first11=C. }}</ref><ref name="pmid30763313"/><ref name="pmid31611378"/> Hence, it is not yet proven ''in vivo'' which of the isozymes takes part in 5α-reduction of 17-OHP in each and every case and condition.<ref name="pmid22170725"/><ref name="pmid28774496"/><ref name="pmid23073980"/> |17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4)<ref name="pmid30763313"/><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has the 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. |5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen).<ref name="pmid22170725"/><ref name="pmid30763313">{{cite journal | last1=O'Shaughnessy | first1=Peter J. | last2=Antignac | first2=Jean Philippe | last3=Le Bizec | first3=Bruno | last4=Morvan | first4=Marie-Line | last5=Svechnikov | first5=Konstantin | last6=Söder | first6=Olle | last7=Savchuk | first7=Iuliia | last8=Monteiro | first8=Ana | last9=Soffientini | first9=Ugo | last10=Johnston | first10=Zoe C. | last11=Bellingham | first11=Michelle | last12=Hough | first12=Denise | last13=Walker | first13=Natasha | last14=Filis | first14=Panagiotis | last15=Fowler | first15=Paul A. | editor-last1=Rawlins | editor-first1=Emma | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | year=2019 | volume = 17 | issue = 2 | pages = e3000002 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002}}</ref><ref name="pmid20613954">{{cite journal |last1=Auchus |first1=Richard J. |title=Management of the Adult with Congenital Adrenal Hyperplasia |journal=International Journal of Pediatric Endocrinology |year=2010 |volume=2010 |page=614107 |doi=10.1155/2010/614107 |pmid=20613954 |pmc=2896848 |doi-access=free }}</ref><ref name="pmid23073980">{{cite journal| title = Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development | journal = Developmental Dynamics | volume = 242 | issue = 4 | pages = 320–9 | pmid = 23073980 | doi = 10.1002/dvdy.23892| s2cid = 44702659 | last1 = Fukami | first1 = Maki | last2 = Homma | first2 = Keiko | last3 = Hasegawa | first3 = Tomonobu | last4 = Ogata | first4 = Tsutomu | year = 2013 }}</ref> |AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5. Type 3 (HSD17B3) is encoded by the ''HSD17B3'' gene in humans. The type 5 is actually an aldo-keto reductase family 1 member C3 (AKR1C3) encoded by the ''AKR1C3'' gene.<ref name="pmid31900912"/> |The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6 (also abbreviated as RL-HSD), HSD17B10, RDH16, RDH5, and DHRS9).<ref name="pmid15519890"/><ref name="pmid31900912"/><ref name="pmid31611378"/><ref name="pmid20613954"/> It is a reverse oxidative step not required in the canonical pathway.}} Therefore, the pathway can be outlined as follows:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21030877">{{cite journal| title = "Getting from here to there"--mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer | journal = Journal of Investigative Medicine : The Official Publication of the American Federation for Clinical Research | volume = 58 | issue = 8 | pages = 938–44 | doi = 10.2310/JIM.0b013e3181ff6bb8 | pmid = 21030877 | pmc = 5589138| last1 = Sharifi | first1 = Nima | last2 = McPhaul | first2 = Michael J. | last3 = Auchus | first3 = Richard J. | year = 2010 }}</ref><ref name="pmid23073980"/><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref><ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref>}} ====5α-reduction of Progesterone==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and has been confirmed first in mice<ref name="pmid15249131"/> and later in humans.<ref name="pmid30763313"/> Therefore, this pathway also essential for normal masculinization.<ref name="pmid21802064"/><ref name="pmid23073980"/> In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1, and, probably, SRD5A2.<ref name="pmid23073980"/><ref name="pmid28774496"/><ref name="pmid32593151">{{cite journal |vauthors=du Toit T, van Rooyen D, Stander MA, Atkin SL, Swart AC |title=Analysis of 52 C19 and C21 steroids by UPC2-MS/MS: Characterising the C11-oxy steroid metabolome in serum |journal=J Chromatogr B Analyt Technol Biomed Life Sci |volume=1152 |issue= |pages=122243 |date=September 2020 |pmid=32593151 |doi=10.1016/j.jchromb.2020.122243 |url=}}</ref> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. Then this metabolic pathway proceeds to DHT the same way as the pathway that started with 17-OHP.<ref name="pmid30763313"/> Therefore, the pathway can be outlined as follows:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21802064"/><ref name="pmid23073980"/>}} === 5α-Dione Pathway === The pathway of A4 converted to androstanedione (5α-dione), and then to DHT (Figure 2) roundabout of T is unlikely to happen in sufficient quantities to have biological relevance in healthy humans. However, this pathway is relevant in CRPC.<ref name="pmid21795608"/> This pathway contains of two main steps: {{ordered list |The SRD5A1 enzyme 5α-reduces A4 to 5α-dione (also known as 5α-androstane-3,17-dione); |The HSD17B3 or AKR1C3 enzyme 17β-reduces 5α-dione to DHT.}} In this pathway, 5α-dione can also be interconverted with AST, which can also be converted to 3α-diol, which, in turn, can be converted to DHT by a number of dehydrogenases.<ref name="pmid11514561"/><ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> It should also be taken into consideration that the conversions of 5α-dione to AST and the conversion of DHT to 3α-diol are commonly considered inactivation reactions, but because these reactions are reversible, 3α-diol and AST may serve as a pool of inactive androgens and potential substrates for DHT. So, the alternative pathway that starts from A4 roundabout of T, called the "5α-dione" pathway, can be simplistically outlined as follows:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965"/><ref name="pmid12915666"/><ref name="pmid15774560"/><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} dy08m0ntg9wn7el2ya7ogk6pcqbt4xq 2408038 2408031 2022-07-19T18:03:41Z Maneesh 2723004 /* 5α-Reduction of 17α-Hydroxyprogesterone */ need to remove ordered list template to make it easier to edit wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313" /><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == === Backdoor Pathways to 5α-Dihydrotestosterone === [[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]]In canonical androgen steroidogenesis, the 5α-reductases type 2 and 3 catalyze the transformation of T to DHT in the terminal step. However, in the initial step into the androgen backdoor pathways to DHT, 5α-reductases type 1 and 2<ref name="pmid28774496"/><ref name="pmid31626910"/> reduce a pregnane — 17-OHP or P4 — which is ultimately converted to DHT. Therefore, while 5α-reduction of a steroid is the last transformation in the canonical pathway, it is the first step in a backdoor pathway. These backdoor pathways are activated during normal prenatal development and lead to early male sexual differentiation in humans and other mammals.<ref name="pmid15249131" /><ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid23073980" /> ====5α-Reduction of 17α-Hydroxyprogesterone ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The pathway from 17-OHP to DHT may take place in steroidogenic tissues when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are simultaneously expressed.<ref name="pmid30763313" /><ref name="pmid25379460">{{cite journal |title=Steroid hormone synthetic pathways in prostate cancer |journal=Transl Androl Urol |volume=2 |issue=3 |pages=212–227 |date=September 2013 |pmid=25379460 |pmc=4219921 |doi=10.3978/j.issn.2223-4683.2013.09.16}}</ref> The pathway consists of five steps: The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione catalyzed by 5α-reductase type 1 (SRD5A1) and 2 (SRD5A2).<ref name="pmid1527072">{{cite journal|last1=Normington|first1=K.|last2=Russell|first2=D. W.|title=Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions|journal=The Journal of Biological Chemistry|year=1992 |volume=267|issue=27|pages=19548–19554|doi=10.1016/S0021-9258(18)41809-1 |issn=0021-9258|pmid=1527072|doi-access=free }}</ref><ref name="pmid22170725"/><ref name="pmid14522586">{{cite journal |title=5alpha-reduced C21 steroids are substrates for human cytochrome P450c17 |journal=Arch Biochem Biophys |volume=418 |issue=2 |pages=151–60 |pmid=14522586 |doi=10.1016/j.abb.2003.07.003|last1=Gupta |first1=Manisha K. |last2=Guryev |first2=Oleg L. |last3=Auchus |first3=Richard J. |year=2003 }}</ref> Since 17-OHP is a poor substrate for CYP17A1,<ref name="pmid9452426"/><ref name="pmid32007561"/> the 5α-reductase conversion of 17-OHP by SRD5A1/SRD5A2<ref name="pmid28774496"/><ref name="pmid31626910"/> will proceed efficiently to 17-OH-DHP via the backdoor pathway, rather than the 17,20-lyase conversion by CYP17A1 to A4 via the Δ⁴ pathway, resulting in negligible A4 being produced from 17-OHP.<ref name="pmid8325965">{{cite journal |title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase |journal=J Clin Endocrinol Metab |volume=77 |issue=1 |pages=98–102 |year=1993 |pmid=8325965 |doi=10.1210/jcem.77.1.8325965 |last1=Swart |first1=P. |last2=Swart |first2=A. C. |last3=Waterman |first3=M. R. |last4=Estabrook |first4=R. W. |last5=Mason |first5=J. I. }}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism |year=2003|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|year=2005 |volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> In a 2017 study by Barnard et al., 6 hours was enough for the full conversion of 17-OHP to 17-OH-DHP ''in vitro'', albeit the catalytic activity of SRD5A1 was higher than that of SRD5A2.<ref name="pmid28774496"/> Some authors<ref name="pmid23073980"/><ref name="pmid31611378"/> believe that 5α-reduction of 17-OHP appears to be primarily performed by SRD5A1 at least in the human fetus, citing a 1971 study by Frederiksen et al. of rat 5α-reductase activity ''in vitro''.<ref name="pmid4396507">{{cite journal |title=Partial characterization of the nuclear reduced nicotinamide adenine dinucleotide phosphate: delta 4-3-ketosteroid 5 alpha-oxidoreductase of rat prostate |journal=J Biol Chem |volume=246 |issue=8 |pages=2584–93|year=1971 |pmid=4396507|last1=Frederiksen |first1=D. W. |last2=Wilson |first2=J. D. |doi=10.1016/S0021-9258(18)62328-2 |doi-access=free }}</ref> However, these 1971 results were not confirmed by later studies, let alone in humans. Quite contrary, a 2017 study by Barnard et al. showed that both human isozymes were very efficient in converting 17-OHP to 17-OH-DHP.<ref name="pmid28774496" /> Both isozymes are expressed in the following fetal tissues of both sexes: adrenal gland, genital skin, and gonads.<ref name="pmid7488021">{{cite journal |title=Expression of the type 1 and 2 steroid 5 alpha-reductases in human fetal tissues |journal=Biochem Biophys Res Commun |year=1995 |volume=215 |issue=2 |pages=774–80 |pmid=7488021 |doi=10.1006/bbrc.1995.2530 |last1=Ellsworth |first1=K. |last2=Harris |first2=G. }}</ref><ref name="pmid17574609">{{cite journal |title=Fetal distribution of 5alpha-reductase 1 and 5alpha-reductase 2, and their input on human prostate development |journal=J Urol |volume=178 |issue=2 |pages=716–21 |year=2007 |pmid=17574609 |doi=10.1016/j.juro.2007.03.089 |last1=Lunacek |first1=A. |last2=Schwentner |first2=C. |last3=Oswald |first3=J. |last4=Fritsch |first4=H. |last5=Sergi |first5=C. |last6=Thomas |first6=L.N. |last7=Rittmaster |first7=R.S. |last8=Klocker |first8=H. |last9=Neuwirt |first9=H. |last10=Bartsch |first10=G. |last11=Radmayr |first11=C. }}</ref><ref name="pmid30763313"/><ref name="pmid31611378"/> Hence, it is not yet proven ''in vivo'' which of the isozymes takes part in 5α-reduction of 17-OHP in each and every case and condition.<ref name="pmid22170725"/><ref name="pmid28774496"/><ref name="pmid23073980"/> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4)<ref name="pmid30763313"/><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has the 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. |5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen).<ref name="pmid22170725"/><ref name="pmid30763313">{{cite journal | last1=O'Shaughnessy | first1=Peter J. | last2=Antignac | first2=Jean Philippe | last3=Le Bizec | first3=Bruno | last4=Morvan | first4=Marie-Line | last5=Svechnikov | first5=Konstantin | last6=Söder | first6=Olle | last7=Savchuk | first7=Iuliia | last8=Monteiro | first8=Ana | last9=Soffientini | first9=Ugo | last10=Johnston | first10=Zoe C. | last11=Bellingham | first11=Michelle | last12=Hough | first12=Denise | last13=Walker | first13=Natasha | last14=Filis | first14=Panagiotis | last15=Fowler | first15=Paul A. | editor-last1=Rawlins | editor-first1=Emma | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | year=2019 | volume = 17 | issue = 2 | pages = e3000002 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002}}</ref><ref name="pmid20613954">{{cite journal |last1=Auchus |first1=Richard J. |title=Management of the Adult with Congenital Adrenal Hyperplasia |journal=International Journal of Pediatric Endocrinology |year=2010 |volume=2010 |page=614107 |doi=10.1155/2010/614107 |pmid=20613954 |pmc=2896848 |doi-access=free }}</ref><ref name="pmid23073980">{{cite journal| title = Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development | journal = Developmental Dynamics | volume = 242 | issue = 4 | pages = 320–9 | pmid = 23073980 | doi = 10.1002/dvdy.23892| s2cid = 44702659 | last1 = Fukami | first1 = Maki | last2 = Homma | first2 = Keiko | last3 = Hasegawa | first3 = Tomonobu | last4 = Ogata | first4 = Tsutomu | year = 2013 }}</ref> |AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5. Type 3 (HSD17B3) is encoded by the ''HSD17B3'' gene in humans. The type 5 is actually an aldo-keto reductase family 1 member C3 (AKR1C3) encoded by the ''AKR1C3'' gene.<ref name="pmid31900912"/> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6 (also abbreviated as RL-HSD), HSD17B10, RDH16, RDH5, and DHRS9).<ref name="pmid15519890"/><ref name="pmid31900912"/><ref name="pmid31611378"/><ref name="pmid20613954"/> It is a reverse oxidative step not required in the canonical pathway. Therefore, the pathway can be outlined as follows:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21030877">{{cite journal| title = "Getting from here to there"--mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer | journal = Journal of Investigative Medicine : The Official Publication of the American Federation for Clinical Research | volume = 58 | issue = 8 | pages = 938–44 | doi = 10.2310/JIM.0b013e3181ff6bb8 | pmid = 21030877 | pmc = 5589138| last1 = Sharifi | first1 = Nima | last2 = McPhaul | first2 = Michael J. | last3 = Auchus | first3 = Richard J. | year = 2010 }}</ref><ref name="pmid23073980"/><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref><ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref>}} ====5α-reduction of Progesterone==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and has been confirmed first in mice<ref name="pmid15249131"/> and later in humans.<ref name="pmid30763313"/> Therefore, this pathway also essential for normal masculinization.<ref name="pmid21802064"/><ref name="pmid23073980"/> In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1, and, probably, SRD5A2.<ref name="pmid23073980"/><ref name="pmid28774496"/><ref name="pmid32593151">{{cite journal |vauthors=du Toit T, van Rooyen D, Stander MA, Atkin SL, Swart AC |title=Analysis of 52 C19 and C21 steroids by UPC2-MS/MS: Characterising the C11-oxy steroid metabolome in serum |journal=J Chromatogr B Analyt Technol Biomed Life Sci |volume=1152 |issue= |pages=122243 |date=September 2020 |pmid=32593151 |doi=10.1016/j.jchromb.2020.122243 |url=}}</ref> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. Then this metabolic pathway proceeds to DHT the same way as the pathway that started with 17-OHP.<ref name="pmid30763313"/> Therefore, the pathway can be outlined as follows:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21802064"/><ref name="pmid23073980"/>}} === 5α-Dione Pathway === The pathway of A4 converted to androstanedione (5α-dione), and then to DHT (Figure 2) roundabout of T is unlikely to happen in sufficient quantities to have biological relevance in healthy humans. However, this pathway is relevant in CRPC.<ref name="pmid21795608"/> This pathway contains of two main steps: {{ordered list |The SRD5A1 enzyme 5α-reduces A4 to 5α-dione (also known as 5α-androstane-3,17-dione); |The HSD17B3 or AKR1C3 enzyme 17β-reduces 5α-dione to DHT.}} In this pathway, 5α-dione can also be interconverted with AST, which can also be converted to 3α-diol, which, in turn, can be converted to DHT by a number of dehydrogenases.<ref name="pmid11514561"/><ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> It should also be taken into consideration that the conversions of 5α-dione to AST and the conversion of DHT to 3α-diol are commonly considered inactivation reactions, but because these reactions are reversible, 3α-diol and AST may serve as a pool of inactive androgens and potential substrates for DHT. So, the alternative pathway that starts from A4 roundabout of T, called the "5α-dione" pathway, can be simplistically outlined as follows:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965"/><ref name="pmid12915666"/><ref name="pmid15774560"/><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} 2612aq0312umprf8kg0exj1yw1cqkmn 2408046 2408038 2022-07-19T20:27:35Z Maneesh 2723004 /* 5α-Reduction of 17α-Hydroxyprogesterone */ ruthless cutting wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313" /><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == === Backdoor Pathways to 5α-Dihydrotestosterone === A more detailed description of each alternative androgen pathway in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1)[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====5α-Reduction of 17α-Hydroxyprogesterone ==== In canonical androgen steroidogenesis, the 5α-reductases type 2 and 3 (SRD5A2 and SRD5A3) catalyze the transformation of T to DHT in the terminal step. However, in the initial step into the androgen backdoor pathways to DHT, 5α-reductases type 1 (SRD5A1)r educes a pregnane — 17-OHP or P4 — which is ultimately converted to DHT. Therefore, while 5α-reduction of a steroid is the last transformation in the canonical pathway, it is the first step in a backdoor pathway.[[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone) catalyzed SRD5A1 according to comprehensive source.<ref name="pmid23073980" /><ref name="pmid31611378" /> This is seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen).<ref name="pmid22170725" /><ref name="pmid30763313">{{cite journal | last1=O'Shaughnessy | first1=Peter J. | last2=Antignac | first2=Jean Philippe | last3=Le Bizec | first3=Bruno | last4=Morvan | first4=Marie-Line | last5=Svechnikov | first5=Konstantin | last6=Söder | first6=Olle | last7=Savchuk | first7=Iuliia | last8=Monteiro | first8=Ana | last9=Soffientini | first9=Ugo | last10=Johnston | first10=Zoe C. | last11=Bellingham | first11=Michelle | last12=Hough | first12=Denise | last13=Walker | first13=Natasha | last14=Filis | first14=Panagiotis | last15=Fowler | first15=Paul A. | editor-last1=Rawlins | editor-first1=Emma | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | year=2019 | volume = 17 | issue = 2 | pages = e3000002 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002}}</ref><ref name="pmid20613954">{{cite journal |last1=Auchus |first1=Richard J. |title=Management of the Adult with Congenital Adrenal Hyperplasia |journal=International Journal of Pediatric Endocrinology |year=2010 |volume=2010 |page=614107 |doi=10.1155/2010/614107 |pmid=20613954 |pmc=2896848 |doi-access=free }}</ref><ref name="pmid23073980">{{cite journal| title = Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development | journal = Developmental Dynamics | volume = 242 | issue = 4 | pages = 320–9 | pmid = 23073980 | doi = 10.1002/dvdy.23892| s2cid = 44702659 | last1 = Fukami | first1 = Maki | last2 = Homma | first2 = Keiko | last3 = Hasegawa | first3 = Tomonobu | last4 = Ogata | first4 = Tsutomu | year = 2013 }}</ref> AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9).<ref name="pmid15519890" /><ref name="pmid31900912" /><ref name="pmid31611378" /><ref name="pmid20613954" /> This oxidation is not required in the canonical pathway. The pathway can be specified as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21030877">{{cite journal| title = "Getting from here to there"--mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer | journal = Journal of Investigative Medicine : The Official Publication of the American Federation for Clinical Research | volume = 58 | issue = 8 | pages = 938–44 | doi = 10.2310/JIM.0b013e3181ff6bb8 | pmid = 21030877 | pmc = 5589138| last1 = Sharifi | first1 = Nima | last2 = McPhaul | first2 = Michael J. | last3 = Auchus | first3 = Richard J. | year = 2010 }}</ref><ref name="pmid23073980"/><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref><ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref>}} ====5α-reduction of Progesterone==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and has been confirmed first in mice<ref name="pmid15249131"/> and later in humans.<ref name="pmid30763313"/> Therefore, this pathway also essential for normal masculinization.<ref name="pmid21802064"/><ref name="pmid23073980"/> In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1, and, probably, SRD5A2.<ref name="pmid23073980"/><ref name="pmid28774496"/><ref name="pmid32593151">{{cite journal |vauthors=du Toit T, van Rooyen D, Stander MA, Atkin SL, Swart AC |title=Analysis of 52 C19 and C21 steroids by UPC2-MS/MS: Characterising the C11-oxy steroid metabolome in serum |journal=J Chromatogr B Analyt Technol Biomed Life Sci |volume=1152 |issue= |pages=122243 |date=September 2020 |pmid=32593151 |doi=10.1016/j.jchromb.2020.122243 |url=}}</ref> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. Then this metabolic pathway proceeds to DHT the same way as the pathway that started with 17-OHP.<ref name="pmid30763313"/> Therefore, the pathway can be outlined as follows:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21802064"/><ref name="pmid23073980"/>}} === 5α-Dione Pathway === The pathway of A4 converted to androstanedione (5α-dione), and then to DHT (Figure 2) roundabout of T is unlikely to happen in sufficient quantities to have biological relevance in healthy humans. However, this pathway is relevant in CRPC.<ref name="pmid21795608"/> This pathway contains of two main steps: {{ordered list |The SRD5A1 enzyme 5α-reduces A4 to 5α-dione (also known as 5α-androstane-3,17-dione); |The HSD17B3 or AKR1C3 enzyme 17β-reduces 5α-dione to DHT.}} In this pathway, 5α-dione can also be interconverted with AST, which can also be converted to 3α-diol, which, in turn, can be converted to DHT by a number of dehydrogenases.<ref name="pmid11514561"/><ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> It should also be taken into consideration that the conversions of 5α-dione to AST and the conversion of DHT to 3α-diol are commonly considered inactivation reactions, but because these reactions are reversible, 3α-diol and AST may serve as a pool of inactive androgens and potential substrates for DHT. So, the alternative pathway that starts from A4 roundabout of T, called the "5α-dione" pathway, can be simplistically outlined as follows:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} 11x3gyrg2w2i4cnjbqf1vz27ybnwzn7 2408047 2408046 2022-07-19T20:35:04Z Maneesh 2723004 /* 5α-Reduction of 17α-Hydroxyprogesterone */ way way too much citing. Cut all those refs, the reviews are sufficient for these claim which have already been cited wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == === Backdoor Pathways to 5α-Dihydrotestosterone === A more detailed description of each alternative androgen pathway in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1)[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====5α-Reduction of 17α-Hydroxyprogesterone ==== In canonical androgen steroidogenesis, the 5α-reductases type 2 and 3 (SRD5A2 and SRD5A3) catalyze the transformation of T to DHT in the terminal step. However, in the initial step into the androgen backdoor pathways to DHT, 5α-reductases type 1 (SRD5A1)r educes a pregnane — 17-OHP or P4 — which is ultimately converted to DHT. Therefore, while 5α-reduction of a steroid is the last transformation in the canonical pathway, it is the first step in a backdoor pathway.[[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone) catalyzed SRD5A1 according to comprehensive source.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> This is seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be specified as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====5α-reduction of Progesterone==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and has been confirmed first in mice<ref name="pmid15249131"/> and later in humans.<ref name="pmid30763313"/> Therefore, this pathway also essential for normal masculinization.<ref name="pmid21802064"/><ref name="pmid23073980"/> In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1, and, probably, SRD5A2.<ref name="pmid23073980"/><ref name="pmid28774496"/><ref name="pmid32593151">{{cite journal |vauthors=du Toit T, van Rooyen D, Stander MA, Atkin SL, Swart AC |title=Analysis of 52 C19 and C21 steroids by UPC2-MS/MS: Characterising the C11-oxy steroid metabolome in serum |journal=J Chromatogr B Analyt Technol Biomed Life Sci |volume=1152 |issue= |pages=122243 |date=September 2020 |pmid=32593151 |doi=10.1016/j.jchromb.2020.122243 |url=}}</ref> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. Then this metabolic pathway proceeds to DHT the same way as the pathway that started with 17-OHP.<ref name="pmid30763313"/> Therefore, the pathway can be outlined as follows:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21802064"/><ref name="pmid23073980"/>}} === 5α-Dione Pathway === The pathway of A4 converted to androstanedione (5α-dione), and then to DHT (Figure 2) roundabout of T is unlikely to happen in sufficient quantities to have biological relevance in healthy humans. However, this pathway is relevant in CRPC.<ref name="pmid21795608"/> This pathway contains of two main steps: {{ordered list |The SRD5A1 enzyme 5α-reduces A4 to 5α-dione (also known as 5α-androstane-3,17-dione); |The HSD17B3 or AKR1C3 enzyme 17β-reduces 5α-dione to DHT.}} In this pathway, 5α-dione can also be interconverted with AST, which can also be converted to 3α-diol, which, in turn, can be converted to DHT by a number of dehydrogenases.<ref name="pmid11514561"/><ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> It should also be taken into consideration that the conversions of 5α-dione to AST and the conversion of DHT to 3α-diol are commonly considered inactivation reactions, but because these reactions are reversible, 3α-diol and AST may serve as a pool of inactive androgens and potential substrates for DHT. So, the alternative pathway that starts from A4 roundabout of T, called the "5α-dione" pathway, can be simplistically outlined as follows:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} n69itpzuuusi4vfbp3vope2djqa8lyu 2408048 2408047 2022-07-19T20:37:56Z Maneesh 2723004 /* Backdoor Pathways to 5α-Dihydrotestosterone */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == === Backdoor Pathways to 5α-Dihydrotestosterone === A more detailed description of each alternative androgen pathway in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1).[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====5α-Reduction of 17α-Hydroxyprogesterone ==== In canonical androgen steroidogenesis, the 5α-reductases type 2 and 3 (SRD5A2 and SRD5A3) catalyze the transformation of T to DHT in the terminal step. However, in the initial step into the androgen backdoor pathways to DHT, 5α-reductases type 1 (SRD5A1)r educes a pregnane — 17-OHP or P4 — which is ultimately converted to DHT. Therefore, while 5α-reduction of a steroid is the last transformation in the canonical pathway, it is the first step in a backdoor pathway.[[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone) catalyzed SRD5A1 according to comprehensive source.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> This is seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be specified as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====5α-reduction of Progesterone==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. This route is also activated in mammals during normal male prenatal development, and has been confirmed first in mice<ref name="pmid15249131"/> and later in humans.<ref name="pmid30763313"/> Therefore, this pathway also essential for normal masculinization.<ref name="pmid21802064"/><ref name="pmid23073980"/> In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway of male fetuses are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1, and, probably, SRD5A2.<ref name="pmid23073980"/><ref name="pmid28774496"/><ref name="pmid32593151">{{cite journal |vauthors=du Toit T, van Rooyen D, Stander MA, Atkin SL, Swart AC |title=Analysis of 52 C19 and C21 steroids by UPC2-MS/MS: Characterising the C11-oxy steroid metabolome in serum |journal=J Chromatogr B Analyt Technol Biomed Life Sci |volume=1152 |issue= |pages=122243 |date=September 2020 |pmid=32593151 |doi=10.1016/j.jchromb.2020.122243 |url=}}</ref> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. Then this metabolic pathway proceeds to DHT the same way as the pathway that started with 17-OHP.<ref name="pmid30763313"/> Therefore, the pathway can be outlined as follows:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT<ref name="pmid21802064"/><ref name="pmid23073980"/>}} === 5α-Dione Pathway === The pathway of A4 converted to androstanedione (5α-dione), and then to DHT (Figure 2) roundabout of T is unlikely to happen in sufficient quantities to have biological relevance in healthy humans. However, this pathway is relevant in CRPC.<ref name="pmid21795608"/> This pathway contains of two main steps: {{ordered list |The SRD5A1 enzyme 5α-reduces A4 to 5α-dione (also known as 5α-androstane-3,17-dione); |The HSD17B3 or AKR1C3 enzyme 17β-reduces 5α-dione to DHT.}} In this pathway, 5α-dione can also be interconverted with AST, which can also be converted to 3α-diol, which, in turn, can be converted to DHT by a number of dehydrogenases.<ref name="pmid11514561"/><ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> It should also be taken into consideration that the conversions of 5α-dione to AST and the conversion of DHT to 3α-diol are commonly considered inactivation reactions, but because these reactions are reversible, 3α-diol and AST may serve as a pool of inactive androgens and potential substrates for DHT. So, the alternative pathway that starts from A4 roundabout of T, called the "5α-dione" pathway, can be simplistically outlined as follows:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} be0mblydiiuzs45d6r9wq66rqju7pb4 2408076 2408048 2022-07-20T02:31:53Z Maneesh 2723004 /* Biochemistry */ lots of cutting of backdoor and 5a dione. still see way too many cites...they need to be cleaned wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone) catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> This seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, relevant in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The term "oxygenated" is used to denote the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|doi=10.1016/S0300-595X(72)80024-0|title=The chemistry of the steroids |year=1972 |last1=Makin |first1=H.L.J. |last2=Trafford |first2=D.J.H. |journal=Clinics in Endocrinology and Metabolism |volume=1 |issue=2 |pages=333–360 }}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal |title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia |journal=Proc Soc Exp Biol Med |volume=85 |issue=3 |pages=428–9 |year=1954 |pmid=13167092 |doi=10.3181/00379727-85-20905 |url=|last1=Bongiovanni |first1=A. M. |last2=Clayton |first2=G. W. |s2cid=8408420 }}</ref><ref name="pmid23386646"/> Some scholars use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|doi=10.1016/0039-128X(64)90003-0|title=The metabolism of 11-Oxyandrogens in human subjects |year=1964 |last1=Slaunwhite |first1=W.Roy |last2=Neely |first2=Lavalle |last3=Sandberg |first3=Avery A. |journal=Steroids |volume=3 |issue=4 |pages=391–416 }}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=429–58 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=430|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O}}</ref> The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} ia4zwwzuf4cjdtdssy054kgh285z6a4 2408077 2408076 2022-07-20T02:37:07Z Maneesh 2723004 /* 11-Oxygenated Androgen Pathways */ moved some stuff to nomenclature wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The term "11-oxygenated" is used to mean that these steroids have a hydroxy (-OH) group or an oxo (=O) group attached to the carbon atom at position 11 (see Figure 1). 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated Androgen Pathways", "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone) catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> This seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, relevant in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of 11-oxygenated androgens also fall under our definition of the alternative androgen pathways. These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016, performing full-dose responses in order to determine half maximal effective concentration (EC₅₀) values.<ref name="pmid27442248">{{cite journal |title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored |journal=PLOS ONE |volume=11 |issue=7 |pages=e0159867 |year=2016 |pmid=27442248 |pmc=4956299 |doi=10.1371/journal.pone.0159867 |doi-access=free |last1=Pretorius |first1=Elzette |last2=Africander |first2=Donita J. |last3=Vlok |first3=Maré |last4=Perkins |first4=Meghan S. |last5=Quanson |first5=Jonathan |last6=Storbeck |first6=Karl-Heinz }}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal |title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells |journal=J Steroid Biochem Mol Biol |volume=218 |issue= |pages=106049 |year=2022 |pmid=34990809 |doi=10.1016/j.jsbmb.2021.106049 |last1=Handelsman |first1=David J. |last2=Cooper |first2=Elliot R. |last3=Heather |first3=Alison K. |s2cid=245635429 }}</ref> and 2022.<ref name="pmid35046557">{{cite journal |title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |journal=Prostate Cancer Prostatic Dis |year=2022 |pmid=35046557 |doi=10.1038/s41391-022-00491-z |last1=Snaterse |first1=Gido |last2=Mies |first2=Rosinda |last3=Van Weerden |first3=Wytske M. |last4=French |first4=Pim J. |last5=Jonker |first5=Johan W. |last6=Houtsmuller |first6=Adriaan B. |last7=Van Royen |first7=Martin E. |last8=Visser |first8=Jenny A. |last9=Hofland |first9=Johannes |s2cid=246040148 |url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf }}</ref> The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens and it's unlikely that they would have any relevant biological activity even in higher concentrations such as in the case of androgen excess.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> The biosynthesis of 11-oxygenated androgens does not ''require'' T or DHT as intermediate products. However, T ''may'' serve as a substrate for 11-oxygenated androgens. 11-Oxygenated androgens are potent and clinically relevant agonists of the androgen receptor.<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T in healthy women, but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> However, there are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} 0gybyic9dgke2m1so42gidvye1uzyh5 2408090 2408077 2022-07-20T03:02:27Z Maneesh 2723004 /* 11-Oxygenated Androgen Pathways */ saving work wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated Androgen Pathways", "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone) catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> This seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, relevant in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} cyf76kc9yq6fah2yqpnu0101ubnk08i 2408118 2408090 2022-07-20T04:41:39Z Maneesh 2723004 /* 5α-Dione Pathway */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated Androgen Pathways", "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone) catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> This seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) (also known as adrenosterone) are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} 74oj1objyneuw5hh1y0t7du375s7fr8 2408119 2408118 2022-07-20T04:42:35Z Maneesh 2723004 /* 11-Oxygenated Androgen Pathways */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated Androgen Pathways", "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone) catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> This seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108" /><ref name="pmid30753518">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women |journal=J Clin Endocrinol Metab |volume=104 |issue=7 |pages=2615–2622 |pmid=30753518 |pmc=6525564 |doi=10.1210/jc.2018-02527|last1=Nanba |first1=Aya T. |last2=Rege |first2=Juilee |last3=Ren |first3=Jianwei |last4=Auchus |first4=Richard J. |last5=Rainey |first5=William E. |last6=Turcu |first6=Adina F. |year=2019 }}</ref> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028" /> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal |title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood |journal=J Clin Endocrinol Metab |volume=105 |issue=8 |year=2020 |pmid=32498089 |pmc=7340191 |doi=10.1210/clinem/dgaa343 |last1=Davio |first1=Angela |last2=Woolcock |first2=Helen |last3=Nanba |first3=Aya T. |last4=Rege |first4=Juilee |last5=o'Day |first5=Patrick |last6=Ren |first6=Jianwei |last7=Zhao |first7=Lili |last8=Ebina |first8=Hiroki |last9=Auchus |first9=Richard |last10=Rainey |first10=William E. |last11=Turcu |first11=Adina F. |pages=e2921–e2929 }}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028">{{cite journal |title=Androgens During the Reproductive Years: What Is Normal for Women? |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5382–5392 |year=2019 |pmid=31390028 |doi=10.1210/jc.2019-01357|last1=Skiba |first1=Marina A. |last2=Bell |first2=Robin J. |last3=Islam |first3=Rakibul M. |last4=Handelsman |first4=David J. |last5=Desai |first5=Reena |last6=Davis |first6=Susan R. |s2cid=199467054 }}</ref> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108">{{cite journal|title = The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1 | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 202 | pages = 105724 | pmid = 32629108 | doi = 10.1016/j.jsbmb.2020.105724 | s2cid = 220323715 | url = | last1 = Barnard | first1 = Lise | last2 = Nikolaou | first2 = Nikolaos | last3 = Louw | first3 = Carla | last4 = Schiffer | first4 = Lina | last5 = Gibson | first5 = Hylton | last6 = Gilligan | first6 = Lorna C. | last7 = Gangitano | first7 = Elena | last8 = Snoep | first8 = Jacky | last9 = Arlt | first9 = Wiebke | last10 = Tomlinson | first10 = Jeremy W. | last11 = Storbeck | first11 = Karl-Heinz |year = 2020 }}</ref> There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518" /> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} dbe0qfph7up7mit4vlxkbeicmyxnrhm 2408121 2408119 2022-07-20T04:43:35Z Maneesh 2723004 /* 11-Oxygenated Androgen Pathways */ move this to clinical wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated Androgen Pathways", "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone) catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> This seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone (ACTH)) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone (11OHP4))<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone, 21-deoxycortisol (21dF)).<ref name="pmid28774496" /> Investigating the ''in vitro'' catalytic activity (min⁻¹) of CYP11B1 and CYP11B2 both enzymes have been shown to convert P4, A4 and T – Δ⁴ steroids, indicated the importance of the oxo group at the carbon position 3 in the steroid nucleus and the potential of androgens and pregnanes serving as substrates for the CYP11B1/CYP11B2 isozymes.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> Since CYP11B1/CYP11B2 isozymes are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Besides CYP11B1/CYP11B2, an essential enzyme towards potent 11-oxygenated androgens is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which converts 11β-hydroxy steroids to 11-oxo steroids, e.g. 11OHT to 11KT.<ref name="pmid23685396" /><ref name="pmid30825506" /> Another prerequsite enzyme towards potent 11-oxygenated androgens is AKR1C3 (known as HSD17B5) as it catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228"/><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646"/><ref name="pmid29936123"/> It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878"/> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794" /> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} 05ofspdlwjs2fdhx4h6uqgkxrpoqd5g 2408126 2408121 2022-07-20T05:18:40Z Maneesh 2723004 /* 11-Oxygenated Androgen Pathways */ lots of editing and moved out paras that do not belong here wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated Androgen Pathways", "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone) catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> This seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== There are the routes from A4 or T towards 11-oxygenated androgens. However, the predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT.<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> In general, the metabolic routes from A4 or T towards 11-oxygenated androgens imply a number of reactions:{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} n2b2lnzza71z6o56wmpn8q0cvakl6ho 2408127 2408126 2022-07-20T05:38:28Z Maneesh 2723004 /* From Androstenedione or Testosterone Towards 11-Oxygenated Androgens */ first sentence wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated Androgen Pathways", "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone) catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> This seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions:{{bulleted list |11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. }} }} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4.<!-- <pre> A4 → 11OHA4 ⇄ 11KA4 ⇄ 11KT ↓ ↓ ↓ 11OH-5αdione ⇄ 11K-5αdione ⇄ 11KDHT ⇄ 11OHDHT ⇅ ⇅ ⇅ ⇅ 11OHAST ⇄ 11KAST 11K-3αdiol → 11OH-3αdiol </pre>^{(the route from androstenedione (A4) towards 11-oxygenated androgens)}<pre> T → 11OHT ⇄ 11KT ↓ ↓ 11OH-3αdiol ⇄ 11OHDHT → 11KDHT ⇄ 11K-3αdiol </pre>^{(the route from testosterone (T) towards 11-oxygenated androgens)} --> ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} 1f18hq482xv0rbiewuw6t5co8knxgne 2408128 2408127 2022-07-20T05:39:55Z Maneesh 2723004 /* From Androstenedione or Testosterone Towards 11-Oxygenated Androgens */ removing list for now, so I can edit visually wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated Androgen Pathways", "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone) catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> This seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} 4tbfsj6xd3aust2udevnoouez9v6oje 2408156 2408128 2022-07-20T11:35:13Z Maxim Masiutin 2902665 minor correction that 11-oxygenated is not only about pathways, but also about any steroid, not necessarily an androgen wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone) catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> This seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} t1nulnvvzkfrq5rwnabusgpvpogb5dw 2408157 2408156 2022-07-20T11:35:42Z Maxim Masiutin 2902665 it was a grammar error wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone) catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> This seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} cscr5eyct80sja4ga4g1oenh7rjnc5m 2408158 2408157 2022-07-20T11:40:47Z Maxim Masiutin 2902665 it was a grammar problem: it was not clear to what the word "this" was related in the sentence "This seems to be based", and the sentence was very complicated. So I split it to the two sentences and clarified to what the word "this" applies. wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} rmo298078z0twn0t5uy3crejb0098wy 2408159 2408158 2022-07-20T11:42:47Z Maxim Masiutin 2902665 removed newlines wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are be produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} jtxjpjvhxepqzdk0agxaxfu6oxvta6r 2408160 2408159 2022-07-20T11:47:40Z Maxim Masiutin 2902665 grammar fix wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === On Serum 11KT Measurements === In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} lt8viqtlfshmp21a8ztwfjs097p4p46 2408161 2408160 2022-07-20T11:53:50Z Maxim Masiutin 2902665 /* Clinical Significance */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === Biological role of 11KT === 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === ??? === Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} mwt98a1thquphwd9swyu5jn2e354bzr 0 271292 2408027 2407909 2022-07-19T15:22:10Z Bobamnertiopsis 24451 /* Results */ integrate table headers into tables wikitext text/x-wiki {{Article info |journal=WikiJournal of Science <!-- WikiJournal of Medicine, Science, or Humanities --> |abstract= '''Background:''' Kunu is a local beverage drink that finds its origin in the northern part of Nigeria. This study was aimed at determining the effect of the liquid drink on the epididymes, testes, sperm parameters and hormonal assay. '''Methods:''' A total of sixteen rats were used for this study and the animals were separated into four groups of four rats each (A-D). The animals were then sacrificed and the testes and epididymes harvested and fixed in 10% formal saline. Group A were fed only rat feed and water. Groups B, C and D were fed 0.2ml, 0.9ml and 2.5ml of Kunu respectively orally using a metal cannula for a period of 21 days. '''Findings:''' There was a significant increase (P<0.05) in the relative testicular weights of groups B, C and D as compared with those of group A. There was a significant decrease (P<0.05) in sperm count in groups B, C and D when compared to group A. There was an insignificant increase (P>0.05) in FSH in groups B, C and D when compared to group A. The histopathological findings revealed that the group B rats of 0.2ml and group C rats of 0.9ml showed epididymal tissue with moderate accumulation of spermatozoa and testicular tubules with moderate enhanced spermatogenesis. The group D rats showed well accumulated spermatozoa in the epididymal lumen and improved spermatogenesis in the testis as did group A. '''Conclusion:''' Kunu beverage may not be used as a natural male fertility booster since it does little to improve sperm count, motility, morphology, pH and hormonal levels of FSH and testosterone.}} == Introduction == In a sexual world like ours, there is an urgency for people across the globe to meet their sexual needs daily. The problem of infertility touches several factors which affect both males and females. In cases of male factor infertility which concentrates on testicular activity and sperm production as well as libido, there are two options for raising testosterone production and enhancing sperm production which is: the use of synthetic steroids and natural boosters.<ref name=":1">{{cite book |last1=Bazar |first1=RM |title=Healthy Prostate: The Extensive Guide To Prevent and Heal Prostate Problems Including Prostate Cancer, BPH Enlarged Prostate and Prostatitis |date=2011 |publisher=Self-published |location=Mansons Landing, British Columbia |isbn=978-1466369252}}</ref> The use of synthetic steroids such as synthetic testosterone and gonadotropins has adverse effects such as reduced testes size, micturition problems, gynecomastia, sleep disturbances, etc.,<ref name=":1" /> which is why a better approach to the problem of male factor infertility (due to azoospermia, oligospermia or any other related spermatic problem) is the use of natural boosters of which the local northern drink Kunu is a prominent example. Kunu is a popular drink consumed throughout Nigeria but mostly in the North. It can be made from grains such as millet, sorghum, maize, and rice. The variety of drinks made from sorghum is a milky light-brown colour while that of maize or millet is whitish. Generally, consumption cuts across all age groups and social statuses with the peak of consumption being the hot season of the year (February – June) when it is served chilled particularly Kunun Zaki.<ref name=":2">{{cite journal |last1=Terna |first1=G |last2=Jideani |first2=IA |last3=Nkama |first3=I |title=Nutritional composition of different types of kunu produced in gauche and gumbo states of Nigeria |journal=International Journal of Food Properties |date=2002 |volume=5 |issue=2 |pages=351–357 |doi=10.1081/JFP-120005790}}</ref> Testes also called testicle in animals is the organ that produces sperm and androgen. In humans, the testes occur as a pair of oval-shaped organs. Both functions of the testes are influenced by gonadotropic hormones produced by the anterior pituitary gland. Luteinizing hormone (LH) is also produced but the anterior pituitary gland results in testosterone release. Both hormones are needed to support the process of spermatogenesis.<ref name=":3">{{cite journal |last1=Skinner |first1=MK |last2=Fritz |first2=IB |title=Testicular peritubular cells secrete a protein under androgen control that modulates Sertoli cell functions |journal=Proceedings of the National Academy of Sciences |date=1985 |volume=82 |issue=1 |pages=114–118 |doi=10.1073/pnas.82.1.114}}</ref> There are two phases in which the testes grow substantially: namely in embryonic and pubertal stages.<ref name=":4">{{cite book |last1=Gilbert |first1=SF |title=Developmental Biology |date=2000 |publisher=Sinauer Associates |location=Sunderland, Massachusetts |isbn=978-0878932436 |edition=6th}}</ref> After puberty, the volume of the testes can be increased by over 500% as compared to the pre-pubertal size.<ref name=":5">{{cite web |last1=Crane |first1=J |last2=Scott |first2=R |title=''Eubalaena glacialis'': North Atlantic right whale |url=https://animaldiversity.org/accounts/Eubalaena_glacialis/ |website=Animal Diversity Web |publisher=University of Michigan Museum of Zoology|date=2002}}</ref> Hence, this work set out to assess the effects of Kunu on the histomorphology of the testes and epididymis, and parameters of sperm count, sperm motility, and sperm viability using the short-term in vivo assays in adult male Wistar rats. == Methods == '''Materials:''' The following materials were used in this experiment: Sixteen male Wistar Rats, oral cannula, kunu (local beverage), four standard cages, distilled water, cotton wool and hand gloves, beakers and measuring cylinder, animal weighing balance (CAMRY LB11), electronic weighing balance (NAPCO Precision Instruments JA-410), diethyl Ether, vital top feed (Jos, Nigeria), dissecting kit, EDTA container and plain container, micro-hematocrit centrifuge SH120, capillary tube, 5 ml hypodermic syringe, Deep and flat feeding plates, Plastic bottles, 10% buffered formalin, hemocytometer filter paper (Whatman qualitative filter paper n. 1, sigma Aldrich WHA1001042), thermostat oven (DHG-9023A, PEC MEDICAL USA), and spectrophotometer (Model 721). Preparation of Kunu:(local beverage): Millet grains were soaked in a bowl of water and left overnight. The soaked millet was mixed with chops of dried sweet potatoes and ginger and blended into a paste. The paste mixture was divided into two equal parts; the one part was stirred with boiling water and left to cool. The other part was then poured into this mixture, and the new mixture was then stirred to achieve thickness, and then sieved to remove the chaff. Experimental Animal: Sixteen male Wistar rats weighing between 170 - 200g were used for this study. The animals were allowed to acclimatize for two weeks, after which they were randomly selected into 4 groups of 4 animals each. Group A served as a control (the animals received only water and feed) Group B received 100 mg/kg or 2 ml of kunu (local beverage) Group C received 400 mg/kg or 9 ml of kunu (local beverage) Group D received 1200 mg/kg or 2.5ml of kunu (local beverage). The administration lasted for 21 days, taking place between 7 to 10 am daily. The animals were then sacrificed after the aforementioned period, semen and blood were collected for seminal analysis and hormonal assay test, while the testes and epididymis were harvested for histopathological findings. '''Acute Toxicity Test (Ld50) of Kunu:''' The acute toxicity test of Kunu (local beverage) was carried out in the Department of Anatomy, Faculty of Basic Medical Sciences, Nnamdi Azikiwe University, Nnewi Campus, Nnewi, Anambra State according to the method employed by Lorke.<ref name=":6">{{cite journal |last1=Lorke |first1=D |title=A new approach to practical acute toxicity testing |journal=Archives of Toxicology |date=1983 |volume=54 |issue=4 |pages=275–287 |doi=10.1007/BF01234480}}</ref> No toxic effect was observed on the treatment of Kunu drink up to the effective dose of 5000 mg/kg body weight of adult Wistar rats. The behavior of the treated rats appeared normal and no deaths occurred. '''Procedure for Semen Collection:''' The caudal epididymis was isolated from the testes and lacerated in a warm physiological solution to collect semen for sperm characteristics studies. A sperm count was conducted according to the method described by Hafez<ref name=":7">{{cite journal |last1=Hafez |first1=DA |title=Effect of extracts of ginger roots and cinnamon bark on fertility of male diabetic rats |journal=Journal of American Science |date=2010 |volume=6 |issue=10 |pages=940–947 |url=https://www.jofamericanscience.org/journals/am-sci/am0610/111_3708am0610_940_947.pdf}}</ref> using a microscope with an improved Neubauer hemocytometer. Sperm motility (%) was determined through a light microscope within 5 minutes of isolation of sperm from the epididymis.<ref name=":8">{{cite journal |last1=Ige |first1=SF |last2=Olaleye |first2=SB |last3=Akhigbe |first3=RE |last4=Akanbi |first4=TA |last5=Oyekunle |first5=OA |last6=Udoh |first6=U-AS |title=Testicular toxicity and sperm quality following cadmium exposure in rats: Ameliorative potentials of ''Allium cepa'' |journal=Journal of Human Reproductive Sciences |date=2012 |volume=5 |issue=1 |pages=37–42 |doi=10.4103/0974-1208.97798}}</ref> Sperm viability was examined based on the method reported by Bearden and Fuquay.<ref name=":9">{{cite book |last1=Bearden |first1=HJ |last2=Fuquay |first2=JW |title=Applied Animal Reproduction |date=1992 |publisher=Prentice Hall |location=Englewood Cliffs, New Jersey |isbn=9780130403469|edition=3rd}}</ref> Eosin and Fast Green were used to distinguish motile (live) sperm from non-motile groups(dead) sperm. These sperm cells were counted under 40× magnification. The average count of motile and non-motile groups was recorded, from which the viability percentage was calculated. The number and percentage of normal sperm were determined according to the method proposed by Chemineau et al.<ref name=":10">{{cite book |last1=Chemineau |first1=P |last2=Geuenin |first2=Y |last3=Orgeur |first3=P |last4=Vallel |first4=C |title=Training Manual on Artificial Insemination in Sheep and Goats |date=1991 |publisher=Food and Agriculture Organization of the United Nations |location=Rome |isbn=9789251028087}}</ref> based on the slides used for the calculation of sperm viability. '''Procedure for Hormonal Assay''' '''Testosterone Test:''' Testosterone levels were determined in the serum of male rats by Elecsys Analyzer, D-Vi-S, using kits from Roche Diagnostics GmbH, D-68298, Mannheim, Germany. '''Determination of Follicle Stimulating Hormone by Radioimmunoassay Technique:''' Serum levels of Follicle-stimulating hormone (FSH) were assayed by RIA using reagents supplied by Rat Pituitary Distribution and NIDDK (Bethesda, MD, USA) '''Statistical Analysis:''' The statistical analysis of this research was done using ANOVA and Student's ''t''-test of SPSS version 23 software package and P < 0.05 was considered as the level of significance. == Results == {| class="wikitable" |+ Table 1: Effects of Kunu on the Body Weight !'''Groups''' !'''Body weight (g)''' !'''Mean ± SEM''' !'''P - Value''' !'''T- Value''' |- | rowspan="2" |'''Group A''' |'''Initial''' |160.00 ± 20.00 | rowspan="2" | 0.588 | rowspan="2" | -0.640 |- |'''Final''' |176.66 ±14.52 |- | rowspan="2" |'''Group B''' |'''Initial''' |186.67 ± 8.81 | rowspan="2" | 0.208 | rowspan="2" | -1.835 |- |'''Final''' |213.33 ±12.01 |- | rowspan="2" |'''Group C''' |'''Initial''' |173.33 ± 8.81 | rowspan="2" | 0.225 | rowspan="2" | -1.732 |- |'''Final''' |203.33 ± 8.81 |- | rowspan="2" |'''Group D''' |'''Initial''' |183.33 ± 6.66 | rowspan="2" | 0.221 | rowspan="2" | -1.075 |- |'''Final''' |193.33 ± 6.66 |} Data were analyzed using One-way ANOVA, and data were considered significant at P < 0.05* and P > 0.05 means not significant. {| class="wikitable" |+Table 2: Effect of Kunu on Relative Testicular Weight and Epididymis Weight !'''Organ weight''' !'''Group''' !'''Mean ±SEM''' !'''P-value''' !'''F-value''' |- | rowspan="4" |'''Relative testicular weight (g)''' |'''Group A''' |0.60 ±0.00 | | |- |'''Group B''' |0.77 ±0.00 |0.000* |39.661 |- |'''Group C''' |0.78 ±0.01 |0.000* | |- |'''Group D''' |0.71 ±0.02 |0.000* | |- | rowspan="4" |'''Relative epididymis weight (g)''' |'''Group A''' |0.50 ±0.00 | | |- |'''Group B''' |0.37 ±0.05 |0.014* |6.606 |- |'''Group C''' |0.34 ±0.01 |0.005* | |- |'''Group D''' |0.46 ±0.02 |0.444 | |} Data were analyzed using One-way ANOVA, followed by LSD comparison, and data were considered significant at P < 0.05 and P > 0.05 means not significant, it is also significant at the level of 0.01 and less. {| class="wikitable" |+Table 3:''' '''The Effect of Kunu on Sperm Motility and Total Sperm Count !'''Sperm parameters''' !'''Groups''' !'''Mean ±SEM''' !'''P-value''' !'''F-value''' |- | rowspan="4" |'''Sperm Motility (%)''' |'''Group A''' |90.00 ±2.88 | | |- |'''Group B''' |83.33 ±1.67 |0.047* |13.888 |- |'''Group C''' |76.67 ±1.66 |0.002* | |- |'''Group D''' |73.00 ±1.52 |0.000* | |- | rowspan="4" |'''Total Sperm Count (x10^6/L)''' |'''Group A''' |6.80 ±0.05 | | |- |'''Group B''' |3.81 ±0.07 |0.459 |13.636 |- |'''Group C''' |6.38 ±0.27 |0.001* | |- |'''Group D''' |6.58 ±0.69 |0.701 | |} Data were analyzed using One-way ANOVA, followed by LSD comparison, and data were considered significant at P < 0.05 and P > 0.05 means not significant, it is also significant at the level of 0.01 and less. {| class="wikitable" |+Table 4: The effect of Kunu on sperm pH !'''Sperm parameters''' !'''Group''' !'''Mean SEM''' !'''P-value''' !'''F-value''' |- | rowspan="4" |'''Sperm pH''' |'''Group A''' |6.16 ±0.16 | | |- |'''Group B''' |6.33 ±0.16 |0.650 |1.296 |- |'''Group C''' |6.50 ±2.88 |0.650 | |- |'''Group D''' |6.83 ±0.33 |0.096 | |} Data were analyzed using One-way ANOVA, followed by LSD comparison and data were considered significant at P < 0.05 and P > 0.05 means not significant, it is also significant at the level of 0.01 and less. {| class="wikitable" |+Table 5: The effect of Kunu on FSH and testosterone level !'''Hormone''' !'''Groups''' !'''Mean ±SEM''' !'''P-value''' !'''F-value''' |- | rowspan="4" |'''Follicular Stimulating Hormone (uIu/L)''' |'''Group A''' |2.80 ±0.10 | | |- |'''Group B''' |2.73 ±0.08 |0.771 |0.545 |- |'''Group C''' |2.70 ±0.05 |1.000 | |- |'''Group D''' |2.60 ±0.05 |0.392 | |- | rowspan="4" |'''Testosterone (ng/mL)''' |'''Group A''' |4.80 ±0.05 | | |- |'''Group B''' |4.03 ±0.12 |0.001* |16.700 |- |'''Group C''' |4.10 ±0.15 |0.002* | |- |'''Group D''' |3.80 ±0.05 |0.000* | |} Data were analyzed using One-way ANOVA followed by LSD comparison and data were considered significant at P < 0.05 and P > 0.05 means not significant, it is also significant at the level of 0.01 and less. {| class="wikitable" |+Table 6: Shows the effect of Kunu on normal sperm and abnormal sperm !'''Hormone''' !'''Groups''' !'''Mean ±SEM''' !'''P-value''' !'''F-value''' |- | rowspan="4" |'''Normal Sperm (%)''' |'''Group A''' |86.67 ±3.33 | | |- |'''Group B''' |86.66 ±1.67 |1.000 |0.667 |- |'''Group C''' |86.00 ±1.67 |1.000 | |- |'''Group D''' |90.00 ±0.00 |0.282 | |- | rowspan="4" |'''Abnormal Sperm (%)''' |'''Group A''' |13.37 ± 3.33 | | |- |'''Group B''' |13.33 ±1.67 |1.000 |0.667 |- |'''Group C''' |14.00 ±1.67 |1.000 | |- |'''Group D''' |10.00 ±0.00 |0.282 | |} Data were analyzed using One-way ANOVA followed by LSD comparison, and data were considered significant at P < 0.05 and P > 0.05 means not significant, it is also significant at the level of 0.01 and less. Photomicrograph sections of normal control of epididymis (PLATE- - A) and testes (PLATE- - B). WAS: well accumulated spermatozoa, S: spermatogenesis, ICL: interstitial cells of Leydig, SC: Sertoli cells Photomicrograph section of epididymis (PLATE- - C) and testes (PLATE- - D) administered with high dose 2.5ml of local millet drink Kunu (x100)() (H/E) showed enhancement of all histoarchitectural structures. WAS: well accumulated spermatozoa, S: spermatogenesis, ICL: interstitial cells of Leydig, SC: Sertoli cells == Discussion == Men take fertility drugs to increase their sperm count and motility. The Male hormones should be adequate to produce healthy sperms. The anterior pituitary is responsible for controlling the male hormones, hence, sperm production. Around 2% of men with infertility experience secondary hypogonadism (pituitary gland disease). This happens when the gland fails to function properly preventing sperm and testosterone production. Men with this condition will either have no or low sperm count.<ref name=":11">{{cite journal |last1=Kumar |first1=P |last2=Kumar |first2=N |last3=Thakur |first3=DS |last4=Patidar |first4=A |title=Male hypogonadism: Symptoms and treatment |journal=Journal of Advanced Pharmaceutical Technology & Research |date=2010 |volume=1 |issue=3 |pages=297–301 |doi=10.4103/0110-5558.72420}}</ref> This condition is treatable by either pharmaceutical or natural means. There are very few drugs, approved by the U.S. Food and Drug Administration (FDA)), may help in stimulating sperm production such as Clomiphene, Letrozole, Synthetic testosterone pills, Bromocriptine, Imipramine, etc.,<ref name=":12">{{cite journal |title=Imipramine for successful treatment of retrograde ejaculation caused by retroperitoneal surgery |journal=International Journal of Andrology |date=1999 |volume=22 |issue=3 |pages=173–177 |doi=10.1046/j.1365-2605.1999.00165.x|last1=Ochsenkühn |first1=R|last2= Kamischke|first2= A|last3= Nieschlag|first3= E}}</ref> yet often they come with various side effects such as breast enlargement, changes in libido, liver problems, high blood pressure, etc.<ref name=":13">{{cite web|url=https://www.momjunction.com/articles/drugs-and-medication-to-treat-male-infertility_00122066/|title=7 fertility drugs for men to boost sperm count and motility|date=25 June 2018|accessdate=14 July 2022|archiveurl=https://web.archive.org/web/20180721012251/http://www.momjunction.com/articles/drugs-and-medication-to-treat-male-infertility_00122066/|archivedate=21 July 2018|last1=Malachi|first1=R|work=MomJunction}}</ref> Hence, there is a growing call, despite the cheapness and commonness of these drugs, to use natural remedies such as beverage (Kunu) this study chose to investigate to lessen the ample evidence indicating a steady decline in human sperm count and quality<ref name=":14">{{cite journal |last1=Auger |first1=J |last2=Kunstmann |first2=JM |last3=Czyglik |first3=F |last4=Jouannet |first4=P |title=Decline in semen quality among fertile men in Paris during the past 20 years |journal=New England Journal of Medicine |date=1995 |volume=332 |issue=5 |pages=281–285 |doi=10.1056/NEJM199502023320501}}</ref> without the backlog of any adverse effects. The results of this study showed that there was no significant change in weight of the experimental rat groups B, C, and D just as that of the control. This could be attributed to the low fat and protein content of the beverage. This study differs from the report made by Akbari ''et al.''<ref name=":15">{{cite journal |last1=Akbari |first1=A |last2=Nasiri |first2=K |last3=Heydari |first3=M |last4=Mosavat |first4=SH |last5=Iraji |first5=A |title=The protective effect of hydroalcoholic extract of ''Zingiber officinale'' Roscoe (ginger) on ethanol-induced reproductive toxicity in male rats |journal=Journal of Evidence-Based Complementary & Alternative Medicine |date=2017 |volume=22 |issue=4 |pages=609–617 |doi=10.1177/2156587216687696}}</ref> who reported that ''Zingiber officinale'' Roscoe (ginger), a condiment of Kunu, increased the body weight significantly in Wistar rats at 1g/kg of body weight. There was a significant increase (P< 0.05) in the relative testicular weight in the other groups when compared with the control group. This agrees with the discovery of Ekaluo ''et al.''<ref name=":16">{{cite journal |last1=Ekaluo |first1=UB |last2=Ikpeme |first2=EV |last3=Etta |first3=SE |last4=Ekpo |first4=PB |title=Effect of aqueous extract of tigernut (''Cyperus esculentus'' L.) on sperm parameters and testosterone level of male albino rats |journal=Asian Journal of Biotechnology |date=2014 |volume=7 |issue=1 |pages=39–45 |doi=10.3923/ajbkr.2015.39.45}}</ref> who reported a significant increase in the weight of the testis of albino rats administered with ''Cyperus esculentus'' (used in making Kunu aya) 1.8g/kg body weight which is due to the availability of the antioxidant vitamin C in Kunu and its protective role against oxidative stress and morphological changes of the testicular tissues. Results also revealed a significant decrease (P< 0.05) in relative epididymal weight group B compared to the control. The mechanism of this discrepancy is not understood, more so it disagrees with the work of Ekaluo ''et al''.<ref name=":16" /> who reported increasing weight of epididymis of the rats given an aqueous extract of Cyperus esculentus 1.8g/kg body weight. There was a significant decrease (P < 0.05) in sperm motility in the experimental groups when compared with the control. This does not agree with the findings of Akbari ''et al.''<ref name=":15" /> who state increased levels of sperm viability and motility of the Wistar rats given ''Zingiber officinale'', (found in Kunu), at 1g/kg body weight. There was also a significant (P > 0.05) decrease in the total sperm count in group B and an insignificant (P < 0.05) decrease in groups C, and D when compared to the control. This contradicts the findings of Hafez<ref name=":7" /> who reported a significant increase in sperm quality and quantity of Wistar rats to fed with 2g/kg body weight ginger roots and cinnamon bark. Sperm pH in groups B, C, and D slightly increased when compared to the control group A. This is in concordance with the work of Ekaluo ''et al''.<ref name=":16" /> on the effects of aqueous extract of ''Cyperus esculentus'' on male albino rats at 1.8g/kg per body weight which revealed a concomitant improvement in semen pH. This is due to higher sperm production as a result of an increase in testosterone stimulation of the spermatogenic cells to undergo successful spermatogenesis, sperm maturation in the epididymis and the secretory activity of the accessory sex glands as a result of the acidic pH environment provided by Kunu. The tabular results also evidence a significant (P<0.05) decrease in testosterone levels in the test groups when compared with the control group. This sharply contrasts with the report of Akinyemi ''et al.''<ref name=":17">{{cite journal |last1=Akinyemi |first1=AJ |last2=Adedara |first2=IA |last3=Thome |first3=GR |last4=Morsch |first4=VM |last5=Rovani |first5=MT |last6=Mujica |first6=LKS |last7=Duarte |first7=T |last8=Duarte |first8=M |last9=Oboh |first9=G |last10=Schetinger |first10=MRC |title=Dietary supplementation of ginger and turmeric improves reproductive function in hypertensive male rats |journal=Toxicology Reports |date=2015 |volume=2 |pages=1357–1366 |doi=10.1016/j.toxrep.2015.10.001}}</ref> on their work on ginger and cinnamon on male albino rats at 10mg/kg body weight. An insignificant decrease (P>0.05) in normal sperm in group B and C and an insignificant increase (P>0.05) in group D was recorded as compared with group A and this counters Khaki ''et al.''<ref name=":18">{{cite journal |last1=Khaki |first1=A |last2=Khaki |first2=AA |last3=Hajhosseini |first3=L |last4=Golzar |first4=FS |last5=Ainehchi |first5=N |title=The anti-oxidant effects of ginger and cinnamon on spermatogenesis dys-function of diabetes rats |journal=African Journal of Traditional, Complementary and Alternative Medicines |date=2014 |volume=11 |issue=4 |pages=1–8 |doi=10.4314/ajtcam.v11i4.1}}</ref> who worked on the Anti-oxidant effect of Ginger and Cinnamon on Spermatogenesis Dys-function of Diabetes Rats. There was an insignificant (P>0.05) decrease in abnormal sperm in group B and D and an insignificant increase (P>0.05) in group C when compared to group A. This is in agreement with the work of Ekaluo ''et al.''<ref name=":16" /> which states that there was no significant (P>0.05) effect of aqueous extract of ''Cyperus esculentus'' on sperm head abnormality but slight increases in a dose-dependent manner. Histopathological results of photomicrographs showed moderate epididymal accumulation of spermatozoa and testicular tissue with slightly enhanced seminiferous tubules and mildly improved spermatogenesis. This opposes the work of Khaki ''et al.''<ref name=":18" /> who reported that 100mg/kg of ginger and cinnamon fed rats showed increased spermatogenesis and testicular architecture. Dissimilar results were also found by the administration of ''Cyperus esculentus'' (Kunu aya) by Ekaluo ''et al''.<ref name=":16" /> in male albino rats. Also, 2.5ml of Kunu shows well enhanced epididymal architecture as well as accumulated luminal spermatozoa with a corresponding enhanced testicular tissue and well-improved spermatogenesis. This hardly corresponds with the study carried out by Akinyemi ''et al.''<ref name=":17" /> on dietary supplementation of ginger and turmeric improves reproductive function in hypertensive male rats and that carried out by Ekaluo ''et al.'',<ref name=":16" /> the effect of aqueous extract of ''Cyperus esculentus'' who reported improved spermatogenesis and testicular tissue enhancement in the 180mg/kg administration of ginger, a major condiment of Kunu. == Conclusion == In conclusion, this scientific study shows that the local millet drink, Kunu (Kunu-zaki) even though a product of ginger (which has antioxidant and androgenic properties with the capacity of increasing sperm parameters) does little to improve sperm count, motility, morphology, pH, and hormonal levels of FSH and testosterone. Kunu, instead attempts to maintain or slightly reduce normal levels of these parameters and the testicular and epididymal architectures as such may not be used as a possible natural fertility booster in males. == Additional information == === Acknowledgements === I sincerely acknowledge the Department of Anatomy, Faculty of Basic Medical sciences, Nnamdi Azikiwe University for their support in the course of this research work. === Competing interests === No conflict of interest. === Ethics statement === Ethical approval with the ethical number; NAU/FBMS/ETH123 was obtained from the ethical committee, Faculty of Basic Medical Sciences, College of Health Sciences, Nnamdi Azikiwe University. === Location of study === This study was carried out at the Animal House of the Faculty of Basic Medical Sciences, College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, Anambra State. === Author contributions === Darlington Cyprain Akukwu contributed to the design and developed the novel theory of the research findings. Godwin Chinedu Uloneme conceived, designed the research work and wrote the paper with input from all the authors. Damian Nnabuihe Ezejindu supervised the findings of this work and contributed to the development of the novel theory. Princewill Sopuluchukwu Udodi prepared the manuscript for publication, analyzed the anthropometric data collected and interpreted the histological slides. Ifesinachi Ogochukwu Ezejindu obtained the anthropometric data which include; the animal weight and the organ weight. Chukwudi Jesse Nwajagu acquired the animals and kept them under his care for the period of acclimatization and also administered the test substance in the entire test group except the control group. Benedict Nzube Obinwa sacrificed the animals, identified the organ of study and harvested the organ in all the animals. Ifechukwu Justicia Obiesie processed the tissue in preparation for the histological study. Emeka Christian Okafor contributed to the theoretical formalism and aid in the analytic calculations. Somadina Nnamdi Okeke contributed to the tissue processing and the labeling of the histological slide. Doris Kasarachi Ogbuokiri was part of the team that designed the model and the computational framework. Ambrose Echefulachi Agulanna worked out almost all of the technical details of the research work. Chisom Esther Oguejiofor was majorly saddled with the responsibility of handling the animals and ensure proper acclimatization of the animals. Chizubelu Irene Omile was the scientist that prepared the local beverage and ensure daily availability of the beverage, she was also part of the animal handling. Joshua Izuchukwu Abugu was primarily saddled with the responsibility of ensuring daily administration of the local beverages and also part of the animal handling team. == References == {{reflist|35em}} 14p953rw4qnveht3g5wwgjeqzmx7350 0 271693 2408139 2407985 2022-07-20T07:41:12Z 118.170.72.95 /* Base 17 */ reduced wikitext text/x-wiki A '''quasi-minimal prime''' is a [[w:Prime number|prime number]] for which there is no shorter [[w:Subsequence|subsequence]] of its [[w:Numerical digit|digit]]s in a given [[w:Radix|base]] ''b'' that form a prime > ''b''. For example, 857 is a quasi-minimal prime in [[w:Decimal|decimal]] because there is no prime > 10 among the shorter subsequences of the digits: 8, 5, 7, 85, 87, 57. The subsequence does not have to consist of consecutive digits, so 149 is not a quasi-minimal prime in decimal (because 19 is prime and 19 > 10). But it does have to be in the same order; so, for example, 991 is still a quasi-minimal prime in decimal even though a subset of the digits can form the shorter prime 19 > 10 by changing the order. (using A−Z to represent digit values 10 to 35) For the quasi-minimal primes in bases up to 36, I have only solved (found all quasi-minimal primes and proved that these are all such primes) bases 2~12, 14~15, 18, 20, 22, 24, 30 (bases 11, 22, 30 need primality proving of the probable primes). For the remain bases 13, 16~17, 19, 21, 23, 25~29, 31~36, there are some ''x''{''d''}''y'' (with ''x'', ''y'' strings (may be [[w:Empty string|empty]]) with digits in base ''b'', ''d'' digit in base ''b'') families which are not solved (not even a probable prime is known nor can be ruled out as only contain composites (only count the numbers > base (''b'')). I left as a challenge to readers the task of solving (finding all quasi-minimal primes and proving that these are all such primes) bases 13, 16~17, 19, 21, 23, 25~29, 31~36 (this will be a hard problem, e.g. base 23 has a quasi-minimal prime 9E₈₀₀₈₇₃, and base 36 has quasi-minimal prime P₈₁₉₉₃SZ). Proving the set of the quasi-minimal primes in base ''b'' is ''S'', is equivalent to: * Prove that all elements in ''S'', when read as base ''b'' representation, are primes > ''b''. * Prove that all [[w:Proper subset|proper]] subsequence of all elements in ''S'', when read as base ''b'' representation, which are > ''b'', are composite. * Prove that all primes > ''b'', when written in base ''b'', contain at least one element in ''S'' as subsequence (equivalently, prove that all strings not containing any element in ''S'' as subsequence, when read as base ''b'' representation, which are > ''b'', are composite). e.g. proving the set of the quasi-minimal primes in base ''b'' = 10 is {11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47, 53, 59, 61, 67, 71, 73, 79, 83, 89, 97, 227, 251, 257, 277, 281, 349, 409, 449, 499, 521, 557, 577, 587, 727, 757, 787, 821, 827, 857, 877, 881, 887, 991, 2087, 2221, 5051, 5081, 5501, 5581, 5801, 5851, 6469, 6949, 8501, 9001, 9049, 9221, 9551, 9649, 9851, 9949, 20021, 20201, 50207, 60649, 80051, 666649, 946669, 5200007, 22000001, 60000049, 66000049, 66600049, 80555551, 555555555551, 5000000000000000000000000000027}, is equivalent to: * Prove that all of 11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47, 53, 59, 61, 67, 71, 73, 79, 83, 89, 97, 227, 251, 257, 277, 281, 349, 409, 449, 499, 521, 557, 577, 587, 727, 757, 787, 821, 827, 857, 877, 881, 887, 991, 2087, 2221, 5051, 5081, 5501, 5581, 5801, 5851, 6469, 6949, 8501, 9001, 9049, 9221, 9551, 9649, 9851, 9949, 20021, 20201, 50207, 60649, 80051, 666649, 946669, 5200007, 22000001, 60000049, 66000049, 66600049, 80555551, 555555555551, 5000000000000000000000000000027 are primes > 10. * Prove that all proper subsequence of all elements in {11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47, 53, 59, 61, 67, 71, 73, 79, 83, 89, 97, 227, 251, 257, 277, 281, 349, 409, 449, 499, 521, 557, 577, 587, 727, 757, 787, 821, 827, 857, 877, 881, 887, 991, 2087, 2221, 5051, 5081, 5501, 5581, 5801, 5851, 6469, 6949, 8501, 9001, 9049, 9221, 9551, 9649, 9851, 9949, 20021, 20201, 50207, 60649, 80051, 666649, 946669, 5200007, 22000001, 60000049, 66000049, 66600049, 80555551, 555555555551, 5000000000000000000000000000027} which are > 10 are composite. * Prove that all primes > 10 contain at least one element in {11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47, 53, 59, 61, 67, 71, 73, 79, 83, 89, 97, 227, 251, 257, 277, 281, 349, 409, 449, 499, 521, 557, 577, 587, 727, 757, 787, 821, 827, 857, 877, 881, 887, 991, 2087, 2221, 5051, 5081, 5501, 5581, 5801, 5851, 6469, 6949, 8501, 9001, 9049, 9221, 9551, 9649, 9851, 9949, 20021, 20201, 50207, 60649, 80051, 666649, 946669, 5200007, 22000001, 60000049, 66000049, 66600049, 80555551, 555555555551, 5000000000000000000000000000027} as subsequence (equivalently, prove that all numbers > 10 not containing any element in {11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47, 53, 59, 61, 67, 71, 73, 79, 83, 89, 97, 227, 251, 257, 277, 281, 349, 409, 449, 499, 521, 557, 577, 587, 727, 757, 787, 821, 827, 857, 877, 881, 887, 991, 2087, 2221, 5051, 5081, 5501, 5581, 5801, 5851, 6469, 6949, 8501, 9001, 9049, 9221, 9551, 9649, 9851, 9949, 20021, 20201, 50207, 60649, 80051, 666649, 946669, 5200007, 22000001, 60000049, 66000049, 66600049, 80555551, 555555555551, 5000000000000000000000000000027} as subsequence are composite). ==Condensed table== {|class=wikitable |''b''||number of quasi-minimal primes base ''b''||base-''b'' form of largest known quasi-minimal prime base ''b''||length of largest known quasi-minimal prime base ''b''||algebraic ((''a''×''b''^''n''+''c'')/''d'') form of largest known quasi-minimal prime base ''b'' |- |2||1||11||2||3 |- |3||3||111||3||13 |- |4||5||221||3||41 |- |5||22||10₉₃13||96||5⁹⁵+8 |- |6||11||40041||5||5209 |- |7||71||3₁₆1||17||(7¹⁷−5)/2 |- |8||75||4₂₂₀7||221||(4×8²²¹+17)/7 |- |9||151||30₁₁₅₈11||1161||3×9¹¹⁶⁰+10 |- |10||77||50₂₈27||31||5×10³⁰+27 |- |11^*||1068||57₆₂₆₆₈||62669||(57×11⁶²⁶⁶⁸−7)/10 |- |12||106||40₃₉77||42||4×12⁴¹+91 |- |13^*||3195~3197||80₃₂₀₁₇111||32021||8×13³²⁰²⁰+183 |- |14||650||4D₁₉₆₉₈||19699||5×14¹⁹⁶⁹⁸−1 |- |15||1284||7₁₅₅97||157||(15¹⁵⁷+59)/2 |- |16^*||2346~2347||4₇₂₇₈₅DD||72787||(4×16⁷²⁷⁸⁷+2291)/15 |- |17^*||10407~10428||F70₁₈₆₇₆₇1||186770||262×17¹⁸⁶⁷⁶⁸+1 |- |18||549||C0₆₂₆₈C5||6271||12×18⁶²⁷⁰+221 |- |20||3314||G0₆₂₆₉D||6271||16×20⁶²⁷⁰+13 |- |22^*||8003||BK₂₂₀₀₁5||22003||(251×22²²⁰⁰²−335)/21 |- |24||3409||N00N₈₁₂₉LN||8134||13249×24⁸¹³¹−49 |- |30^*||2619||OT₃₄₂₀₅||34206||25×30³⁴²⁰⁵−1 |} ^* Data assumes the primality of the [[w:probable prime|probable prime]]s. Except bases ''b'' = 13, 16, 17, all bases in this table are completely solved (if we allow strong probable primes > 10²⁰⁰⁰⁰), also, except bases ''b'' = 11, 13, 16, 17, 22, 30, all bases in this table are completely solved even if we only allow definitely primes (thus, we can complete the classification of the quasi-minimal primes in these bases, i.e. the “quasi-minimal problems” in these bases are now theorems), for the quasi-minimal primes see the data below. Base ''b'' = 13 has 3195 known quasi-minimal primes (or PRPs), see the data below, and if there are more quasi-minimal primes in base 13, then they must be of the form 9{5} or A{3}A (we are unable to determine if these two families contain a prime or not, i.e. these two families have no known prime members, nor can these two families be ruled out as only containing composites), and must have at least 82000 digits in base 13, besides, since these two families can contain at most one quasi-minimal prime, there are at most 3197 quasi-minimal primes in base 13. (i.e. the quasi-minimal primes in base 13 are the 3195 known quasi-minimal primes in base 13 (they are given in the data section) plus the smallest prime in the family 9{5} in base 13 (if exists) plus the smallest prime in the family A{3}A in base 13 (if exists)) Base ''b'' = 16 has 2346 known quasi-minimal primes (or PRPs), see the data below, and if there are more quasi-minimal primes in base 16, then they must be of the form {3}AF (we are unable to determine if this family contains a prime or not, i.e. this family have no known prime members, nor can this family be ruled out as only containing composites), and must have at least 76000 digits in base 16, besides, since this family can contain at most one quasi-minimal prime, there are at most 2347 quasi-minimal primes in base 16. (i.e. the quasi-minimal primes in base 16 are the 2346 known quasi-minimal primes in base 16 (they are given in the data section) plus the smallest prime in the family {3}AF in base 16 (if exists)) ==Data for quasi-minimal primes== ===Base 2=== 11 ===Base 3=== 12, 21, 111 ===Base 4=== 11, 13, 23, 31, 221 ===Base 5=== 12, 21, 23, 32, 34, 43, 104, 111, 131, 133, 313, 401, 414, 3101, 10103, 14444, 30301, 33001, 33331, 44441, 300031, 100000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000013 ===Base 6=== 11, 15, 21, 25, 31, 35, 45, 51, 4401, 4441, 40041 ===Base 7=== 14, 16, 23, 25, 32, 41, 43, 52, 56, 61, 65, 113, 115, 131, 133, 155, 212, 221, 304, 313, 335, 344, 346, 364, 445, 515, 533, 535, 544, 551, 553, 1022, 1051, 1112, 1202, 1211, 1222, 2111, 3031, 3055, 3334, 3503, 3505, 3545, 4504, 4555, 5011, 5455, 5545, 5554, 6034, 6634, 11111, 11201, 30011, 30101, 31001, 31111, 33001, 33311, 35555, 40054, 100121, 150001, 300053, 351101, 531101, 1100021, 33333301, 5100000001, 33333333333333331 ===Base 8=== 13, 15, 21, 23, 27, 35, 37, 45, 51, 53, 57, 65, 73, 75, 107, 111, 117, 141, 147, 161, 177, 225, 255, 301, 343, 361, 401, 407, 417, 431, 433, 463, 467, 471, 631, 643, 661, 667, 701, 711, 717, 747, 767, 3331, 3411, 4043, 4443, 4611, 5205, 6007, 6101, 6441, 6477, 6707, 6777, 7461, 7641, 47777, 60171, 60411, 60741, 444641, 500025, 505525, 3344441, 4444477, 5500525, 5550525, 55555025, 444444441, 744444441, 77774444441, 7777777777771, 555555555555525, 44444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444447 ===Base 9=== 12, 14, 18, 21, 25, 32, 34, 41, 45, 47, 52, 58, 65, 67, 74, 78, 81, 87, 117, 131, 135, 151, 155, 175, 177, 238, 272, 308, 315, 331, 337, 355, 371, 375, 377, 438, 504, 515, 517, 531, 537, 557, 564, 601, 638, 661, 702, 711, 722, 735, 737, 751, 755, 757, 771, 805, 838, 1011, 1015, 1101, 1701, 2027, 2207, 3017, 3057, 3101, 3501, 3561, 3611, 3688, 3868, 5035, 5051, 5071, 5101, 5501, 5554, 5705, 5707, 7017, 7075, 7105, 7301, 8535, 8544, 8555, 8854, 20777, 22227, 22777, 30161, 33388, 50161, 50611, 53335, 55111, 55535, 55551, 57061, 57775, 70631, 71007, 77207, 100037, 100071, 100761, 105007, 270707, 301111, 305111, 333035, 333385, 333835, 338885, 350007, 500075, 530005, 555611, 631111, 720707, 2770007, 3030335, 7776662, 30300005, 30333335, 38333335, 51116111, 70000361, 300030005, 300033305, 351111111, 1300000007, 5161111111, 8333333335, 300000000035, 311111111161, 544444444444, 2000000000007, 5700000000001, 7270000000007, 88888888833335, 100000000000507, 5111111111111161, 7277777777777777707, 8888888888888888888335, 30000000000000000000051, 1000000000000000000000000057, 56111111111111111111111111111111111111, 7666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666662, 27777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777707, 300000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000011 ===Base 10=== 11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47, 53, 59, 61, 67, 71, 73, 79, 83, 89, 97, 227, 251, 257, 277, 281, 349, 409, 449, 499, 521, 557, 577, 587, 727, 757, 787, 821, 827, 857, 877, 881, 887, 991, 2087, 2221, 5051, 5081, 5501, 5581, 5801, 5851, 6469, 6949, 8501, 9001, 9049, 9221, 9551, 9649, 9851, 9949, 20021, 20201, 50207, 60649, 80051, 666649, 946669, 5200007, 22000001, 60000049, 66000049, 66600049, 80555551, 555555555551, 5000000000000000000000000000027 ===Base 11=== 12, 16, 18, 21, 27, 29, 34, 38, 3A, 43, 49, 54, 56, 61, 65, 67, 72, 76, 81, 89, 92, 94, 98, 9A, A3, 10A, 115, 117, 133, 139, 153, 155, 171, 193, 197, 199, 1AA, 225, 232, 236, 25A, 263, 315, 319, 331, 335, 351, 353, 362, 373, 379, 391, 395, 407, 414, 452, 458, 478, 47A, 485, 4A5, 4A7, 502, 508, 511, 513, 533, 535, 539, 551, 571, 579, 588, 595, 623, 632, 70A, 711, 715, 731, 733, 737, 755, 759, 775, 791, 797, 7AA, 803, 847, 858, 85A, 874, 885, 887, 913, 919, 931, 937, 957, 959, 975, 995, A07, A1A, A25, A45, A74, A7A, A85, AA1, AA7, 1101, 11A9, 1305, 1451, 1457, 15A7, 175A, 17A5, 17A9, 2023, 2045, 2052, 2083, 20A5, 2333, 2A05, 2A52, 3013, 3026, 3059, 3097, 3206, 3222, 3233, 3307, 3332, 3505, 4025, 4151, 4157, 4175, 4405, 4445, 4487, 450A, 4575, 5017, 5031, 5059, 5075, 5097, 5099, 5105, 515A, 517A, 520A, 5301, 5583, 5705, 577A, 5853, 5873, 5909, 5A17, 5A57, 5A77, 5A8A, 6683, 66A9, 7019, 7073, 7079, 7088, 7093, 7095, 7309, 7451, 7501, 7507, 7578, 757A, 75A7, 7787, 7804, 7844, 7848, 7853, 7877, 78A4, 7A04, 7A57, 7A79, 7A95, 8078, 8245, 8333, 8355, 8366, 8375, 8425, 8553, 8663, 8708, 8777, 878A, 8A05, 9053, 9101, 9107, 9305, 9505, 9703, A052, A119, A151, A175, A515, A517, A575, A577, A5A8, A719, A779, A911, AAA9, 10011, 10075, 10091, 10109, 10411, 10444, 10705, 10709, 10774, 10901, 11104, 11131, 11144, 11191, 1141A, 114A1, 13757, 1411A, 14477, 144A4, 14A04, 14A11, 17045, 17704, 1774A, 17777, 177A4, 17A47, 1A091, 1A109, 1A114, 1A404, 1A411, 1A709, 20005, 20555, 22203, 25228, 25282, 25552, 25822, 28522, 30037, 30701, 30707, 31113, 33777, 35009, 35757, 39997, 40045, 4041A, 40441, 4045A, 404A1, 4111A, 411A1, 42005, 44401, 44474, 444A1, 44555, 44577, 445AA, 44744, 44A01, 47471, 47477, 47701, 5057A, 50903, 5228A, 52A22, 52A55, 52A82, 55007, 550A9, 55205, 55522, 55557, 55593, 55805, 57007, 57573, 57773, 57807, 5822A, 58307, 58505, 58A22, 59773, 59917, 59973, 59977, 59999, 5A015, 5A2A2, 5AA99, 60836, 60863, 68636, 6A609, 6A669, 6A696, 6A906, 6A966, 70048, 70103, 70471, 70583, 70714, 71474, 717A4, 71A09, 74084, 74444, 74448, 74477, 744A8, 74747, 74774, 7488A, 74A48, 75773, 77144, 77401, 77447, 77799, 77A09, 78008, 78783, 7884A, 78888, 788A8, 79939, 79993, 79999, 7A051, 7A444, 7A471, 80005, 80252, 80405, 80522, 80757, 80AA5, 83002, 84045, 85307, 86883, 88863, 8A788, 90073, 90707, 90901, 95003, 97779, 97939, 99111, 99177, 99973, A0111, A0669, A0966, A0999, A0A09, A1404, A4177, A4401, A4717, A5228, A52AA, A5558, A580A, A5822, A58AA, A5A59, A5AA2, A6096, A6966, A6999, A7051, A7778, A7808, A9055, A9091, A9699, A9969, AA52A, AA58A, 100019, 100079, 101113, 101119, 101911, 107003, 140004, 144011, 144404, 1A0019, 1A0141, 1A5001, 1A7005, 1A9001, 222223, 222823, 300107, 300202, 300323, 303203, 307577, 310007, 332003, 370777, 400555, 401A11, 404001, 404111, 405AAA, 41A011, 440A41, 441011, 451777, 455555, 470051, 470444, 474404, 4A0401, 4A4041, 500015, 500053, 500077, 500507, 505577, 522A2A, 525223, 528A2A, 531707, 550777, 553707, 5555A9, 555A99, 557707, 55A559, 5807A7, 580A0A, 580A55, 58A0AA, 590007, 599907, 5A2228, 5A2822, 5A2AAA, 5A552A, 5AA22A, 5AAA22, 60A069, 683006, 6A0096, 6A0A96, 6A9099, 6A9909, 700778, 701074, 701777, 704408, 704417, 704457, 704484, 707041, 707441, 707708, 707744, 707784, 710777, 717044, 717077, 740008, 74484A, 770441, 770744, 770748, 770771, 777017, 777071, 777448, 777484, 777701, 7778A8, 777A19, 777A48, 778883, 78A808, 790003, 7A1009, 7A4408, 7A7708, 80A555, 828283, 828883, 840555, 850505, 868306, 873005, 883202, 900701, 909739, 909979, 909991, 970771, 977701, 979909, 990739, 990777, 990793, 997099, 999709, 999901, A00009, A00599, A01901, A05509, A0A058, A0A955, A10114, A555A2, A55999, A59991, A5A222, A5A22A, A60609, A66069, A66906, A69006, A79005, A87888, A90099, A90996, A96006, A96666, A97177, A97771, AA0A58, AA5A22, AAA522, 1000501, 1011141, 1030007, 1070047, 111114A, 1111A14, 1111A41, 1144441, 14A4444, 1700005, 1700474, 1A44444, 2555505, 2845055, 3030023, 3100003, 3333397, 4000111, 4011111, 41A1111, 4411111, 444441A, 4444771, 4470004, 4505005, 4744417, 4774441, 4777404, 4777417, 4777747, 4A11111, 4A40001, 5000093, 50005A7, 5005777, 5050553, 5055503, 5070777, 5222222, 5222AAA, 52AAAA2, 52AAAAA, 5505053, 5552AAA, 5555599, 5555A58, 5558A0A, 5558A55, 5558AAA, 55A0009, 55AAA52, 580000A, 5822222, 58AAAAA, 5A2222A, 5AA2222, 6000A69, 6000A96, 6A00069, 7000417, 7000741, 7000835, 7000857, 7007177, 7008305, 7014447, 7017444, 7074177, 7077477, 7077741, 7077747, 7100447, 7174404, 717444A, 7400404, 7700717, 7701077, 7701707, 7707778, 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DDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD ===Base 15=== 12, 14, 18, 1E, 21, 27, 2B, 2D, 32, 38, 3E, 41, 47, 4B, 4D, 54, 58, 5E, 67, 6B, 6D, 72, 74, 78, 87, 8B, 92, 94, 9E, A1, A7, AD, B2, B8, BE, C1, CB, CD, D2, D4, E1, ED, 111, 11B, 131, 137, 13B, 13D, 157, 15B, 15D, 171, 177, 197, 19D, 1B7, 1BB, 1D1, 1DB, 1DD, 234, 298, 311, 31B, 337, 33D, 344, 351, 357, 35B, 364, 377, 391, 39B, 39D, 3A4, 3BD, 3C4, 3D7, 3DB, 3DD, 452, 51B, 51D, 531, 53B, 551, 55D, 562, 571, 577, 5A2, 5B1, 5B7, 5BB, 5BD, 5C2, 5D1, 5D7, 634, 652, 681, 698, 717, 71B, 731, 737, 757, 75D, 77D, 79B, 79D, 7B1, 7B7, 7BD, 7D7, 7DD, 801, 852, 88D, 8D8, 91D, 93B, 93D, 95B, 95D, 971, 977, 97B, 97D, 988, 991, 9BD, 9C8, 9D1, A98, AAB, B1D, B31, B3B, B44, B51, B57, B7B, B7D, B97, B9B, BB7, BC4, BD1, BD7, BDD, C07, C34, C52, C7E, C98, CC7, CE7, D0E, D1D, D31, D51, D5B, D68, D77, D7B, D91, D97, DA8, DAE, DCE, DD1, EB4, EEB, 107B, 1091, 10B1, 1107, 110D, 1561, 1651, 1691, 1B01, 2052, 2502, 2522, 303B, 307D, 3097, 30BB, 30D1, 3107, 3361, 3701, 3907, 3B01, 3B0B, 3C97, 4434, 4498, 4834, 4898, 49A8, 4E34, 5037, 507D, 5091, 509B, 5107, 5161, 5202, 53C7, 5552, 570B, 590B, 590D, 59C7, 5A5B, 5C97, 5D0D, 5DAB, 6061, 6151, 6191, 6511, 6601, 6911, 707B, 7091, 7097, 70AE, 70BB, 70CE, 70DB, 7561, 760E, 7691, 76CE, 7907, 7961, 7A0E, 7A3B, 7AEE, 7B0B, 7BAB, 7C0E, 7C77, 7CAE, 7D0B, 7D61, 7DAB, 7E5B, 7E6E, 7E7B, 7EBB, 8098, 811D, 8191, 835D, 853D, 8881, 8908, 8951, 8968, 899D, 8D3D, 8D5D, 8D6E, 8DDD, 8E98, 9011, 9037, 9097, 90D7, 9301, 93C7, 95C7, 9611, 9631, 96A8, 9811, 9851, 989D, 990B, 990D, 998D, 99AB, 99C7, 99D8, 9A08, 9A9B, 9AA8, 9ABB, 9B61, 9BC7, 9D0B, 9DAB, 9DC7, 9DD8, A052, A304, A502, A55B, A9BB, AB04, AB64, B09D, B107, B10B, B161, B1AB, B1C7, B30D, B3C7, B50B, B664, B691, B6A4, B707, B761, B90D, B961, BA5B, BABB, BBAB, BBB4, BC37, BC77, C777, C937, C997, D011, D03D, D05D, D09B, D0B1, D0BD, D101, D10B, D30D, D3AB, D507, D50D, D66E, D761, D7DE, D811, D85D, D86E, D89D, D8C8, D8E8, D9AB, D9D8, DA3B, DA9B, DABB, DB01, DB61, DBAB, DC88, DD07, DD0B, DD7E, DD8D, DDE7, DE6E, E252, E33B, E522, E57B, E7AE, E7CE, E898, E997, E9A8, E9BB, EA34, EB5B, EE98, EEC7, 10017, 10B0D, 170AB, 17A0B, 19001, 19601, 1A09B, 1D0C7, 22E52, 2EA52, 30017, 3001D, 300B1, 301C7, 30334, 30631, 307AB, 3300B, 3333B, 36031, 36301, 37A0B, 37BBB, 39997, 3A30B, 3B0C7, 3D001, 3D601, 40034, 40968, 43334, 49668, 49998, 50022, 5009D, 501C7, 50222, 50507, 505C7, 50611, 50C57, 53007, 53997, 55537, 5555B, 5557B, 5599B, 56101, 56691, 56961, 5700D, 5755B, 59001, 59557, 59997, 5999D, 599DB, 59DDD, 5D99B, 5DD3D, 5DD9D, 60931, 63031, 65691, 66951, 69031, 69361, 69561, 70011, 70051, 7005B, 7006E, 7030D, 703AB, 70501, 70701, 707C7, 71601, 71951, 7300D, 7333B, 75001, 7555B, 75911, 76011, 76051, 766EE, 76EEE, 7700B, 77191, 77661, 7776E, 77771, 777BB, 77911, 77BBB, 79001, 7A05B, 7A66E, 7AA6E, 7AAAE, 7ACCE, 7C6EE, 7CCEE, 7CECE, 7CEEE, 7D3BB, 7E7C7, 7EECE, 80034, 80304, 80434, 809DD, 80A34, 84A34, 850DD, 85961, 86661, 88151, 88331, 88511, 88591, 88898, 890DD, 89998, 89D0D, 8D90D, 8E434, 90017, 90051, 900A8, 900DB, 901C7, 90C57, 90D8D, 91007, 91061, 9199B, 95997, 96068, 96561, 99397, 99537, 9999B, 999B7, 999D7, 999DB, 999DD, 99BBB, 99DBB, 99DD7, 99DDD, 9B007, 9B00B, 9B0AB, 9BB11, 9BBBB, 9D007, 9D08D, 9D537, 9D9BB, 9D9DB, 9DD57, 9DDB7, 9DDDB, 9DDDD, A0A34, A0B5B, A0BBB, A0E34, A2E52, A330B, A8434, A8834, A8E34, A909B, AAA34, AAE52, AB0BB, AB334, ABB34, AE034, AE834, AE99B, AEA52, AEE52, B0011, B0071, B0077, B00B1, B0611, B0A64, B500D, B599D, B6101, B7771, B7911, BA064, BAAA4, BAB34, BB061, BB304, BB53D, BB601, BBB91, BBB9D, BBBBD, BDA0B, BDBBB, D0088, D00D7, D0307, D05C7, D070D, D0888, D0B07, D0BC7, D0C08, D0DC7, D0DD8, D1661, D59DD, D5D3D, D5DDD, D6611, D700D, D8D0D, D900B, D9908, D999D, D9BBB, D9D9D, D9DDB, DB007, DB00D, DB1B1, DB53D, DB59D, DB99D, DBBB1, DD0D8, DD33B, DD3B7, DD3BB, DD57D, DD898, DD9DD, DDB37, DDBDB, DDD08, DDD3D, DDD5D, DDD7D, DDD88, DDD9D, DDDB7, DDDC8, DDDD7, DDE98, DE037, DE998, DEB07, E0098, E00C7, E0537, E0557, E077B, E0834, E0968, E3334, E37AB, E39C7, E4034, E5307, E55AB, E705B, E750B, E766E, E76EE, E8304, E8434, E9608, E9C37, EAE52, EBB0B, EC557, EC597, EC957, 1000BD, 1009AB, 10A90B, 1900AB, 190661, 19099B, 190A0B, 1A900B, 222A52, 2AAA52, 31000D, 330331, 333334, 3733AB, 373ABB, 3BBB61, 430004, 490068, 490608, 5000DB, 500D0B, 505557, 505A0B, 50D00B, 50DDDB, 50DDDD, 522222, 5500AB, 5500C7, 550957, 550A0B, 555A9B, 559057, 560011, 590661, 633331, 666331, 666591, 666661, 7050AB, 705A0B, 706101, 70A50B, 7300AB, 761661, 76666E, 777011, 777101, 77750B, 777A5B, 777CEE, 779051, 791501, 7E7797, 7ECCCE, 7EEE97, 800D9D, 808834, 836631, 83D661, 843004, 856611, 884034, 884304, 888E34, 88A434, 88AE34, 8A4034, 8AEE34, 8E8034, 8E8E34, 8EEE34, 9000BB, 9001AB, 900B07, 900D98, 903661, 905661, 906651, 9080DD, 9099A8, 909D9B, 90A668, 90DD9B, 90DDBB, 910001, 9100AB, 91A00B, 930007, 950001, 956661, 9909A8, 995907, 999068, 999507, 999907, 9B0B1B, 9B0BB1, 9BB01B, 9C5597, 9C5957, 9D09DD, 9D0D9D, 9D800D, 9DB307, 9DD09D, A00034, A0033B, A033B4, A2A252, AAAA52, ABBBBB, B00004, B0001B, B0003D, B00A04, B0555B, B07191, B07711, B07777, B0B911, B0BDBB, B77011, B777C7, BB0001, BB0034, BB035D, BB055B, BB0BDB, BB9101, BBB0DB, BBB50D, BBBB01, BBD0BB, C55397, C55557, C55597, D0003B, D00057, D0007D, D000B7, D000C8, D008DD, D00DAB, D0333B, D05537, D099DD, D09DDD, D0DDBB, D555C7, D5C537, D88008, D88088, D888EE, D909DD, D9D0DD, D9DD0D, DB0BBB, DBBB0B, DBBB0D, DC0008, DC5537, DDDDD8, DDDEBB, DDE99B, DE0808, DE0C57, DE300B, DE5537, DE8888, DEE088, DEE307, DEE888, DEEE37, DEEE57, DEEEC8, E0000B, E007BB, E00A52, E03BC7, E07ABB, E09B07, E0A99B, E0C397, E0E76E, E50057, E55007, E55597, E55937, E730AB, E73A0B, E80E34, E88834, E8E034, E90008, E95557, EA099B, EE4304, EE5057, EE5507, EE8E34, EE9307, EEE434, 100001D, 1000A9B, 1000DC7, 22AA252, 3000BC7, 3033301, 3076661, 333B304, 33B3034, 3B33304, 3D66661, 50007AB, 5005957, 5500597, 5550057, 5559007, 5559597, 5595007, 5966661, 5DDDDDB, 6366631, 7010001, 7066651, 7100061, 733BBBB, 766A6AE, 77505AB, 7776501, 777775B, 777AACE, 777ECCE, 777EEAE, 7CCCCCE, 7E30A0B, 7EEEEAE, 8300004, 8363331, 8693331, 880E834, 8833304, 8888034, 8888434, 888A034, 88A3334, 88E8834, 88EE034, 88EE304, 8AA3334, 8D0009D, 8EE8834, 9000361, 9000668, 9003331, 9005557, 9006008, 9008D0D, 9083331, 9090968, 90BBB01, 90D0908, 9500661, 9555597, 9555957, 9660008, 9900968, 9995597, 9996008, 9999557, 9999597, 9999908, 9A66668, A003B34, A003BB4, AA22252, B00B034, B00B35D, B033334, B0B6661, B0BB01B, B100001, B333304, B777777, B99999D, BA60004, BAA0334, BBB001B, BBB6611, BBBBB11, BBBD00B, BD000AB, D0000DB, D009098, D00CCC8, D00D908, D00D99D, D03000B, D0BB0BB, D0D9008, D0D9998, D1000C7, D800008, D8DDEEE, D90080D, DBBBBBB, DD09998, DDD5557, DDDDBBB, DDDDDBD, DDDE8EE, DECC008, DECCCC8, DEE0CC8, DEEC0C8, E000397, E0003BB, E000434, E00076E, E000937, E007A5B, E00909B, E0090B7, E009307, E00B077, E00E434, E00E797, E00E937, E05999B, E09009B, E0900B7, E0E0937, E0E7E97, E0EAA52, E0EEA52, E555057, E5555C7, E7777C7, E77E797, E88EE34, E999998, EA5999B, EB000BB, EB0BBBB, EE00434, EE0E797, EEE076E, EEE706E, EEE8834, EEEE557, EEEE797, 30333331, 30B66661, 33000034, 33030004, 33B33004, 500575AB, 55000007, 5500075B, 55500907, 55555057, 55555907, 55559507, 60003301, 60033001, 60330001, 7000003D, 70106661, 70666611, 77000001, 7777770B, 777777C7, 77777ACE, 77777EAE, 777E30AB, 777E3A0B, 7CCCC66E, 800005DD, 88AA0834, 90000008, 900008DD, 90099668, 90500557, 90555007, 90666668, 90909998, 90990998, 90996668, 9099999D, 90D00098, 90D90998, 95500057, 99099098, 99555057, 99900998, 99966608, 99966668, 99999668, 99999998, 9D009008, 9D090998, A0803334, A2222252, AAA52222, B00005AB, B000B55B, B0BBBB5B, B3330034, BB0BBB1B, BBAA3334, BBB0BB1B, BBB0BB5B, BBDB000B, D000BBBB, D00100C7, D8888888, D900008D, D9000098, DBB000BB, DC0CCCC8, DCC0CCC8, DCCCC008, DD000908, DD09009D, DDDDDDAB, DDDDDEEE, DDDEEE8E, DDDEEEE8, DEE80008, E0777E97, E0E0E397, E0E77797, E0EE0397, E7777797, E9066668, EE00E397, EE077797, EE0E0397, EEE00797, EEE07E97, EEE0AA52, EEE55397, EEE55557, EEEAAA52, EEEEE834, EEEEEA52, 300003331, 300007661, 300330031, 333000004, 333300001, 333B00034, 3700000AB, 3B3300034, 500000057, 555555007, 555555557, 5DDDDDDDD, 600000331, 7500000AB, 75000A00B, 75A00000B, 761000001, 77000E0C7, 777700EC7, 7777730AB, 7777777AE, 77777EE97, 7777E7E97, 777999997, 7A500000B, 7BBBBBB5B, 88888A834, 900000031, 900666608, 909990098, 90D009998, 950000557, 966666008, 990000007, 990555507, 999999997, A000000B4, A0005999B, AAEEEEE34, B000AA334, BBBBB005B, BBBBBBB5B, D09999998, D0D90009D, D800000DD, D90009998, DCCCC0CC8, DE88EEEEE, DEEEEEE88, E000B7777, E000BBBBB, E003ABBBB, EE0000797, EE0EEE397, EE5555557, EE777EE97, EEEEEE537, EEEEEE937, 2222222252, 3000000071, 3330030001, 3333303001, 3333330001, 500000007B, 5555555097, 7000000071, 77000000C7, 8333333331, 8888883334, 8888888834, 888888AA34, 900000009B, 900000009D, 900000DD9D, 9000099998, 9955555507, 9D0000099D, 9D05555557, AB0000005B, B000000DAB, B00000BBDB, BB00BB0B5B, BB0BB00B5B, D000099998, D00090008D, D0D000909D, D0DDDDDDDB, D300000007, D88EEEEEEE, D900999998, DD00900008, DDD6EEEEEE, DDDDDDD6EE, DDDDDDDDDE, DDDEEEEEEE, DEEEEE8008, E000000797, 7777777CCCE, 88888830004, 90000009D9D, 99955555557, 9999999999D, B00000D00AB, BB000BBB05B, BBBB0000B5B, D000009080D, D000090800D, D090800000D, DDDDDDD999B, DDDDDDDDD9B, EEEEEE00397, EEEEEEE0397, 333000000301, 5000000000DD, 73A00000000B, 9000000000B7, 903333333331, ABB00000000B, D000000001C7, DCCCCCCCCCC8, E0EEEEEEE397, 19A000000000B, 3333333333331, 3BBBBBBBBBBBB, 9333333333331, A00000000099B, B00000000050D, EEEEEEEEEE76E, 1000000000999B, 71000000000001, 908D000000000D, BBBBBBBBBB6661, 77777777777777B, BB00000000BBB5B, DEEEEEEEEEEEEEE, 7777777777777E97, B0BBBBBBBBBBBB1B, BB0000000000DB0B, D000000000000998, D908000000000000D, DDDDDDDDDDDDDDDDB, E9666666666666668, 3330000000000000031, D00000000000000908D, E0BBBBBBBBBBBBBBBBB, 2EEEEEEEEEEEEEEEEE52, 77777777777777777ECE, 5000000000000000005AB, 777777777777777777997, 7BBBBBBBBBBBBBBBBBBBB, BB0000000000000000DBB, DD000000000000000909D, D900000000000000000DDD, DD0000000000000000099D, BBBBBBBBBBBBBBBBBBBBBB1, B00000000000000000000005B, B0700000000000000000000001, B70000000000000000000000001, 705000000000000000000000000B, 633000000000000000000000000001, EBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB, 500000000000000000000000000000000017, 77777777777777777777777777777777777777777777777777777777777CCE, 7777777777777777777777777777777777777777777777777777777777777777777777777CE, 96666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666608, EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE397, 7777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777797 ===Base 16=== 11, 13, 17, 1D, 1F, 25, 29, 2B, 2F, 35, 3B, 3D, 43, 47, 49, 4F, 53, 59, 61, 65, 67, 6B, 6D, 71, 7F, 83, 89, 8B, 95, 97, 9D, A3, A7, AD, B3, B5, BF, C1, C5, C7, D3, DF, E3, E5, E9, EF, F1, FB, 14B, 15B, 185, 199, 1A5, 1BB, 1C9, 1EB, 223, 22D, 233, 241, 277, 281, 287, 28D, 2A1, 2D7, 2DD, 2E7, 301, 337, 373, 377, 38F, 3A1, 3A9, 41B, 42D, 445, 455, 45D, 481, 4B1, 4BD, 4CD, 4D5, 4E1, 4EB, 50B, 515, 51B, 527, 551, 557, 55D, 577, 581, 58F, 5AB, 5CB, 5CF, 5D1, 5D5, 5DB, 5E7, 623, 709, 727, 737, 745, 74B, 755, 757, 773, 779, 78D, 7BB, 7C3, 7C9, 7CD, 7DB, 7EB, 7ED, 805, 80F, 815, 821, 827, 841, 851, 85D, 85F, 8A5, 8DD, 8E1, 8F5, 923, 98F, 99B, 9A9, 9EB, A21, A6F, A81, A85, A99, A9F, AA9, AAB, ACF, B1B, B2D, B7B, B8D, B99, B9B, BB7, BB9, BCB, BDD, BE1, C0B, CB9, CBB, CEB, D01, D21, D2D, D55, D69, D79, D81, D85, D87, D8D, DAB, DB7, DBD, DC9, DCD, DD5, DDB, DE7, E21, E27, E4B, E7D, E87, EB1, EB7, ED1, EDB, EED, F07, F0D, F4D, FD9, FFD, 1069, 1505, 1609, 1669, 16A9, 19AB, 1A69, 1AB9, 2027, 204D, 2063, 207D, 20C3, 20ED, 2221, 22E1, 2327, 244D, 26C3, 274D, 2E01, 2E0D, 2ECD, 3023, 3079, 3109, 3263, 3341, 36AF, 3941, 3991, 39AF, 3E41, 3E81, 3EE1, 3EE7, 3F79, 4021, 40DB, 440B, 444B, 44A1, 44AB, 44DB, 4541, 45BB, 4A41, 4B0B, 4BBB, 4C4B, 4D41, 4DED, 5045, 50A1, 50ED, 540D, 5441, 555B, 556F, 5585, 560F, 56FF, 5705, 574D, 580D, 582D, 5855, 588D, 5A01, 5AA1, 5B01, 5B4B, 5B87, 5BB1, 5BEB, 5C4D, 5CDD, 5CED, 5DD7, 5DDD, 5E0D, 5E2D, 5EBB, 68FF, 6A69, 6AC9, 6C8F, 6CA9, 6CAF, 6F8F, 6FAF, 7033, 7063, 7075, 7087, 70A5, 70AB, 7303, 7393, 74DD, 754D, 7603, 7633, 7663, 7669, 7705, 772D, 775D, 77D5, 7807, 7877, 7885, 7939, 7969, 7993, 79AB, 7A05, 7A69, 7A9B, 7AA5, 7B77, 7BA9, 7D4D, 7D75, 7D77, 8077, 808D, 80D7, 80E7, 8587, 86CF, 8777, 8785, 8885, 88CF, 88ED, 88FD, 8C6F, 8C8F, 8E8D, 8EE7, 8F2D, 8F8D, 9031, 9041, 90AF, 90B9, 9221, 9319, 9401, 944B, 9881, 9931, 9941, 9991, 99AF, 9A0F, 9A1B, 9A4B, 9AFF, 9BA1, 9BB1, 9CAF, 9E81, 9EA1, 9FAF, A001, A05B, A0C9, A105, A10B, A4CB, A55B, A6C9, A88F, A91B, A9B1, A9BB, AA15, AB01, AB0B, AB19, ABBB, AC09, AF09, B041, B04B, B069, B07D, B087, B0B1, B0ED, B1A9, B201, B40B, B40D, B609, B70D, B7A9, B807, B9A1, BA41, BAA1, BB4B, BBB1, BBDB, BBED, BD19, BD41, BDBB, BDEB, BE07, BEE7, C0D9, C203, C24D, C6A9, C88D, C88F, C8CF, C8ED, C9AF, C9CB, CA09, CA4B, CA69, CAC9, CC0D, CC23, CC4D, CC9B, CD09, CDD9, CE4D, CEDD, CFA9, CFCD, D04B, D099, D405, D415, D44B, D4A5, D4DD, D50D, D70B, D74D, D77B, D7CB, D91B, D991, DA05, DA09, DA15, DA51, DB91, DBEB, DD7D, DDA1, DDED, DE0B, DE41, DE4D, DEA1, E02D, E07B, E0D7, E1CB, E2CD, E401, E801, EABB, EACB, EAEB, EBAB, EC4D, ECDD, ED07, EDD7, EE7B, EE81, EEAB, EEE1, F08F, F0A9, F227, F2ED, F3AF, F485, F58D, F72D, F763, F769, F787, F7A5, F7E7, F82D, F86F, F877, F88D, F8D7, F8E7, F8FF, FCCD, FED7, FF85, FF8F, FFA9, 100AB, 10BA9, 1A0CB, 1BA09, 200E1, 2C603, 2CC03, 30227, 303AF, 30AAF, 32003, 32207, 32CC3, 330AF, 33169, 33221, 33391, 33881, 33AFF, 38807, 38887, 3AFFF, 3F203, 3F887, 3FAFF, 400BB, 4084D, 40A4B, 42001, 44221, 44401, 444D1, 4480D, 4488D, 44CCB, 44D4D, 44E8D, 4804D, 4840D, 4A0CB, 4A54B, 4CACB, 4D0DD, 4D40D, 4D44D, 5004D, 50075, 502CD, 5044D, 50887, 50EE1, 5448D, 548ED, 55A45, 55F45, 5844D, 5A4A5, 5AE41, 5B0CD, 5B44D, 5BBCD, 5D4ED, 5E0E1, 5EB4D, 5EC8D, 5ECCD, 5EE41, 5F06F, 5F7DD, 5F885, 5F8CD, 5FC8D, 5FF75, 6088F, 60AFF, 630AF, 633AF, 660A9, 668CF, 669AF, 66A09, 66A0F, 66FA9, 6886F, 6A00F, 6A0FF, 6A8AF, 6AFFF, 7002D, 7024D, 70B0D, 70B7D, 7200D, 73363, 73999, 7444D, 770B7, 777D7, 77B07, 77D7D, 77DD7, 79003, 79999, 7B00D, 7D05D, 7D7DD, 8007D, 800D1, 8074D, 82CCD, 82E4D, 8448D, 8484D, 8704D, 8724D, 87887, 88001, 8800D, 880CD, 88507, 88555, 8866F, 8872D, 8877D, 888D1, 888D7, 88AA1, 88C2D, 88D57, 88D75, 88D77, 8AFAF, 8C2CD, 8C40D, 8C8CD, 8CCED, 8CE2D, 8CFED, 8E007, 8E20D, 8E24D, 8F6FF, 8FAAF, 900CB, 901AB, 90901, 909A1, 90AB1, 90AE1, 90EE1, 910AB, 93331, 940AB, 963AF, 966AF, 99019, 99109, 99A01, 9AAE1, 9B00B, 9B0AB, 9B441, 9BABB, 9BBBB, 9E441, A00BB, A0405, A044B, A08AF, A0A51, A0B91, A0C4B, A1B09, A54A5, A5B41, A6609, A904B, A94A1, A9C4B, A9E01, A9E41, AA0A1, AA441, AA501, AA8AF, AAEE1, AAF45, AAF8F, ABBA1, ACC69, AE0BB, AE0EB, AEAE1, AEE0B, AEEA1, AEECB, AF045, AF4A5, AFA8F, B00A1, B00D7, B044D, B0777, B0A0B, B0A91, B0BBD, B0BCD, B0C09, B0DA9, B0EAB, B2207, B4001, B6669, B7707, B7D07, B8081, B9021, BA091, BA109, BA4BB, BB001, BB0EB, BB8A1, BBBEB, BBE0B, BBEBB, BC009, BCECD, BD0A9, BE44D, BEB0D, BEBBB, BEEBB, C0263, C02C3, C02ED, C040D, C0CA9, C0CCD, C2663, C2CED, C32C3, C3323, C400D, C40ED, C44CB, C44ED, C480D, C484D, C4CAB, C60AF, C686F, C6A0F, C86FF, C8C2D, CAA0F, CAFAF, CBCED, CC0AF, CC44B, CC82D, CC8FF, CCAF9, CCAFF, CCCFD, CCFAF, CD00D, CD4CB, CD4ED, CDDDD, CF2C3, CFC8F, CFE8D, D0045, D07DD, D09BB, D0D4D, D0DD7, D0EBB, D0EEB, D1009, D1045, D10B9, D1BA9, D54BB, D54ED, D5AE1, D5D07, D5EE1, D70DD, D7707, D7777, D77DD, D7DD7, D9441, D9AE1, D9B0B, DA9A1, DA9E1, DAA41, DAAA1, DBB0B, DBBA1, DC4CB, DD227, DD44D, DDDD7, E0081, E00E1, E010B, E088D, E08CD, E0B0D, E0BBD, E100B, E4D0D, E777B, E77AB, E7CCB, E844D, E848D, E884D, E88A1, EB0BB, EBB4D, EBBEB, EBEEB, EC8CD, ECBCD, ECC8D, ED04D, EE001, EE0EB, EE4A1, EEEBB, F0085, F09AF, F0C23, F0CAF, F2663, F2C03, F3799, F3887, F4A05, F4AA5, F506F, F5845, F5885, F5C2D, F5ECD, F5F45, F66A9, F688F, F6AFF, F7399, F777D, F8545, F8555, F8AAF, F8F87, F9AAF, FA0F9, FA405, FA669, FAFF9, FC263, FCA0F, FCAFF, FCE8D, FCF23, FD777, FDDDD, FDEDD, FEC2D, FEC8D, FF545, FF6AF, FF739, FF775, FF9AF, FFC23, 100055, 100555, 10A9CB, 1A090B, 1A900B, 1CACCB, 1CCACB, 20DEE1, 266003, 3000AF, 300A0F, 300AFF, 308087, 308E07, 3323E1, 333A0F, 339331, 33CA0F, 33CF23, 33CFAF, 33F323, 380087, 3A00AF, 3A0F0F, 3AA0FF, 3AAF0F, 3C33AF, 3C3A0F, 3C3FAF, 3CCAAF, 3F0FAF, 3F32C3, 3FF0AF, 3FFAAF, 4004CB, 400A05, 4048ED, 404DDD, 40AA05, 40D04D, 40DD4D, 40E0DD, 40E48D, 440041, 44008D, 44044D, 4404DD, 44440D, 4448ED, 4484ED, 448E4D, 44E44D, 48888D, 4AA005, 4DD00D, 4DD04D, 4DDD0D, 4E048D, 4E448D, 4E880D, 5000DD, 500201, 50066F, 5008CD, 500C2D, 500D7D, 50C20D, 520C0D, 544EDD, 54AA05, 54AAA5, 54ED4D, 566AAF, 57D00D, 580087, 5A5545, 5C20CD, 5C8CCD, 5CC2CD, 5D000D, 5D070D, 5F666F, 5FAA45, 5FFF45, 60008F, 600A0F, 603AAF, 6060AF, 6066AF, 60A0AF, 63AA0F, 6663AF, 66668F, 666AAF, 668A8F, 66AFF9, 68888F, 693AAF, 7007B7, 70404D, 70770B, 70770D, 707BE7, 70DD0D, 733339, 733699, 74004D, 74040D, 77007B, 770CCB, 777B4D, 777BE7, 777CCB, 77ACCB, 77B74D, 77D0DD, 7A0CCB, 7B744D, 7CACCB, 7DDD99, 80044D, 800807, 80200D, 8044ED, 80C04D, 80CC2D, 80E44D, 8404ED, 84888D, 84E04D, 84E40D, 86686F, 8668AF, 8686AF, 86F66F, 86FFFF, 87000D, 87744D, 880807, 886AFF, 88824D, 88870D, 888787, 88884D, 88886F, 88887D, 88888D, 888C4D, 888FAF, 88AA8F, 88CC8D, 88F6AF, 88F8AF, 88FA8F, 88FF6F, 88FF87, 88FFAF, 8A8FFF, 8C0C2D, 8C802D, 8CCFFF, 8CE00D, 8CE0CD, 8CFCCF, 8E00CD, 8E044D, 8E0CCD, 8EC0CD, 8F68AF, 8F88F7, 8FCFCF, 8FF887, 8FFCCF, 8FFF6F, 9002E1, 9004AB, 9008A1, 900919, 900ABB, 900B21, 90B801, 90CCCB, 9332E1, 944441, 94ACCB, 990001, 9900A1, 9A4441, 9A4AA1, 9AA4A1, 9AAA41, 9AAAAF, 9B66C9, 9BBA0B, 9BC0C9, 9BC669, 9BC6C9, 9C4ACB, A0094B, A00ECB, A09441, A0A08F, A0E0CB, A0ECCB, A0F669, A40A05, A4AAA5, A50E41, A5AA45, A60069, A8FAFF, A9AA41, AA5E41, AAA4A5, AAA545, AC6669, ACCC4B, ACCCC9, AEAA41, AFF405, AFF669, AFFA45, AFFFF9, B00921, B00BEB, B00CC9, B00D91, B08801, B0D077, B70077, B70E77, B77E77, B88877, B88881, B94421, BAE00B, BB00AB, BB0DA1, BB444D, BB44D1, BB8881, BBBBBD, BBBC4D, BBCCCD, BC0CC9, BC66C9, BCC669, BCC6C9, BCCC09, BE000D, BE00BD, BE0B4D, BE0CCD, BEA00B, BECCCD, C0084D, C00A0F, C0608F, C0668F, C0844D, C0A0FF, C0AFF9, C0C3AF, C0C68F, C0CAAF, C0CDED, C0D0ED, C0E80D, C0EC2D, C0EC8D, C0FA0F, C0FAAF, C2CC63, C30CAF, C333AF, C3CAAF, C3CCAF, C4048D, C40D4D, C4404D, C4408D, C4440D, C44DDD, C4ACCB, C4DCCB, C4DD4D, C6068F, C66AAF, C68AAF, C6AA8F, C8044D, C8440D, C8666F, CA00FF, CA0FFF, CAAAAF, CAAFFF, CAFF0F, CBE0CD, CC008F, CC0C8F, CC3CAF, CC4ACB, CC608F, CC66AF, CCBECD, CCC4AB, CCCA0F, CCCC8F, CCCE8D, CE0C8D, CF0F23, CF0FAF, CFAFFF, CFCAAF, CFFAFF, D0005D, D00BA9, D05EDD, D077D7, D10CCB, D22207, D4000B, D4040D, D4044D, D40CCB, D70077, D7D00D, D90009, D900BB, DB00BB, DB4441, DD400D, DDD109, DDD1A9, DDD919, DDD941, DED00D, E00D4D, E00EEB, E0AAE1, E0AE41, E0AEA1, E0B44D, E0BCCD, E0BEBB, E0D0DD, E0E441, E4048D, E4448D, E800CD, E8200D, EA0E41, EAA0E1, EBB00B, ECCCAB, EDDDDD, EEBE0B, F00263, F0056F, F00A45, F02C63, F03F23, F05405, F060AF, F08585, F0A4A5, F0F2C3, F0F323, F2CCC3, F33203, F33C23, F5F66F, F5FF6F, F68CCF, F6AA8F, F888AF, FA0F45, FAA045, FAA545, FAFC69, FC0AAF, FC66AF, FCCCAF, FCFFAF, FF0323, FF056F, FF3203, FF7903, FFA045, FFA4A5, FFAA45, FFC0AF, FFF4A5, FFF575, FFFA45, FFFCAF, 10A009B, 20000D1, 2CCC663, 30A00FF, 30CCCAF, 30FA00F, 30FCCAF, 3333C23, 333C2C3, 33C3AAF, 33FCAAF, 33FFFAF, 3A0A00F, 3AAAA0F, 3AF000F, 3AFAAAF, 3C0CA0F, 3CCC3AF, 3CFF323, 3F33F23, 3FAA00F, 3FF3323, 4004441, 400DDD1, 400E00D, 400ED0D, 404404D, 404448D, 404E4DD, 440EDDD, 4440EDD, 44444ED, 4444E4D, 44DDDDD, 4A000A5, 4CCCCAB, 4D0CCCB, 4E4404D, 4E4444D, 4E4DDDD, 5000021, 5004221, 5006AAF, 500FF6F, 5042201, 508CCCD, 5400005, 5400AA5, 5555405, 5808007, 5AA4005, 5C0008D, 5CCC8CD, 5D4444D, 5EEEEEB, 5F40005, 5F554A5, 5F6AAAF, 60000AF, 60006A9, 600866F, 6008AAF, 600AA8F, 600F6A9, 606608F, 606686F, 608666F, 60AA08F, 60AAA8F, 66000AF, 66666A9, 6666AF9, 6866A8F, 6AAAAAF, 70070D7, 70077DD, 700DDDD, 707077D, 707D007, 70D00DD, 770077D, 770400D, 770740D, 7777775, 77777B7, 77777DD, 7777ACB, 77B88E7, 77DD00D, 77DDDDD, 7D0D00D, 7DD0D07, 7DDD00D, 800002D, 8000CED, 80C0E0D, 80CECCD, 840400D, 844000D, 844E00D, 868688F, 880444D, 884404D, 887D007, 8888801, 8888881, 8888E07, 8888F77, 8888FE7, 88A8AFF, 88AAAFF, 88FAFFF, 8A8AAAF, 8A8AAFF, 8AAA8FF, 8C00ECD, 8C8444D, 8E4400D, 8FCCCCF, 900BBAB, 90CC4AB, 9908AA1, 99E0E01, 9B00801, 9B6CCC9, A000FF9, A006069, A00A8FF, A01CCCB, A05F545, A0BEEEB, A0E4AA1, AA0008F, AA08FFF, AA40AA5, AA8FFFF, AAAA405, AE04AA1, AE44441, AE4AAA1, AECCCCB, AF40005, AFA5A45, AFFFC69, B000BAB, B000EBB, B0D0007, B222227, B6CCCC9, B8880A1, BA000EB, BA0BEEB, BAEEEEB, BB000CD, BB00C0D, BB0B00D, BC6CC69, BC6CCC9, BCCCC69, BCCCCED, C0000A9, 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4444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444DD ===Base 17=== 12, 16, 1C, 1E, 23, 27, 29, 2D, 32, 38, 3A, 3G, 43, 45, 4B, 4F, 54, 5C, 5G, 61, 65, 67, 6B, 78, 7C, 81, 83, 8D, 8F, 94, 9A, 9E, A3, A9, AB, B4, B6, BA, BC, C7, D2, D6, D8, DC, E1, E3, ED, F2, F8, FE, FG, G5, G9, GB, 104, 111, 115, 117, 11B, 137, 139, 13D, 14A, 14G, 155, 159, 15F, 171, 17B, 17D, 188, 191, 197, 19F, 1A4, 1A8, 1B3, 1BB, 1BF, 1DB, 1DD, 1F3, 1FD, 1G8, 1GA, 1GG, 20F, 214, 221, 225, 241, 25A, 25E, 285, 2B8, 2C5, 2CF, 2E5, 2EB, 2F6, 30E, 313, 331, 33B, 346, 34C, 351, 35F, 36E, 375, 37B, 391, 39B, 39D, 3B7, 3B9, 3BF, 3D3, 3D5, 3D9, 3DF, 3E4, 3EC, 3F1, 3F7, 407, 418, 447, 44D, 472, 474, 47E, 47G, 489, 49C, 4A1, 4C1, 4CD, 4D4, 4G1, 502, 506, 508, 50E, 519, 522, 528, 52A, 52E, 533, 53F, 551, 55D, 562, 566, 573, 577, 57F, 582, 593, 599, 59B, 59F, 5A6, 5B5, 5D1, 5D3, 5EA, 5EE, 5F9, 60D, 62F, 634, 649, 689, 692, 6CD, 6EF, 6F4, 6FA, 704, 706, 70G, 71D, 726, 737, 739, 73D, 73F, 753, 755, 764, 766, 76G, 771, 77B, 793, 7AA, 7AE, 7B3, 7BB, 7D7, 7E6, 7F3, 7F9, 7FF, 7G2, 7GE, 7GG, 825, 82B, 849, 852, 85E, 869, 876, 87A, 87G, 88B, 892, 898, 89C, 8C5, 8E7, 8G7, 908, 90G, 913, 91F, 92C, 935, 937, 93B, 951, 953, 957, 95D, 968, 96G, 979, 97B, 98C, 98G, 99D, 9B1, 9B3, 9B9, 9BD, 9BF, 9DB, 9DF, 9F1, 9F5, 9G6, A07, A0D, A1A, A2F, A4D, A72, A7A, A7E, AA1, AA7, ACF, ADA, AG1, AG7, B02, B08, B17, B1D, B28, B2G, B57, B71, B73, B79, B7F, B88, B8E, B8G, B9B, B9F, BB5, BB7, BD7, BDD, BEG, BFF, BGG, C01, C2F, C3E, C56, C6D, C89, C92, C9G, CA5, CBG, CC1, CC5, CF4, CFA, D04, D0A, D15, D3D, D3F, D55, D59, D5B, D71, D75, D7D, D91, D97, D99, D9D, DA4, DAG, DB3, DDB, DF1, DF7, DF9, DFF, E05, E0B, E2B, E52, E58, E69, E92, E9C, EAF, EB8, EC9, ECB, EE5, F04, F15, F1B, F35, F3B, F46, F51, F53, F64, F6A, F73, F79, F95, FAC, FB1, FCA, FD5, FDB, FF1, FF7, FFD, G0D, G0F, G18, G1A, G1G, G2F, G34, G63, G7G, GA7, GC3, GDG, GEF, GFA, GG7, GGD, 1013, 101D, 1033, 1035, 1051, 105B, 105D, 1077, 108A, 109B, 10AG, 10B1, 10B7, 10BD, 10FB, 1149, 1189, 11AF, 11G3, 1303, 130B, 1314, 1341, 1479, 14D9, 1501, 1503, 15A1, 15B8, 1734, 1749, 17AF, 17G3, 1844, 185B, 1875, 1877, 18AG, 18B5, 1903, 1909, 1958, 19BG, 19G3, 1A5D, 1A75, 1A7F, 1ADF, 1AF1, 1B01, 1B09, 1B18, 1B85, 1B89, 1BDG, 1BGD, 1D07, 1D49, 1D9G, 1DF4, 1F09, 1F47, 1F5A, 1F74, 1F7A, 1FA1, 1FAF, 2018, 201G, 202B, 208B, 20G1, 215B, 218G, 21AG, 21B1, 222F, 22AF, 22BG, 22EF, 22F4, 22GF, 251B, 2526, 25F1, 266F, 26FC, 280B, 2A05, 2A58, 2AFC, 2AGF, 2B1B, 2B1F, 2BGE, 2C1G, 2C2B, 2C8B, 2CG1, 2E2F, 2EGF, 2F0C, 2F55, 2FAA, 2FC4, 2FFF, 2GA1, 2GFC, 2GG1, 2GGF, 301B, 301F, 3037, 3053, 3057, 3079, 3095, 30B3, 30BD, 30C4, 31F4, 330D, 3334, 333E, 3349, 3376, 337E, 33CD, 33EF, 3411, 3417, 3499, 3503, 3505, 3509, 353E, 35E5, 35EB, 3604, 36FD, 3701, 3741, 374D, 376F, 3796, 37D4, 37F4, 3956, 3B03, 3B05, 3B0B, 3BBE, 3C04, 3C15, 3C19, 3C4E, 3C59, 3C64, 3CB3, 3CDB, 3CE6, 3D07, 3D14, 3DDE, 3E77, 3E79, 3E7F, 3E99, 3EEE, 3EFB, 3F05, 3F0D, 3FCB, 3FF4, 4009, 4021, 4069, 4098, 40DG, 40GD, 419D, 4201, 4401, 4492, 46AD, 46C9, 46DA, 4719, 476A, 4779, 479D, 47A6, 4906, 4911, 4917, 4919, 491D, 492G, 4982, 4988, 49D7, 49D9, 49GG, 4ADE, 4AE7, 4C49, 4C96, 4CC9, 4D79, 4DAE, 4DEG, 4E7A, 4E96, 4EG7, 4G6D, 4G87, 501B, 5037, 5059, 507D, 50BB, 50BF, 50D7, 50DD, 50F1, 5105, 51A7, 51AD, 521B, 525F, 52FB, 5307, 5356, 53BE, 53DE, 53E9, 5507, 550B, 5587, 5598, 55EF, 560A, 568E, 56AA, 56F3, 5709, 5725, 572B, 575A, 575E, 5769, 57A1, 57B2, 5868, 586E, 58AE, 58B9, 590D, 5918, 5952, 5958, 596D, 5A17, 5A1F, 5ADD, 5ADF, 5AE8, 5B07, 5B21, 5B2F, 5B3E, 5BEF, 5DA7, 5DEB, 5E57, 5E5F, 5E86, 5E97, 5EB9, 5EBF, 5EF5, 5F01, 5F1A, 5F6F, 5FA7, 5FDA, 60AF, 60G3, 64AD, 64DE, 64DG, 663E, 666D, 66AF, 693D, 69CG, 69D3, 69D9, 69G8, 69GC, 6ADE, 6AGD, 6C98, 6D33, 6D4E, 6D93, 6D9F, 6DDD, 6DEE, 6DF3, 6DFD, 6DGE, 6E09, 6G36, 6G4D, 6G6D, 6GD4, 6GDE, 6GFC, 702E, 7057, 705B, 7073, 7079, 7095, 70B5, 70BD, 70D1, 70E2, 70F5, 7107, 7149, 719G, 71BG, 71F4, 724E, 724G, 725F, 72A2, 72BF, 72EE, 72GA, 7314, 733E, 7341, 7363, 73EB, 7419, 742A, 742G, 7442, 74EG, 7501, 750F, 751A, 756D, 757E, 75A1, 75A7, 75BE, 75DA, 75E9, 75F6, 7622, 769F, 76EA, 7734, 773E, 776D, 779G, 77AF, 7905, 790B, 7976, 79B2, 79F6, 79GD, 7A1F, 7A5D, 7AD5, 7ADF, 7AF1, 7AFD, 7B01, 7B09, 7B2F, 7B52, 7B72, 7BE5, 7D01, 7D05, 7D9G, 7DAF, 7DBG, 7E0A, 7E75, 7EA2, 7EA4, 7EB5, 7EBF, 7EE2, 7EF7, 7EG4, 7F0B, 7F14, 7F5A, 7F76, 7FA7, 7G1F, 7G46, 7GA6, 7GD3, 7GDF, 8009, 8058, 80B8, 80E9, 84A7, 850A, 8557, 857B, 85A8, 870E, 8744, 8777, 879B, 87B5, 87B7, 87EE, 8805, 8872, 8887, 8889, 88E9, 8906, 8959, 8966, 89GG, 8A87, 8AE5, 8B0G, 8B59, 8B95, 8B97, 8CB2, 8CB8, 8CE9, 8E56, 8EE9, 9026, 9031, 903D, 907F, 9091, 909B, 90FB, 9101, 910D, 9118, 917G, 9185, 9189, 91B8, 9202, 9288, 92B5, 92FB, 92GG, 93C1, 9505, 950B, 950F, 952B, 956F, 9592, 9596, 9598, 9602, 96D9, 96FD, 971G, 9725, 9752, 97DG, 9855, 9862, 9895, 9899, 98B7, 98BB, 9901, 990B, 9921, 992F, 99G3, 9B0B, 9B2B, 9B8B, 9BB8, 9BBG, 9C19, 9C1B, 9C31, 9C59, 9C95, 9CD5, 9CFB, 9CGC, 9D03, 9D07, 9D7G, 9DG1, 9DGD, 9F0B, 9F76, 9FCB, 9G11, 9G1D, 9G28, 9G3F, 9G7D, 9GCC, 9GD7, 9GF7, 9GFD, 9GG8, A025, A041, A058, A0C5, A0F6, A0GF, A11F, A184, A1F7, A21G, A258, A401, A421, A476, A511, A517, A57D, A5A8, A5E8, A6AD, A6FC, A6GF, A751, A77F, A7F5, A7FD, A7G6, A847, AACD, AC1G, AC41, AC58, AC5E, ACGD, AD0E, AD0G, AD1F, AD51, ADD5, ADE4, ADF5, ADGE, AE56, AE74, AEF6, AEFA, AF77, AF7D, AFA4, AFCC, AFD7, AFDD, AGAF, AGF4, B00G, B037, B055, B05B, B075, B0D5, B0FD, B10F, B198, B25F, B2F1, B2F5, B307, B309, B35E, B3EF, B50D, B589, B7BE, B7BG, B7E7, B875, B952, B958, B97G, B99G, B9G7, B9GD, BB01, BB2F, BB3E, BB89, BB98, BBDE, BD03, BD09, BD5E, BDE5, BDEB, BDG1, BE5F, BF01, BF0D, BG13, BG1F, BG3F, BGD1, BGE2, BGE8, C00B, C034, C05A, C0AF, C0EF, C0GF, C153, C15B, C199, C1B9, C1D1, C1D5, C1F9, C205, C21A, C21G, C252, C258, C2B2, C335, C33D, C35D, C364, C395, C3B3, C3F5, C3FB, C3FD, C414, C41A, C469, C496, C4DA, C4GD, C535, C55B, C5B1, C5BD, C5D9, C5DF, C5E8, C5F3, C5F5, C6E9, C85A, C885, C8B8, C8BE, C8CB, C8E5, C919, C931, C959, C95F, C9D3, CA0F, CA18, CA1G, CAD4, CADE, CAEF, CAGD, CB22, CB33, CB35, CB3F, CB5D, CB82, CB99, CBB1, CBFB, CC49, CCCB, CCDE, CD11, CD1D, CD39, CD4A, CD53, CD93, CDAE, CDD5, CDF3, CDFD, CDG4, CE49, CE5A, CE8B, CF13, CF19, CF5D, CF5F, CFB9, CFBF, CFD9, CFDF, CG14, CG41, CG6F, CGCF, CGF6, CGG1, D01F, D039, D079, D09B, D09F, D0B7, D0BB, D0D1, D0EG, D0GG, D10D, D19G, D1G3, D30B, D347, D3BE, D4E4, D50D, D57E, D5AD, D5FA, D707, D73E, D7E7, D7GF, DA1F, DA57, DAAE, DB01, DB09, DB0D, DB7E, DB9G, DD05, DD7E, DDA5, DDFA, DDG3, DE0G, DE44, DE4A, DE77, DEAE, DEB9, DEBB, DF03, DF05, DG0E, DGDF, E009, E06F, E072, E07G, E089, E0CF, E0E9, E0G7, E47A, E498, E4E7, E50A, E559, E55F, E575, E5B9, E5BF, E5F5, E5F7, E6FC, E722, E724, E72A, E72E, E744, E746, E75B, E76E, E79B, E7A4, E7A6, E7AG, E7B5, E7B7, E7EG, E7G4, E887, E89G, E8E9, E906, E955, E95B, E95F, E988, E99F, E9F9, E9G8, E9GG, EA25, EA7G, EAC5, EAE7, EB7B, EBF5, EBF7, EBFB, EC6F, ECCF, ECEF, EE72, EE76, EE89, EE9G, EF0A, EF44, EF77, EF97, EFA4, EFB5, EFC6, EFFF, EG6F, EG74, EGE7, EGFC, EGGF, F019, F01F, F075, F091, F09B, F0BF, F0FB, F10F, F1A7, F1AD, F1D4, F376, F3CD, F3F4, F40A, F411, F444, F44A, F497, F499, F49D, F4D7, F509, F57A, F5AD, F5F6, F6D3, F6D9, F70D, F741, F747, F76D, F7F6, F7FA, F907, F976, F9CB, FA11, FA7D, FADD, FB09, FC4C, FC5D, FC5F, FC91, FCB9, FD1A, FD41, FD47, FDF4, FF0B, FF56, G021, G07A, G0A1, G0E7, G11F, G17F, G1DF, G1F1, G1F7, G201, G2A1, G306, G311, G36C, G377, G37F, G3CC, G3CE, G3D1, G476, G487, G4DE, G6AF, G6D4, G6F6, G6GF, G713, G724, G731, G742, G74E, G76E, G7A2, G872, G874, GA21, GAC1, GC6F, GCAF, GCD4, GCDA, GCG1, GD73, GD7F, GDAE, GDDF, GDEA, GDFD, GE47, GE7E, GF13, GF33, GF3F, GF4C, GF71, GF7F, GFDD, GG01, GG21, GGAF, GGC1, 1000G, 10053, 100AA, 100B9, 100F1, 100FF, 10301, 10587, 10705, 1075A, 107GF, 10895, 108B9, 10985, 1099G, 10B98, 10B9G, 10D03, 10D0F, 10D7A, 10DG3, 10DG7, 10G1F, 10G3F, 110GF, 1140D, 11D93, 11DG4, 11F0A, 11G4D, 11GD4, 13333, 133FF, 13F44, 14109, 14499, 150A7, 153B1, 1570A, 17005, 17799, 177AG, 17995, 17A7G, 17G47, 18079, 18507, 185A7, 18B07, 18B9G, 19333, 199B5, 1A00A, 1A00G, 1A0F5, 1AAAA, 1AAAG, 1AF05, 1AFFA, 1B07G, 1B10G, 1B807, 1D001, 1D1AA, 1D7G4, 1DG03, 1DG41, 1F001, 1F00F, 1F01A, 1F0A7, 1F199, 1F1F9, 1F414, 1F449, 1F7F5, 1F999, 1FF0A, 1FFAA, 1FFB5, 1G073, 1G14D, 1G1F4, 1G301, 1G477, 1GD01, 1GD47, 1GF07, 1GFF4, 20005, 200A1, 2010A, 20586, 20588, 20A01, 20B11, 20B15, 20BEE, 20C1A, 20CBE, 210B5, 21A1F, 21A51, 21F1A, 21G1F, 21GFF, 222BE, 228B2, 228BE, 22BE2, 22C0B, 22F0A, 252BB, 25505, 25552, 26GAF, 2A001, 2A1FF, 2A55F, 2AEEF, 2AF44, 2B051, 2B20E, 2BB2B, 2BBBG, 2BE22, 2BEE2, 2BEEE, 2BF0B, 2C0BE, 2C18A, 2F101, 2F1FA, 2F44C, 2FCBB, 2G1FF, 2GA6F, 2GF44, 30035, 300B1, 300FB, 30101, 303C5, 30444, 30497, 304D1, 304D7, 30703, 30714, 30734, 30763, 30774, 30CF5, 30CFD, 30D41, 30FC5, 3100B, 31779, 31F5B, 31FB5, 31FFF, 330C5, 330F4, 33357, 33373, 33379, 33555, 33557, 33777, 3379F, 337FD, 33997, 33D44, 33D4E, 33F3D, 33FF5, 34019, 34044, 340D1, 353DD, 35535, 355B3, 355E6, 35BB3, 35DDD, 3636D, 364DD, 3663D, 36DD4, 37003, 3700F, 3717F, 373EE, 37609, 3774E, 37773, 37797, 37977, 3797F, 37EEF, 39007, 390C5, 39777, 39973, 3B355, 3B553, 3BBDB, 3BDB1, 3C03D, 3C0F5, 3C10F, 3C141, 3C444, 3CBE5, 3CD0D, 3CE5B, 3CEBB, 3CEF9, 3D401, 3DEBE, 3E006, 3E066, 3E57E, 3E5E9, 3E666, 3E90F, 3EF6F, 3F33D, 3F3C4, 3F5BB, 3FB33, 3FDDD, 3FF59, 4006D, 400DE, 4011D, 401D9, 40414, 4041G, 404C9, 40966, 40D11, 40D19, 40D1D, 40E49, 41019, 411DA, 41AAG, 4210A, 44049, 4410G, 44144, 441G4, 44441, 444E9, 446E9, 44986, 44E49, 4609G, 460E9, 466DE, 469DD, 46E9G, 4711A, 476D9, 4770D, 47A77, 47D09, 49099, 490D1, 49226, 49622, 49699, 496DD, 49996, 4999G, 499G7, 49G22, 49G77, 4A7DD, 4AA6D, 4ADD7, 4C0E9, 4C999, 4D1DA, 4DADD, 4DD01, 4DD1G, 4DD7A, 4DDA7, 4DDE9, 4DG0G, 4DGAA, 4DGGA, 4DGGE, 4E049, 4E449, 4E49G, 4E4E9, 4E797, 4G7DD, 4GDAA, 4GDD7, 50011, 50079, 50095, 500B1, 500F3, 501A5, 501AF, 50503, 507A5, 50AF7, 50F03, 50F7A, 510A1, 510DA, 511AA, 511DF, 5135B, 515B7, 5180B, 51A0F, 51F0A, 520B1, 53005, 531BD, 53559, 53609, 53B11, 55205, 55357, 553E6, 5555B, 5556E, 55588, 5558A, 555F3, 555FB, 556AF, 556E9, 55759, 5575B, 55805, 55885, 55896, 558B8, 55926, 55BE2, 55E8B, 55F57, 560FF, 5700D, 570A5, 570DA, 575B9, 576AD, 576DA, 579D5, 57A05, 57A52, 57B9D, 57DBD, 58057, 58509, 5855A, 585A7, 587EB, 58857, 588E8, 58A75, 58B0B, 58B87, 58BBE, 58BEB, 58E5B, 591D5, 59201, 59256, 59715, 59807, 5A88A, 5AA88, 5AFAD, 5B001, 5B00B, 5B1F1, 5B31B, 5B7E2, 5B80B, 5BB13, 5BBE8, 5BBFB, 5BE87, 5BE8B, 5BF37, 5BFBD, 5D00F, 5DA05, 5DA5A, 5DAE5, 5DBBD, 5DD95, 5DDAA, 5DFDD, 5E879, 5E8B7, 5E8BB, 5F07A, 5F0AD, 5F37D, 5F70A, 5F7BD, 5FB7B, 5FBBB, 5FBF3, 5FFF3, 6003E, 60098, 603E6, 606GF, 60986, 609C8, 60G6F, 60GCF, 6336D, 633E9, 63CCE, 63E06, 63E66, 6609G, 660E9, 66AD4, 66D4A, 66DG4, 66DGG, 66E98, 66FD9, 66GF6, 69806, 69866, 69C86, 69CC8, 6A66F, 6AAGF, 6AF06, 6AF66, 6AGGF, 6C6G3, 6C6GF, 6CCGF, 6CG03, 6DA0E, 6DAEA, 6DD9G, 6DDE9, 6DEGA, 6DGD3, 6E986, 6EEE9, 6F69D, 6F6DF, 6F96D, 6FD03, 6FD09, 6G003, 6G3F3, 6G3FF, 6G6CF, 6GAAF, 6GCCF, 70031, 70099, 700BF, 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IIIIIIIIIBIII3, J0000000000GJJ, JJJJJJJE00000J, K00000000006GD, K0000000000CFF, K0000000000JI7, K000000000B055, K00000000K0KB5, K022222222222D, K0KKKKKKK00045, K0KKKKKKKKK545, K6CCCCCCCCCCCF, KEEEEEEEEEEE07, KKKKKKKKKKK0B5, L0LLLLLLLLLK77, L88888888888EJ, LK0000000000FF, LLLLLLLLLK00E7, LLLLLLLLLL9G33, LLLLLLLLLLGI33, LLLLLLLLLLL3G3, LLLLLLLLLLL9EL, LLLLLLLLLLLGI3, 200000000000JJ7, 2A0000000000001, 2CCCCCCCCCCCCCL, 2K00000000000K5, 3000000000009G9, 4HHHHHHHHHHHEEH, 50000000000010D, 500000000000KB5, 50E0000000000I7, 700000077777II7, 700777777777II7, 7700000000007I7, 7700700000000I7, 7707000000000I7, 777777777777727, 7IIIIIIIIIIIIIF, 7LLLIIIIIIIIIIF, 80008888888888J, 80088888888888J, 80D00000000000D, 89000000000080J, A0000000000I4IH, B00000000000HEH, B000000000BBEBD, B0BBBBBBBBBBBB5, BBBBBBBBBBBBBB1, BBBBE000000000D, C00000000000LEL, CEEEEEEEE0EEE0L, D555555555550A5, DHHHHHHHHHHHHHH, EKEEEEEEEEEEEE7, FFFFFFFFFFFFG45, FFFFFFFFFFFIIAF, G000000000000B5, G0GGGGGGGGGGGG3, GG000000000002J, H000000000000B1, I77777777777777, K000000000K0BK5, K0000000KKKKK25, K000EEEEEEEEEE7, K05555555555KB5, KEEEEEEEEEEE7E7, KEKEEEEEEEEEEE7, KK00000000005EF, KK0K000000000B5, L000000000006B3, L0000000000ILB3, L0000000000LIB3, LCLEEEEEEEEEEEL, LLLLLLLLLL00KE7, LLLLLLLLLLILLB3, LLLLLLLLLLLK0E7, LLLLLLLLLLLL4G3, 20000000000000K7, 3AF000000000000F, 4000000000000IEH, 4IIIIIIIIIIIII33, 500000000000IJG9, 509B00000000000J, 59000000000000BJ, 6000000000008KK1, 60I00000000000B3, 6GGGGGGGGGGGGGED, 70000000000000I7, 700000000000EKE7, 7070000000007II7, 70777777777777I7, 7077777777777II7, 77000007000000I7, 80000000000000DD, 80000000000000E1, 888888888888888J, 900000000000088J, 988000000000000J, A000000000000001, A000000000000015, A0000000000002A1, BBBB0000000000ED, BH00000000000001, CLEEEEEEEEEEEEEL, D055555555555555, DDDHHHHHHHHHHHHH, EEEEEEEEEEEEEEEH, EELLLLLLLLLLLLB7, EHHHHHHHHHHHHHHH, GI0G00000000000H, HEEEEEEEEEBEEEEH, HHHHHHHHHHHHHH2D, I0000000000000B3, IEEEEEEEEEEEE7E7, J0000000000000GH, J000000000000JBJ, J00000000000JIJJ, JJ00000000000IJJ, JJJJE0000000000J, K000000000000K25, KFFFFFFFFFFFFCFF, L00000000000000J, LLLLLLLLLLL0LIB3, LLLLLLLLLLLECLLL, LLLLLLLLLLLLILB3, LLLLLLLLLLLLLG33, LLLLLLLLLLLLLKFF, 2KK00000000000005, 44EHHHHHHHHHHHHHH, 55555555555555BB5, 5B0BBBBBBBBBBBBBD, 7000000000000I40H, 707777777777777K7, 77000000000000I77, 8000000000000008D, A0000000000000CB1, A0000000000000EEH, B00000000000000D1, BAA55555555555555, BIIIIIIIIIIIIII63, C00000000000002IL, C0000000000000CEL, CCEEEEEEEEEEEEEEL, CEEEEEEEEEE0EEEEL, CEEEEEEEEEEEE0EEL, D000002222222222D, D5555505555555555, D5555555555505555, DGGGGGGGGGGGGGEED, F0000000000000EBD, F000000000000262D, F000000000000E0BD, F000000000000F6B3, F000000000000K6FF, F000000F6000000B3, GGGGGGGGGGGGGGGGD, HHEEBEEEEEEEEEEEH, HHHHHHHHHHHHH2GGD, HHHHHHHHHHHHHGBBD, JJE0000000000000J, JJJJJJJJJJJJJK00J, K0000000000000B55, K80000000000000I7, L0000000000000IB3, L0000000000009E2J, LLLLLLLLLLEB00007, LLLLLLLLLLLLLBGG3, 2D0000000000000001, 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5IIIIIIIIIIIIIIIIIIIIIIIIIIF, D555555555555555555555550555, EEAAAAAAAAAAAAAAAAAAAAAAAAAF, HHHHHHHHHHHHHHHHHHHHHHHHEEBH, K66666666666666666666666666F, LLLLLLLLLLLLLLLLLLLLLLLLEEB7, D5555555555555555555555555A55, GGGGGGGGGGGGGGGGGGGGGGGGGGGG3, GIG0000000000000000000000000H, HH00000000000000000000000001H, K0000000000000000000000005KEF, 5BBBBBBBBBBBBBBBBBBBBBBBBBBBBD, HB0000000000000000000000000001, K000000000000000000000000505EF, L7777777777777777777777777772L, 2000000000000000000000000000CB1, C8CCCCCCCCCCCCCCCCCCCCCCCCCCCC9, IKKKKKKKKKKKKKKKKKKKKKKKKKKKKFF, JE0000000000000000000000000000J, K000000000000000000000000000261, A0000000000000000000000000004I4H, HD000000000000000000000000000001, K000000000000000000000000000EC01, K0FFFFFFFFFFFFFFFFFFFFFFFFFFFFCF, D0002222222222222222222222222222D, FFFFFFFFFFFFFFFFFFFFFFFFFFFFFFL2L, I700000000000000000000000000000GH, K00000000000000000000000000000E61, 20000000000000000000000000000000JJ, DD5KKKKKKKKKKKKKKKKKKKKKKKKKKKKKKF, 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6000000000000000000000000000000000000000000000000000000000000000000000000000000043, KKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKB5, HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHEEH, 4HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHEH, 50000000000000000000000000000000000000000000000000000000000000000000000000000000002C1, K0000000000000000000000000000000000000000000000000000000000000000000000000000000000055EF, H700000000000000000000000000000000000000000000000000000000000000000000000000000000000000000H, 80000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000K1, EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE0I7, HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHEH, 5000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000BB5, J000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000BIJ, C4IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII3, F0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000066B3, G0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000A5, D5KKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKF, HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHBH, L0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000IKF, 4IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII3, A400000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000H, DKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKF, 4HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH, E0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000071, 7LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLIL, LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLK77, EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEI7, LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLIB3, I7G00000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000H, 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77EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEK7, JJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJKJ, 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LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLKE7, 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BKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKK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80BN, 80FH, 80LN, 80MN, 840N, 848N, 866B, 86FB, 880B, 880N, 884N, 88CB, 88FB, 88LN, 88MN, 8BBB, 8BLB, 8C6B, 8CCH, 8CFH, 8F0B, 8FHH, 8FLB, 8H0H, 8HCH, 8IGN, 8ILN, 8KKH, 8L8B, 8LBB, 8LFB, 8LIN, 8M8N, 8MLN, 8N0N, 8NGN, 8NLN, 9061, 9091, 90EJ, 90F1, 90GJ, 90K1, 940J, 9501, 95F1, 9CC1, 9E0J, 9E95, 9F61, 9FI5, 9G3J, 9II5, 9K01, 9KK1, 9M01, A007, A05D, A0AD, A33D, A3AD, A3F5, A44J, A727, A9EJ, AA0D, AAAD, AAAJ, ACM7, AD8D, ADKD, AE27, AE9J, AEAJ, AEE7, AIAD, AIDD, AIID, AJ9J, AK5D, AM07, AM27, AM35, AMK5, B08B, B0CB, B0GB, B18B, B1CB, B80B, B8CB, BB21, BB4N, BBCB, BBF1, BBFB, BBK1, BC8B, BCF1, BCLB, BF1B, BF8B, BFB1, BFM1, BGC1, BGF1, BK21, BL8B, BLFB, BM1B, BM3N, BMB1, BMMN, BNF1, C00D, C06B, C077, C0D7, C0H7, C0L7, C0LB, C0M1, C60H, C6LB, C76H, C7E7, CAID, CC01, CCFH, CCKH, CDLB, CGE7, CH07, CHE7, CI8D, CIAD, CK0D, CL8B, CLDB, CLE7, CM01, CM07, CME7, CMM1, D007, D08D, D0C7, D0HH, D0LN, D0M7, D0NN, D207, D2KH, D2M7, D777, D7E7, D80H, D8LD, DA27, DAC7, DAM7, DBFB, DBMB, DC77, DCLB, DDL7, DE77, DF0H, DF2H, DFFH, DFMB, DH27, DH8H, DHC7, DHHH, DILN, DK0H, DK2H, DK8H, DKHH, DLIN, DLL7, DLM7, DLMB, DM07, DMH7, DMMB, DNGN, E07J, E09J, E335, E355, E555, E5A5, E5K5, E79J, E93J, E995, EA35, EE95, EKE5, F00B, F00H, F06H, F08B, F0I5, F11B, F18B, F1L1, F20H, F26H, F2FH, F355, F661, F6K1, F80B, F86B, F8BB, FBGB, FBK1, FBLB, FC0B, FC6H, FCLB, FEK5, FGB1, FH05, FH0H, FH35, FH6H, FHCH, FHF5, FHHH, FI05, FK91, FKK1, FL1B, FLB1, FLBB, FM61, FMBB, FMK1, G00J, G021, G027, G0EJ, G0JJ, G0M1, G0M7, G1CB, G2E7, G40J, G4AJ, G4IJ, G4JJ, G6C1, G701, G94J, G9IJ, GAEJ, GAJJ, GB21, GBM1, GC01, GCF1, GCLB, GE0J, GEAJ, GEE7, GEG7, GEIJ, GEL7, GFM1, GGE7, GGMB, GI0J, GIIJ, GIIN, GJ9J, GM27, GMB1, GNM7, H005, H0K5, H0M5, H207, H2E7, H335, H3I5, H595, H5K5, H60H, H68H, H76H, H80H, H8HH, HAAJ, HE7J, HEC7, HGE7, HGM7, HH35, HI55, HIM5, I00J, I035, I08D, I0CD, I4JJ, IC0D, ICID, II0D, II0J, II35, IIAD, IILD, IIM5, IIMN, IJ9J, ILCD, IM05, IM35, IMNN, INLD, J03J, J0HJ, J0JH, J2CH, J39J, J3ID, J60H, J62H, J8CH, J9IJ, JGAJ, JGJJ, JH9J, JI0J, JIDD, JJ0H, JJCD, JJJD, JJLD, JL3D, JLCD, K0E5, K0I5, K0K1, K0KH, K191, K211, K2F1, K2G1, K591, K5AD, K6F1, K6G1, K9I5, KA0D, KAAD, KAM5, KCCH, KCHH, KD8D, KDDD, KFI5, KG01, KG61, KH0H, KHHH, KI55, KIDD, KK21, KK8H, KKF1, KKK1, KKKD, KM8H, KMHH, KMK5, L027, L0M7, L1C1, L1MB, L211, L727, L8BB, L8BN, L8FB, L8LN, L9C1, L9M1, LB8B, LBC1, LBM1, LCAD, LD77, LDIN, LDL7, LDM7, LF8B, LG21, LIIN, LLLN, LLN7, LM07, LM1B, LM77, LMG1, LN77, LNM1, M00N, M01B, M03N, M055, M077, M08B, M0B1, M0C1, M0GB, M0K1, M0M7, M0N7, M18B, M1BB, M1MB, M26H, M335, M3GN, M3M5, M3MN, M3NN, M501, M53N, M5M1, M5NN, M6BB, M6C1, M6G1, M6KH, M88B, M88N, M8BB, M8NN, MBB1, MC01, MCC1, MCKH, MCM1, ME07, ME35, MEK5, MGGB, MGMB, MH35, MH8H, MHE7, MHM5, MK8H, MKC1, MKG1, MKHH, MKK5, ML8N, MM01, MM8B, MMC1, MMLN, MMM5, MMMN, MMN1, MN0N, MN27, MNGN, MNLN, N007, N027, N077, N0C7, N0DN, N0IN, N1M1, N227, N2M7, N661, N707, N727, N8LD, NA27, NA3D, NC07, ND0D, ND0N, NDLD, NF11, NF61, NGG7, NILN, 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5M0M1, 5MNNN, 5N03D, 5N3LD, 5NA8D, 5NADD, 5NDGN, 5NNGN, 600KH, 61661, 616L1, 61MM1, 66161, 66611, 666B1, 666L1, 666LB, 66BB1, 66BG1, 66BLB, 66G61, 66KF1, 66LBB, 66LG1, 6BBBB, 6BFCB, 6CC11, 6F1M1, 6F66B, 6F6B1, 6F6L1, 6FBCB, 6FLMB, 6FMCB, 6FMM1, 6FMMB, 6GCM1, 6GM61, 6GMC1, 6K1C1, 6K1K1, 6KK11, 6KKL1, 6KL11, 6L1G1, 6LBFB, 6LCC1, 6LFMB, 6MM61, 6MM6B, 70291, 702C1, 702G1, 72CF1, 72EE7, 7433J, 7443J, 77A07, 79901, 799F1, 7AAEJ, 7EE27, 7H9EJ, 7K2KH, 7KK2H, 7KKKH, 7KKMH, 7L2C1, 800NN, 806BB, 808BB, 808LB, 80F8B, 80IIN, 833ID, 860KH, 8886B, 888NN, 8BG4N, 8CH6H, 8CKHH, 8FC0H, 8FFCH, 8HHHH, 8IIIN, 8K0HH, 8LL4N, 8M0NN, 8MNNN, 8NNND, 9000J, 900M1, 9034J, 90IIJ, 94IIJ, 96CM1, 96KF1, 96MM1, 990C1, 990M1, 99591, 99961, 999C1, 99F91, 99FM1, 99KF1, 99M61, 99MK1, 9AAA5, 9FEE5, 9FFA5, 9FFF5, 9II4J, 9K6C1, 9K9C1, 9K9F1, 9KF91, 9M6M1, 9MK61, A02M7, A0A35, A0AM5, A0C77, A0D0D, A0DDD, A0EC7, A0M55, A0MM7, A2ME7, A3335, A33M5, A3555, A3MM5, A550D, A58ID, A5D0D, A5DDD, A74AJ, A7E07, AA0M5, AA3ID, AA3M5, AA83D, AA8ID, AAAM5, AACID, AAICD, AAM05, AC08D, AC0ID, AC0KD, AC8ID, ACA8D, AFA35, AIC8D, AJAJJ, AK0KD, AKI0D, AKKM5, AKM05, AM505, B00FB, B00LB, B0LBB, B1MBB, B1MMB, B2GM1, B3MGN, B88BB, BB3MN, BBB3N, BBB8B, BBBBN, BBBMN, BBCC1, BBGB1, BBGLB, BBMC1, BBMGB, BBNM1, BFB0B, BFBMB, BFGLB, BFGMB, BGGLB, BGMM1, BLMMB, BMC0B, BMGM1, BMMK1, BMNM1, C006H, C00CH, C00M7, C0C11, C0CC1, C0E07, C0F6H, C0GG7, C0K8D, C0KDH, C0KHH, C1CC1, C1CM1, C1MC1, C70F1, C886B, CC06H, CCCCH, CCCF1, CCCM1, CDHH7, CE707, CE7L7, CEE77, CEEG7, CEL07, CFFHH, CGLL7, CHC6H, CHCCH, CHH7H, CHHH7, CHHM7, CI0LD, CK0HH, CKHCH, CL007, CLD07, CLLL7, CM777, CMMM7, D008H, D07L7, D0DE7, D0EL7, D0L77, D0M8H, D0NA7, D22E7, D70A7, D7227, DBLBB, DCL07, DD7A7, DDAE7, DDD8D, DDE07, DDK0D, DDM77, DEE27, DKK8D, DL227, DL707, DLBBB, DLDFB, DLE27, DM2E7, DMM77, DMME7, DN0A7, DNIIN, DNLLN, E000J, E0227, E02E7, E0AAJ, E0GL7, E0I0J, E2E07, E7AAJ, E7E27, EAA55, EAK55, EC777, ECEE7, ECEL7, ECGL7, ECL77, EEC77, EECL7, EEEC7, EEG27, EEGG7, EG0E7, EG0L7, EG207, EGE07, EGG07, EGG27, EGL07, EI9IJ, F02HH, F06LB, F0C6B, F0CCH, F0CHH, F0E55, F0EA5, F0FH5, F0GGB, F0M2H, F0MGB, F0MMB, F1BMB, F3FF5, F3I35, F3II5, F6BCB, FA035, FB1MB, FBBM1, FBBMB, FBM8B, FC0HH, FC88B, FCFHH, FFC0H, FFCFH, FFCHH, FFF0H, FFF6H, FFFH5, FFHI5, FFI55, FG1MB, FGGCB, FGM1B, FHK55, FI5I5, FKEA5, FKKI5, FKL11, FM16B, FM1CB, FM62H, FM6CB, FMBG1, FMM0B, G0001, G00E7, G039J, G06F1, G07C1, G07F1, G0A9J, G0G07, G0GG7, G0I4J, G0I9J, G0LL7, G22M7, G2M07, G339J, G433J, G62M1, G6M61, G6MM1, G903J, G933J, GAA9J, GBCC1, GE007, GGGGB, GGGL7, GJ0IJ, GL007, GL2M7, GLL07, GLLM7, GMGCB, GMM07, GMM1B, H007H, H05I5, H0CCH, H0CM7, H0GG7, H0H27, H0H8H, H0HC7, H0HH5, H0I35, H0MM7, H3555, H35F5, H3F55, H3FF5, H5055, H50F5, H7HEJ, H9995, H9GEJ, HCC0H, HCC6H, HCGG7, HCHM7, HE027, HE0G7, HEE07, HEEG7, HEG27, HF0F5, HF505, HF555, HFF05, HFKF5, HG0G7, HH06H, HH08H, HH0H5, HH5I5, HH7HJ, HH9EJ, HH9I5, HHCHH, HHE07, HHGG7, HHH05, HHH7H, HHH9J, HHKI5, HHM05, HHM07, HHM27, HI0I5, HJ86H, HJC0H, HK055, HK9F5, HKF05, HKFF5, HKFK5, HKII5, HKK95, HM2M7, HME27, HMKM5, HMM05, HMM27, HMM55, HMMM7, I00DD, I00M5, I044J, I0505, I09IJ, I0AAD, I0D0D, I0DDD, I0I05, I0IDD, I0II5, I0IJJ, I0JIJ, I33M5, I4I4J, I5INN, I888N, I8NND, I8NNN, I904J, I94IJ, IA8ID, IAADD, IAI8D, IDDDD, IDINN, II88N, II8NN, IID8D, IIDIN, III8N, IIIDD, IIIID, IIIIN, IIIND, IIN8D, IINDD, IJJ0J, IJJJJ, ILILN, ILLIN, IMM8N, INA0D, INDNN, INGIN, INNDN, INNND, J000H, J002H, J00AJ, J00GJ, J00KH, J02KH, J068H, J080H, J090J, J0A9J, J0AAJ, J0C0H, J0G0J, J0IIJ, J0JGJ, J0JIJ, J0K8H, J2K0H, J2KKH, J6K8H, J86KH, JC00H, JC0KH, JCCCH, JCK0H, JCKCH, JDDLD, JG93J, JIIJJ, JJ0IJ, JJ2KH, JJ9GJ, JJCCH, JJG9J, JJGIJ, JJJ9J, JJJJH, JJK8H, JK08H, JK0CH, JK8KH, JKC0H, JKKKH, K0001, K0091, K020H, K02C1, K03ID, K0611, K06L1, K083D, K08HH, K0961, K09C1, K0CF1, K0F91, K0KM5, K0LG1, K1G21, K20HH, K29K1, K2KHH, K5001, K500D, K58ID, K5D0D, K5L11, K6621, K6C11, K6LC1, K8CKH, K8KCH, K96C1, K99E5, K9F91, K9FA5, K9FE5, K9K91, KA55D, KC011, KCF11, KD02H, KD0MH, KD20H, KDM2H, KEA55, KEAA5, KEK95, KEKK5, KF1G1, KF1K1, KF611, KF6L1, KFEA5, KH8CH, KI005, KIMM5, KK05D, KK0AD, KK0DH, KK2CH, KK2KH, KK33D, KK961, KK9C1, KKA5D, KKD0D, KKE55, KKI0D, KKIID, KKIM5, KKK0H, KKKM5, KLGC1, KMK2H, L188B, L1991, L2007, L22M7, L2EE7, L2MM7, L333D, L3LIN, L7291, L72G1, L88IN, L8C8B, L9991, LBB1B, LBBBB, LBBBN, LD0E7, LDBBN, LE207, LFMCB, LGCC1, LL227, LL3IN, LL48N, LLM27, LLMM7, LMBCB, LME27, LMMBB, LMMM7, LN33D, LN3AD, LNAAD, LNACD, M0007, M0061, M00K5, M0207, M066B, M0BCB, M0EE5, M0G01, M0GM1, M0M8N, M27KH, M2E27, M2M07, M2M27, M5005, M5555, M66CB, M66K1, M6K61, M6MCB, M7007, M7EE7, M8C0B, M8KCH, M8MGN, MBBGB, MBGM1, MCCCH, MCHCH, MEE55, MGBC1, MGMM1, MH227, MH2M7, MHH7H, MKM55, ML3LN, MM0CB, MM16B, MM227, MM661, MM6K1, MME55, MMEE7, MMKE5, MMM07, MMM6B, MMMB1, MMMGB, MMMM7, MNM61, MNN3N, N00CD, N00KD, N03LN, N0A8D, N0AM7, N0D8D, N0KKD, N0L3N, N0LAD, N0NDD, N16L1, N3GIN, N3LAD, N3LIN, N3NNN, N61L1, N96M1, N9M61, NA0CD, NAK0D, NAKKD, NCA8D, NCM77, NDGIN, NDIIN, NDLLN, NF991, NGM07, NIIIN, NINNN, NKKDD, NLNAD, NN0LN, NN191, NN3NN, NN6L1, NN83D, NNAAD, NNDIN, NNGIN, NNL3N, NNLND, NNM61, NNNIN, 166G21, 16G621, 19MMM1, 1BBBMB, 1BBGM1, 1GCCC1, 1GCCM1, 1MMM1B, 200E27, 2E0027, 2HH0HH, 2HHC0H, 2KK0HH, 2M0E27, 2M22E7, 30NNNN, 3333M5, 333AID, 333I35, 33I555, 3F5FF5, 3I3MM5, 3I88GN, 3II8LN, 3IIII5, 400IJJ, 40J00J, 40JJ3J, 40JJJJ, 44403J, 444I0J, 44IJJJ, 44J0JJ, 44JJIJ, 48I8IN, 4I440J, 4II8IN, 4IJ0IJ, 4JIIIJ, 4JJ0JJ, 4JJJ0J, 50033D, 5003AD, 5008ID, 500D8D, 500G01, 500L11, 500LAD, 500MG1, 503LAD, 508ILD, 50DDLD, 50ILAD, 50M001, 516G61, 519MM1, 538NNN, 53NNNN, 55005D, 5508ID, 550D8D, 558ILD, 55F5I5, 56G661, 58333D, 58NNNN, 5999F5, 59AAF5, 5DNNNN, 5F55I5, 5FMMM1, 5G6661, 5K9AA5, 5KK9F5, 5KKK95, 5M0001, 5NDD8D, 5NDINN, 5NN33D, 5NNLAD, 5NNNAD, 5NNNDN, 608K0H, 61CCM1, 61G621, 661G21, 666621, 6666CB, 6666F1, 66K661, 6BCCC1, 6BKKC1, 6F6BBB, 6G6621, 6GCCC1, 6GMMM1, 6K6K61, 6M666B, 70A077, 70L991, 7722E7, 772E27, 7772E7, 777A27, 777L27, 77A777, 77EL27, 7A7077, 7A7777, 7E7227, 7L2E27, 7LEL27, 7LL2E7, 7LLE27, 7LLL27, 800GIN, 80NINN, 80NNNN, 8BBMGN, 8C888B, 8C88LB, 8MM0GN, 900001, 90043J, 959MM1, 96K661, 9999F1, 9999K1, 999AF5, 999FF5, 99EEE5, 99K991, 99MMM1, 9AAFF5, 9EIIIJ, 9F9991, 9F9MM1, 9FEAA5, 9G444J, 9K9991, 9M6661, A000CD, A000KD, A000M5, A0083D, A00I0D, A00M05, A022E7, A07E77, A0FF35, A0K3ID, A0K83D, A4AJJJ, A77777, AA0035, AA0355, AAA035, ADDD0D, ADDDDD, AF0035, AFFF35, AKK8ID, AM0M05, AM7777, B0F0MB, BBBBM1, BBLBMB, BFBBBB, BFM0MB, BFMMMB, BLBBMB, BLMBBB, C00071, C000E7, C007C1, C00G07, C07KKH, C0CC6H, C0CH6H, C0EEE7, C0HHHH, C777L7, C77L77, C7L777, C7LL07, C8088B, CAAK8D, CAKKAD, CC000H, CC0CHH, CD000H, CD0KKH, CE0007, CEE0E7, CELL77, CG0007, CGGL07, CH0CHH, CHCH0H, CHHH6H, CK0C0H, CKAK8D, CKKA8D, CL7707, D002FH, D0D0KD, D0DA77, D0DKKD, D0IIIN, D0K0DD, D0KDKD, D0KKDD, D0KKKH, DC0EE7, DCEEE7, DD0227, DD0D27, DD0DKD, DD0KKD, DD2E27, DDD0D7, DDD0LD, DDD227, DDDA77, DDDBCB, DDDCE7, DDDDFB, DDDMM7, DDEEE7, DDMBCB, DEEC07, DH000H, DHMEE7, DIIIGN, DK0KDD, DKMKKH, DMBBBB, DMEEE7, DMMM27, E00G27, E07727, E0C707, E0CE77, E0E027, E0EEG7, E0EGE7, E0EL27, E0GE27, E0L207, E0LE27, E0LL27, E2E2E7, E7L2E7, E900IJ, E9EEE5, EAAKK5, EC00E7, EC0G07, EC7007, ECEG07, EE0G07, EE0GE7, EE72E7, EE7L27, EECE07, EECEG7, EEEEE5, EEEK55, EEEKA5, EEEL27, EEGLL7, EELE27, EGLLL7, EKK595, EKKA55, EKKAK5, EKKKK5, F000E5, F0AA35, F0F035, F0FFFH, F0HKK5, F0KKE5, F16BB1, F16MM1, F1BBBB, F1MC6B, F666BB, F66BBB, F6GMM1, FB0BBB, FB1BBB, FBBB0B, FBMMG1, FC0FFH, FCFCCH, FEEE55, FEEEA5, FF03F5, FF0FFH, FF3F35, FFEE35, FFF2CH, FFFCCH, FFFFE5, FFI335, FFKFE5, FGLMMB, FK55I5, FKFE55, FLM8CB, FMC66B, FMMC6B, G0AA4J, G0CCC1, G0LE07, G666F1, GG0007, GG00G7, GG0L07, GGLLL7, GGLMM7, GI444J, GJJ33J, GLLE27, GLMMCB, GM0661, GMMM61, H00G07, H05555, H09FF5, H0C0E7, H0CE07, H0CEE7, H0E227, H0H007, H0H5F5, H0H995, H0HHE7, H0HHH7, H55505, H55II5, H5FII5, H99FF5, HEG007, HFFK55, HH0007, HH02M7, HH0C0H, HH7AEJ, HHC0E7, HHE227, HHH0C7, HHH0M7, HHH995, HHHC0H, HHHE27, HHHEAJ, HHHH07, HHHH8H, HHHHE7, HHHHI5, HHHHJH, HHHJ8H, HHHJCH, HHJ00H, HHK095, HHKKM5, HKK0F5, HKK5F5, HKKK55, HKKKK5, HKM555, HMEEE7, I00555, I05555, I0I94J, I333I5, I33555, I444IJ, I55055, I55505, I55555, IAAC8D, ID000D, IDD0LD, II9I4J, III4IJ, III505, IIIC8D, IIJIJJ, IJIIIJ, IM8LLN, IN00AD, INAACD, INCAAD, ININGN, J00CCH, J0IJJJ, J0J09J, J3333D, JIJIIJ, JJ68KH, JJIJIJ, JJJAJJ, JJJHGJ, JJJJAJ, JJJJGJ, JJJJIJ, K0008H, K00161, K001G1, K001L1, K002CH, K002HH, K00521, K00AKD, K00C0H, K00GF1, K00I0D, K00K95, K00M05, K01621, K05021, K0505D, K051G1, K059F5, K05K95, K0C0C1, K0L291, K0M005, K0M505, K1K661, K2CK0H, K33IAD, K3IIID, K5550D, K56121, K59AA5, K612K1, K61CC1, K66661, K6K611, K900C1, K99661, K9AFF5, K9C001, KAKI8D, KC00C1, KDK00D, KF9991, KI0IID, KK000D, KK01L1, KK0661, KK0I8D, KK0L11, KK0M2H, KK5661, KK59F5, KK61C1, KK9995, KK9EE5, KKA3ID, KKA83D, KKAI8D, KKC001, KKC0C1, KKC1C1, KKCCC1, KKD2HH, KKK595, KKK9A5, KKKK95, KKKKKH, KKKMCH, KKM505, KKMEE5, KKMKCH, KM0005, L222E7, L33AAD, L38I8N, LCCC11, LDFBCB, LEL2E7, LELE27, LELL27, LGMMM1, LLE2E7, LM2ME7, M000M5, M006MB, M00E27, M00MM1, M02227, M06M61, M06MM1, M0E227, M0EE27, M0KME5, M0M5GN, M0MM61, M0MMCB, M0MNNN, M0NNM1, M38LLN, M5K505, M77707, M7E227, M7E727, M8CHHH, MBMMCB, MBMMM1, MEEE77, MHH027, MHH505, MHHC6H, MHHH6H, MHHK05, MKK001, MM2ME7, MM7707, MM7E77, MMBMK1, MMM2E7, MMMC0B, MMMK61, N0003D, N0008D, N0030N, N030NN, N0C0AD, N0CKAD, N0DKDD, N0N3GN, N0NN3N, N333AD, N777A7, N77A77, NAACKD, NAAKDD, NACAKD, NACKAD, NC0AKD, NC0KAD, NCA0KD, NCKAKD, NDNNLN, NNNLAD, NNNNLD, 1BBBBBB, 1BBBBG1, 1M6MMMB, 1MMBBBB, 1MMMMK1, 2000227, 2000EE7, 20EEEE7, 2C0FFFH, 2E2EEE7, 2KKKHCH, 2MEE227, 2MEEE27, 333333D, 3333355, 3335555, 333FFF5, 333IIID, 388NNNN, 38INNNN, 3INNNNN, 4000IMN, 4000JJJ, 400IIIN, 444444J, 44JJJJJ, 488888N, 4IIJIIJ, 4JJJ33J, 50002M1, 5001G21, 5006621, 500LGM1, 555083D, 55555I5, 5616G21, 59MMMM1, 5K999A5, 61CCCC1, 66666K1, 6K0000H, 6K0080H, 70000A7, 70077A7, 70700A7, 7070A77, 77700A7, 77770A7, 7777227, 7777E27, 77L2227, 7LE22E7, 888888B, 888888N, 8888BBN, 8888IIN, 888B88B, 888I8IN, 88IINNN, 88NIINN, 88NNIIN, 8INNNNN, 90444IJ, 904I44J, 9666661, 9666FK1, 9666K61, 9966FK1, A00KK0D, A0K000D, AAAAA35, AAKKI8D, BB8888B, BBB0BLB, BBBB1BB, BBBBBB1, BBBBBGB, BBBBBLB, BBBLMBB, C0007KH, C000F11, C00FFFH, C00HH0H, C00K00H, C0C0HHH, C0CCHHH, C0CHH0H, C0CHHCH, C0FFFFH, C0H0H0H, C0KKC0H, CC0HH0H, CCCCC11, CCCCCC1, CCHHHHH, CDKKKKH, CEL7777, CGGG0G7, CGGGGG7, CH00HHH, CHGGGG7, CHHHH0H, CHHHHCH, CHHHHHH, CK0000H, CKDKKKH, D00DDKD, DD0DDD7, DDBBBLB, DDD2EE7, DDDBBLB, DDDDD27, DDDDDBB, DDDDDC7, DDDDDKD, DDDDDMB, DDDDEE7, DDDDKKD, DDDDLDB, DDDFBBB, DDDLFCB, DDDMEE7, DDM2227, DHHEEE7, DK000KD, DK00D0D, DK0D00D, DNN000N, E000CL7, E000EG7, E000GE7, E00C0G7, E00CE07, E00EE27, E0C00G7, E0C0EG7, E0CE007, E0EC0G7, E0EE207, E0G0007, E20EE27, E22EEE7, E2EE227, E2EEE27, E772227, E77LL27, E7L2227, E9IIIIJ, EAKKKA5, EC000G7, ECG00G7, EE00L27, EE0E0G7, EE20EE7, EEE0EG7, EEE22E7, EEEE727, EEEEE27, EEEEG07, EEEEGE7, EEEKKK5, EELLL27, EI0IIIJ, EKKKAA5, ELLLE27, F00FA35, F0333F5, F0F0FE5, F333335, FAAFF35, FCF0FCH, FEEEE35, FF03335, FF0FA35, FF0FE35, FF0FMCH, FFF0A35, FFF0F35, FFFAF35, FFFF5I5, FFFFM2H, FFFI3I5, FFFIII5, FFH5555, FH55555, FL1MMM1, G0000G7, G0000L7, GGGG007, GLE2227, GLLLLE7, GLLLLL7, H000007, H0000C7, H000HCH, H000HM7, H000M27, H000ME7, H00G227, H00HHM7, H02M227, H0C0HHH, H0CH00H, H0E0007, H0FFF35, H0FFFF5, H0H0ME7, H0HFII5, H0HHHCH, H0M0227, H555555, H5F5FF5, HC000G7, HC00H0H, HCCHHCH, HCHHHCH, HCHHHHH, HEEEE27, HFF5FF5, HFF5FI5, HFKKK05, HG00007, HH00E27, HH0G227, HHH2MM7, HHH55F5, HHH9FF5, HHHFFK5, HHHFK55, HHHH7EJ, HHHHCM7, HHHHHAJ, HHHHHF5, HHHHHHJ, HKK5505, I000055, I00A0ID, I0I4IIJ, I0IIIIJ, I88NIIN, III0055, III0I55, III444J, IINNLIN, J000IJJ, K0000DH, K0000KD, K00033D, K000A5D, K000K5D, K00555D, K009995, K00K00D, K00K8ID, K00KI8D, K00KIAD, K01GCC1, K05033D, K0999F5, K2KKKCH, K53333D, K956661, K999991, KCCC1C1, KFFFE55, KFFKKE5, KFKFKE5, KK009A5, KK00C11, KK01GC1, KK99001, KKIII05, KKK09F5, KKKE9E5, KKKEAK5, KKKKI05, KKKKKE5, KMMEEE5, L1BBBG1, LBMMMCB, LBMMMMB, LDEEE07, LEE22E7, LEE2E27, LEEE2E7, LLLLE27, M0000CB, M000C6B, M02EEE7, M0K0005, M0M0005, M2CHHHH, M2HHHHH, M6MMMM1, MC0000B, MCHHHHH, ME7E777, MEE7777, MEEE2E7, MG06661, MHHHCCH, MHHHH27, MHHHHH7, MHM0027, MM6666B, MM77777, MMC000B, MMM7727, MMNM777, N000NLN, N00333D, N003AAD, N0A00DD, N0NN33D, N0NNLLN, N30000N, N777777, NDNNNNN, NN0N0GN, NN0N30N, NNN300N, NNN333D, NNN3LLN, NNNDDDD, NNNNN3N, NNNNNND, 33333F35, 33FFFF35, 3555FFF5, 3FFFFF55, 3NNNNNLN, 40000I0J, 40I0IIIJ, 444440IJ, 4J0000IJ, 500006G1, 5D00DDDD, 5L1MMMM1, 5MMMMMG1, 5NNDDDDD, 5NNNNDDD, 5NNNNN8D, 6000080H, 777777A7, 77777A77, 7944444J, 800000IN, 996666K1, 999999I5, 9999FEA5, A00003ID, AAAAFF35, BBBGMMMB, C0000011, C000007H, C0CC0H0H, C666666B, CCCH0HHH, CCHH0HCH, CE777777, CEEEEE07, CHH0H00H, D00000GN, D000D0LD, D000IIGN, D0DDDDD7, DDD0E2E7, DDDDDDDB, DDDDDME7, DEEEELE7, DEEELEE7, DEELEEE7, DELEE0E7, E00000C7, E00000G7, E0000CG7, E000C0E7, E000G007, E00CG007, E00E0CG7, E0C00007, E0CGGGG7, E0GGGGG7, E20000E7, EAAKAAA5, EAKKAAA5, EE00E727, EE020007, EEEE2027, ELEE2227, F00003F5, F0000A35, F0003335, F0FFFA35, F1999991, F1999MM1, FAAAAF35, FBBBBBG1, FEAAAAA5, FF000A35, FF00FF35, FF0KEEE5, FFAAAF35, FFF555I5, FFFF33I5, FFFFF035, FFFFF3F5, FFFFFKI5, FFFFFMHH, FKFKEEE5, FKKFEEE5, FMMMMMCB, FMMMMMM1, G2000007, GGGGGMM7, GJJJJJ0J, GJJJJJ3J, H0000E27, H0000G27, H000C0G7, H000CEG7, H000CHH7, H000E0E7, H000EE27, H00CHHG7, H00EEE27, H00M0EE7, H05FF5F5, H0E00EE7, H55FF5F5, HCHH0H0H, HE000EE7, HFFIIII5, HGGG2227, HH00CEG7, HH00H0CH, HH0EEEE7, HH0FFFI5, HHEEEEE7, HHH000CH, HHH00EG7, HHHC00G7, HHHFFFF5, HHHHHKK5, HHHK5F55, HK5555F5, I4IIIIIJ, IA0000ID, II0005I5, III000I5, III055I5, III5NNNN, IIIII9IJ, IIIIIII5, IIINNNGN, JAJJJJJJ, JJAJJJJJ, K000005D, K00009A5, K0000M55, K000M555, K008IIID, K00D0K0D, K00III8D, K00K550D, K00LCC11, K0999951, K0D0000H, K0K00595, K0K9AAF5, K0KK0095, K0KK9FF5, K3333IID, KFKFEEE5, KFKKEEE5, KK00000H, KK0000M5, KK099991, KK55583D, KKKEEEA5, KKKKKKI5, LEEEE227, LLLEEE27, LLLL2E07, M000006B, M000M6CB, M0MMMMM1, M222EEE7, M777E777, M7E77777, ME222EE7, ME2EEEE7, MEE222E7, MM0NNNNN, MME77727, MMM6MMM1, N00003GN, N0000ADD, N000N0GN, N000NNND, N033333D, N0NN0NGN, NDDDDKDD, NN000N3N, NN00N03N, NN03000N, NNN003GN, NNNNDNLN, NNNNNADD, 199999MM1, 200FFFFFH, 222MEEEE7, 2FFFFFFCH, 30000000N, 30N00000N, 400000J3J, 500000M01, 5000166G1, 5000666G1, 50DDDDDDD, 8NN33333D, 999999991, C000000FH, C00000K0H, C000H00HH, C77777707, CH00H000H, CHH0000HH, D00000DKD, D00000DLD, D0000200H, D0000KK0D, D000KK00D, D00D0DDLD, D0D00DDLD, D0LEEEEE7, DDBBBBBBB, DDD000KDD, DDDDDDDE7, DK00000DD, DNNNNNNNN, E00000E27, E00007L27, E0000E727, E0E000C07, E20000027, EAAAAKAA5, EAKAAAAK5, EE0000C07, EEE000E27, EEEEEEGL7, F00FFFF35, F0FFFFF35, FF0000035, FF0FFFF35, FF5555FI5, FFFFFFA35, FFFFFFF35, FFFFFFFI5, FKKKKEEE5, FMMMMMMMB, GGGGG2227, GGGGGG207, GJJJJJJJJ, GLMMMMMMB, H000022M7, H000222M7, H000EEEE7, H0EEEEEE7, H0H0000CH, H0IIIIII5, HCH00000H, HE0EEEEE7, HFFFFFI35, HFFFFKKK5, HHHHHHG27, HHHHHHH55, HHHHHHHH7, HHHHHHM55, HHHKK5555, HHIIIII05, HIIIIII05, HKK5555I5, I000000AD, I000000ID, I000A000D, I00A0000D, IIIII0555, IIIIIII9J, K000000AD, K00000595, K000009F5, K0000550D, K099999A5, K0C00000H, K0I00000D, KK0000595, KK0000HCH, KKK000095, KKKFKFFE5, KKKIIIII5, M77777777, MEEEE2227, MMMMMMMM1, N0000000D, N0000003N, N000003NN, N00000N3N, N00000NGN, N00N000GN, N00NNNN8D, N0NNN00GN, N0NNNN3AD, N0NNNNNGN, N999999M1, NN0NNNNGN, NNN000NGN, NNNNNDD8D, NNNNNN0GN, 16MMMMMMMB, 1MMMMMMBCB, 3333333335, 33333333I5, 400000000N, 40IIIIIIJJ, 4IIIIIIIJJ, 4IIIIIIJIJ, 50000000M1, 70F9999991, 777E777727, 9999995MM1, ADD000000D, C00000088B, C000000CF1, C00000F0HH, CH00000H0H, D00KD0000D, D0D0DDDDLD, D0E2EEEEE7, D2EEEEEEE7, DBBBBBBBBB, DD000000KD, DD0000DDLD, DLE0EEEEE7, EEE0000727, EEEAAAAAA5, EEEEEE00G7, EEEEEEE0G7, F000000F35, F00FFKEEE5, F00KFFEEE5, F0M666666B, FCFFFFFFFH, FFFFFFF2HH, FFFKKKEEE5, GGGGGGG227, H00000C06H, H0000HHH6H, H555FFFFF5, H55FFFFF55, H5FFFFFF55, HF5FFFFFF5, HHHH0H0HCH, HHHHH0HHCH, HHHHHH0HCH, HHHHHHHHM5, HHHIIIIII5, IIDNNNNNLN, IIIIIJJIIJ, IIINNNNNLN, IINNNNNNGN, INNNNNNNLN, J0000000IJ, K0000II8ID, K099999995, K0I0000AID, K0K0009FF5, K9999999F5, KK00000095, KKFFFKEEE5, LLLLLLLME7, LLLMEEEEE7, LMEEEEEEE7, M000000005, MHHHHHHHH5, MK00000005, MMMMMMMBCB, NN000000GN, NN0000NNGN, NN99999991, 2HHHHHHHHHH, 38NNNNNNNNN, 3MNNNNNNNNN, 40IIIIIIIIJ, 4AJJJJJJJJJ, 4J000000J0J, 4JJJJJJJJJJ, 506666666G1, 5DDDDDDDDLD, 999999999F5, 99999999EA5, 99999999FE5, A0000000035, C0000000007, C00000000G7, C00000000KH, CEEEEEEEEL7, D0000000FMH, D000DDDDDLD, D0KD000000D, DDDD00000KD, DEEE0EEEEE7, DEL0EEEEEE7, DELEEEEEE07, E0000E20007, E7777777727, EE000000207, EEE20000007, FFFFFFFFMCH, FM66666666B, GGGGGGGG2M7, HFFFFFFFF55, HHHHHHHHH6H, HHHHHHHHHCH, HHHHHK55555, I9IIIIIIIIJ, IIIIIIII44J, IIIIIIIJJIJ, IINNNNNNNNN, JDDDDDDDDDD, JJIIIIIIIIJ, K00000I8IID, LLLLLLLLL27, 9999999EEAA5, AI000000000D, C77700000007, CH0HH000000H, D00D000000LD, DEEEEEEE0EE7, DN000000000N, EAKAAAAAAAA5, EKAAAAAAAAK5, F6666666666B, H000HHHHHH6H, H55FFFFFFFF5, HFFFFFFFFKK5, K00000000I8D, K999999999A5, 3555555555FF5, 5000000000001, 6G66666666661, 99999999999A5, C00000000000H, CFFFFFFFFFFCH, CHHH00000000H, D00000000K0KD, D0000000K00KD, D0D00000000LD, DEEEEEEEEEL07, E000E20000007, E00E200000007, EEE0000000027, GGGGGGGGGGGM7, GGGGGGGGGGM07, H00000000CHHH, H00HC0000000H, HFFFFFFFFFFK5, I0A000000000D, J000000000J9J, K000000000095, K000000000M2H, M0000000000M1, M0EEEEEEEEEE7, MHHHHHHHHHHHH, MMNNNNNNNNNNN, MNNNNNNNNNNNN, N000000DDDDDD, N000DDDDDDDDD, NNDDDDDDDDDDD, 22EEEEEEEEEEE7, 35FFFFFFFFFFF5, 400000000000JJ, 800000000000GN, DDDDDDDDDDD077, DDDDDDDDDDDDD7, E0000000000L27, EAAAAAAAAAAKA5, EEG00000000007, H0000000000C6H, I5500000000005, II0000000000I5, M0666666666661, M6MMMMMMMMMMMB, 4JJ00000000000J, 506666666666661, BGMMMMMMMMMMMCB, CFFFFFFFFFFFFFH, D0000000000KD0D, D0HEEEEEEEEEEE7, F0BBBBBBBBBBBBB, HGGGGGGGGGGGGG7, K0000000000000D, K00000000000MCH, M0M6MMMMMMMMMMB, 5DDDDDDDDDDDDDDD, C00000000000008B, D00000000000000H, DEEEEEEEEEEEE0L7, DEEEEEEEEEEEEEL7, EEE2EEEEEEEEEEE7, GM66666666666661, H5FFFFFFFFFFFFF5, IIIIIIIIIIIIIJJJ, BGMMMMMMMMMMMMMMB, DLEEEEEEEEEEEEEE7, H0000000000000CHH, H000000000C0000HH, I000000000000000D, IIIIIIIIIIIIIIIJJ, INNNNNNNNNNNNNNNN, J000000000000009J, M666666666666666B, N0000000000000LLN, N00DDDDDDDDDDDDDD, 355555555555555555, 60000000000000008H, 6M6666666666666661, C000000000000000F1, N0DDDDDDDDDDDDDDDD, 666666666666666666B, 800000000000000000N, AD000000000000000DD, DEEEEEEEEEEEEEEEEE7, I500000000000000005, 20000000000000000027, 4000000000000000003J, 400000000000000000IJ, 99999999999999999995, DD00DDDDDDDDDDDDDDLD, E2EEEEEEEEEEEEEEEEE7, N00000000000000000LN, 500000000066666666661, EE0000000000000000727, GGGGGGGGGGGGGGGGGGG07, H0000000000000000006H, 40000000000000IIIIIIIJ, AD0000000000000000000D, K0000000000000000000M5, CL777777777777777777777, D000000000000000000000N, D0000000000000000000IIN, HHHHHHHHHHHHHHHHHHHHHK5, NDDDDDDDDDDDDDDDDDDDDDD, 1MMMMMMMMMMMMMMMMMMMMMBB, D00DDDDDDDDDDDDDDDDDDDLD, FFFFFFFFFFFFFFFFFFFFFFFH, 4J0000000000000000000000J, 566666666666666666666666G1, EKKAAAAAAAAAAAAAAAAAAAAAA5, 6666666666666666666666666G1, AJJJJJJJJJJJJJJJJJJJJJJJJJJJ, H00000000000000000000000008H, N0000000000000000000000000GN, DD0000000000000000000000000LD, IIIIIIIIIIIIIIIIIIIIIIIIIIIIJ, G0666666666666666666666666666661, GGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGG7, K000000000000000000000000000000000H, EAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA5, LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLM7, M2EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE7, C000000000000000000000000000000000000000001, MMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMCB, E00000000000000000000000000000000000000000000727, 777777777777777777777777777777777777777777777777727, EG000000000000000000000000000000000000000000000000000007, D000000000000000000000000000000000000000000000000000000000LD, 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==Unsolved families== Families for which not even a probable prime is known nor can be ruled out as only contain composites (only count the numbers > base (''b'')). {|class=wikitable |base (''b'')||unsolved family (base-''b'' form)||unsolved family (algebraic ((''a''×''b''^''n''+''c'')/''d'') form)||current search limit of length||factorization of numbers in this family |- |13||9{5}||(113×13^''n''−5)/12||88000||[http://factordb.com/index.php?query=%28113*13%5En-5%29%2F12&use=n&n=1&VP=on&VC=on&EV=on&OD=on&PR=on&FF=on&PRP=on&CF=on&U=on&C=on&perpage=200&format=1&sent=Show] |- |13||A{3}A||(41×13^''n''+1+27)/4||82000||[http://factordb.com/index.php?query=%2841*13%5E%28n%2B1%29%2B27%29%2F4&use=n&n=0&VP=on&VC=on&EV=on&OD=on&PR=on&FF=on&PRP=on&CF=on&U=on&C=on&perpage=200&format=1&sent=Show] |- |16||{3}AF||(16^''n''+2+619)/5||76000||[http://factordb.com/index.php?query=%2816%5E%28n%2B2%29%2B619%29%2F5&use=n&n=0&VP=on&VC=on&EV=on&OD=on&PR=on&FF=on&PRP=on&CF=on&U=on&C=on&perpage=200&format=1&sent=Show] |} (If these three families contain primes (and they are excepted to contain primes), then the smallest prime in families 9{5} and A{3}A in base ''b'' = 13 will be index 3196 and 3197 quasi-minimal prime in base ''b'' = 13, and the smallest prime in families {3}AF in base ''b'' = 16 will be index 2347 quasi-minimal prime in base ''b'' = 16) === Base 17 === * 15{0}D * 1{7} * 1F{0}7 * 4{7}A * 51{0}D * 70F{0}D * 8{B}9 * 9{5}9 * 95{F} * A{D}F * B{0}B3 * B{0}DB * {B}E9 * {B}2BE * {B}2E * {B}EE * D0G{D} * E9{B} * F1{9} * FD0{D} * G{7}F ==Primality certificates for the proven primes > 10²⁹⁹== See also: [[w:Primality certificate|Primality certificate]] and [[w:Elliptic curve primality|Elliptic curve primality]] {|class=wikitable |base (''b'')||index of this quasi-minimal prime in base ''b''||quasi-minimal prime (base-''b'' form)||quasi-minimal prime (algebraic ((''a''×''b''^''n''+''c'')/''d'') form)||factordb entry of this prime||primality certificate of this prime |- |9||149||76₃₂₉2||(31×9³³⁰−19)/4||[http://factordb.com/index.php?id=1100000002359003642]||[http://factordb.com/cert.php?id=1100000002359003642] |- |9||150||27₆₈₆07||(23×9⁶⁸⁸−511)/8||[http://factordb.com/index.php?id=1100000002495467486]||[http://factordb.com/cert.php?id=1100000002495467486] |- |9||151||30₁₁₅₈11||3×9¹¹⁶⁰+10||[http://factordb.com/index.php?id=1100000002376318423]||[http://factordb.com/cert.php?id=1100000002376318423] |- |11||1065||A₇₁₃58||11⁷¹⁵−58||[http://factordb.com/index.php?id=1100000003576826487]||[http://factordb.com/cert.php?id=1100000003576826487] |- |11||1066||7₇₅₉44||(7×11⁷⁶¹−367)/10||[http://factordb.com/index.php?id=1100000002505568840]||[http://factordb.com/cert.php?id=1100000002505568840] |- |11||1067||557₁₀₁₁||(607×11¹⁰¹¹−7)/10||[http://factordb.com/index.php?id=1100000002361376522]||[http://factordb.com/cert.php?id=1100000002361376522] |- |13||3165||50₂₇₀44||5×13²⁷²+56||[http://factordb.com/index.php?id=1100000002632397005]||[http://factordb.com/cert.php?id=1100000002632397005] |- |13||3166||9₂₇₁095||(3×13²⁷⁴−6103)/4||[http://factordb.com/index.php?id=1100000003590431654]||[http://factordb.com/cert.php?id=1100000003590431654] |- |13||3167||10₂₈₆7771||13²⁹⁰+16654||[http://factordb.com/index.php?id=1100000003590431633]||[http://factordb.com/cert.php?id=1100000003590431633] |- |13||3168||9₃₀₈1||(3×13³⁰⁹−35)/4||[http://factordb.com/index.php?id=1100000000840126705]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], factor ''N''−1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=13&Exp=308&c0=-&EN= 13³⁰⁸−1] |- |13||3169||B₃₄₁C4||(11×13³⁴³+61)/12||[http://factordb.com/index.php?id=1100000003590431618]||[http://factordb.com/cert.php?id=1100000003590431618] |- |13||3170||8B₃₄₃||(107×13³⁴³−11)/12||[http://factordb.com/index.php?id=1100000002321018736]||[http://factordb.com/cert.php?id=1100000002321018736] |- |13||3171||710₃₇₁111||92×13³⁷⁴+183||[http://factordb.com/index.php?id=1100000003590431609]||[http://factordb.com/cert.php?id=1100000003590431609] |- |13||3172||75₃₇₅7||(89×13³⁷⁶+19)/12||[http://factordb.com/index.php?id=1100000003590431596]||[http://factordb.com/cert.php?id=1100000003590431596] |- |13||3173||9B0₃₉₁9||128×13³⁹²+9||[http://factordb.com/index.php?id=1100000002632396790]||[http://factordb.com/cert.php?id=1100000002632396790] |- |13||3174||7B0B₃₉₇||(15923×13³⁹⁷−11)/12||[http://factordb.com/index.php?id=1100000003590431574]||[http://factordb.com/cert.php?id=1100000003590431574] |- |13||3175||10₄₁₄93||13⁴¹⁶+120||[http://factordb.com/index.php?id=1100000002523249240]||[http://factordb.com/cert.php?id=1100000002523249240] |- |13||3176||81010₄₁₅1||17746×13⁴¹⁶+1||[http://factordb.com/index.php?id=1100000003590431555]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], ''N''−1 is trivially 100% factored |- |13||3177||8110₄₃₅1||1366×13⁴³⁶+1||[http://factordb.com/index.php?id=1100000002373259109]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], ''N''−1 is trivially 100% factored |- |13||3178||B7₄₈₆||(139×13⁴⁸⁶−7)/12||[http://factordb.com/index.php?id=1100000002321015892]||[http://factordb.com/cert.php?id=1100000002321015892] |- |13||3179||B₅₆₃C||(11×13⁵⁶⁴+1)/12||[http://factordb.com/index.php?id=1100000000000217927]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], factor ''N''−1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=13&Exp=564&c0=-&EN= 13⁵⁶⁴−1] |- |13||3180||1B₅₇₆||(23×13⁵⁷⁶−11)/12||[http://factordb.com/index.php?id=1100000002321021456]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], factor ''N''−1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=13&Exp=576&c0=-&EN= 13⁵⁷⁶−1] |- |13||3181||80₆₉₃87||8×13⁶⁹⁵+111||[http://factordb.com/index.php?id=1100000002615636527]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], ''N''−1 has a large prime factor, factordb entry of this prime factor is [http://factordb.com/index.php?id=1100000002615636532], and primality certificate of this prime factor is [http://factordb.com/cert.php?id=1100000002615636532] |- |13||3182||CC5₇₁₃||(2021×13⁷¹³−5)/12||[http://factordb.com/index.php?id=1100000002615627353]||[http://factordb.com/cert.php?id=1100000002615627353] |- |13||3183||B₈₃₄74||(11×13⁸³⁶−719)/12||[http://factordb.com/index.php?id=1100000003590430871]||[http://factordb.com/cert.php?id=1100000003590430871] |- |13||3184||9₉₆₈B||(3×13⁹⁶⁹+5)/4||[http://factordb.com/index.php?id=1100000000258566244]||[http://factordb.com/cert.php?id=1100000000258566244] |- |13||3185||10₁₂₉₅181||13¹²⁹⁸+274||[http://factordb.com/index.php?id=1100000002615445013]||[http://factordb.com/cert.php?id=1100000002615445013] |- |13||3186||9₁₃₆₂5||(3×13¹³⁶³−19)/4||[http://factordb.com/index.php?id=1100000002321017776]||[http://factordb.com/cert.php?id=1100000002321017776] |- |13||3187||7₁₅₀₄1||(7×13¹⁵⁰⁵−79)/12||[http://factordb.com/index.php?id=1100000002320890755]||[http://factordb.com/cert.php?id=1100000002320890755] |- |13||3188||930₁₅₅₁1||120×13¹⁵⁵²+1||[http://factordb.com/index.php?id=1100000000765961452]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], ''N''−1 is trivially 100% factored |- |13||3189||720₂₂₉₇2||93×13²²⁹⁸+2||[http://factordb.com/index.php?id=1100000002632396910]||[http://factordb.com/cert.php?id=1100000002632396910] |- |13||3190||1770₂₇₀₃17||267×13²⁷⁰⁵+20||[http://factordb.com/index.php?id=1100000003590430825]||[http://factordb.com/cert.php?id=1100000003590430825] |- |13||3191||390₆₂₆₆1||48×13⁶²⁶⁷+1||[http://factordb.com/index.php?id=1100000000765961441]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], ''N''−1 is trivially 100% factored |- |13||3192||B0₆₅₄₀BBA||11×13⁶⁵⁴³+2012||[http://factordb.com/index.php?id=1100000002616382906]||[http://factordb.com/cert.php?id=1100000002616382906] |- |13||3193||C₁₀₆₃₁92||13¹⁰⁶³³−50||[http://factordb.com/index.php?id=1100000003590493750]||[http://factordb.com/cert.php?id=1100000003590493750] |- |14||649||34D₇₀₈||47×14⁷⁰⁸−1||[http://factordb.com/index.php?id=1100000001540144903]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 is trivially 100% factored |- |14||650||4D₁₉₆₉₈||5×14¹⁹⁶⁹⁸−1||[http://factordb.com/index.php?id=1100000000884560233]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 is trivially 100% factored |- |16||2328||880₂₄₆7||136×16²⁴⁷+7||[http://factordb.com/index.php?id=1100000002468140199]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 has a large prime factor, and this prime factor is < 10²⁹⁹ |- |16||2329||D4₂₆₃D||(199×16²⁶⁴+131)/15||[http://factordb.com/index.php?id=1100000002468170238]||[http://factordb.com/cert.php?id=1100000002468170238] |- |16||2330||E0₂₆₁4DD||14×16²⁶⁴+1245||[http://factordb.com/index.php?id=1100000003588388352]||[http://factordb.com/cert.php?id=1100000003588388352] |- |16||2331||8C0₂₉₀ED||140×16²⁹²+237||[http://factordb.com/index.php?id=1100000003588388307]||[http://factordb.com/cert.php?id=1100000003588388307] |- |16||2332||DA₃₀₅5||(41×16³⁰⁶−17)/3||[http://factordb.com/index.php?id=1100000003588388284]||[http://factordb.com/cert.php?id=1100000003588388284] |- |16||2333||CE80₄₂₂D||3304×16⁴²³+13||[http://factordb.com/index.php?id=1100000003588388257]||[http://factordb.com/cert.php?id=1100000003588388257] |- |16||2334||5F₅₄₄6F||6×16⁵⁴⁶−145||[http://factordb.com/index.php?id=1100000002604723967]||[http://factordb.com/cert.php?id=1100000002604723967] |- |16||2335||88F₅₄₅||137×16⁵⁴⁵−1||[http://factordb.com/index.php?id=1100000000413679658]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 is trivially 100% factored |- |16||2336||BE0₇₉₂BB||190×16⁷⁹⁴+187||[http://factordb.com/index.php?id=1100000003588387938]||[http://factordb.com/cert.php?id=1100000003588387938] |- |16||2337||D9₁₀₅₂||(68×16¹⁰⁵²−3)/5||[http://factordb.com/index.php?id=1100000002321036020]||[http://factordb.com/cert.php?id=1100000002321036020] |- |16||2338||FAF₁₀₆₂45||251×16¹⁰⁶⁴−187||[http://factordb.com/index.php?id=1100000003588387610]||[http://factordb.com/cert.php?id=1100000003588387610] |- |16||2339||F8₁₅₁₇F||(233×16¹⁵¹⁸+97)/15||[http://factordb.com/index.php?id=1100000000633744824]||[http://factordb.com/cert.php?id=1100000000633744824] |- |16||2340||20₁₇₁₃321||2×16¹⁷¹⁶+801||[http://factordb.com/index.php?id=1100000003588386735]||[http://factordb.com/cert.php?id=1100000003588386735] |- |16||2341||300F₁₉₆₀AF||769×16¹⁹⁶²−81||[http://factordb.com/index.php?id=1100000003588368750]||[http://factordb.com/cert.php?id=1100000003588368750] |- |16||2342||90₃₅₄₂91||9×16³⁵⁴⁴+145||[http://factordb.com/index.php?id=1100000000633424191]||[http://factordb.com/cert.php?id=1100000000633424191] |- |16||2343||5BC₃₇₀₀D||(459×16³⁷⁰¹+1)/5||[http://factordb.com/index.php?id=1100000000993764322]||[http://factordb.com/cert.php?id=1100000000993764322] |- |16||2344||D0B₁₇₈₀₄||(3131×16¹⁷⁸⁰⁴−11)/15||[http://factordb.com/index.php?id=1100000003589278511]||[http://factordb.com/cert.php?id=1100000003589278511] |- |18||547||80₂₉₈B||8×18²⁹⁹+11||[http://factordb.com/index.php?id=1100000002355574745]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 has sum-of-two-cubes algebraic factorization, 6×18⁹⁹+1 is an algebraic factor of ''N''+1, factordb entry of 6×18⁹⁹+1 is [http://factordb.com/index.php?id=1100000000900149167] |- |18||548||H₇₆₆FH||18⁷⁶⁸−37||[http://factordb.com/index.php?id=1100000003590430490]||[http://factordb.com/cert.php?id=1100000003590430490] |- |18||549||C0₆₂₆₈C5||12×18⁶²⁷⁰+221||[http://factordb.com/index.php?id=1100000003590442437]||[http://factordb.com/cert.php?id=1100000003590442437] |- |20||3301||H₂₄₇A0H||(17×20²⁵⁰−59677)/19||[http://factordb.com/index.php?id=1100000003590502619]||[http://factordb.com/cert.php?id=1100000003590502619] |- |20||3302||7₂₄₉A7||(7×20²⁵¹+1133)/19||[http://factordb.com/index.php?id=1100000003590502602]||[http://factordb.com/cert.php?id=1100000003590502602] |- |20||3303||J7₂₇₀||(368×20²⁷⁰−7)/19||[http://factordb.com/index.php?id=1100000002325395462]||[http://factordb.com/cert.php?id=1100000002325395462] |- |20||3304||J₃₃₀CCC7||20³³⁴−58953||[http://factordb.com/index.php?id=1100000003590502572]||[http://factordb.com/cert.php?id=1100000003590502572] |- |20||3305||40₃₈₇404B||4×20³⁹¹+32091||[http://factordb.com/index.php?id=1100000003590502563]||[http://factordb.com/cert.php?id=1100000003590502563] |- |20||3306||EC0₄₂₉7||292×20⁴³⁰+7||[http://factordb.com/index.php?id=1100000002633348702]||[http://factordb.com/cert.php?id=1100000002633348702] |- |20||3307||G₄₄₇99||(16×20⁴⁴⁹−2809)/19||[http://factordb.com/index.php?id=1100000000840126753]||[http://factordb.com/cert.php?id=1100000000840126753] |- |20||3308||3A₅₂₇3||(67×20⁵²⁸−143)/19||[http://factordb.com/index.php?id=1100000003590502531]||[http://factordb.com/cert.php?id=1100000003590502531] |- |20||3309||E₅₆₆C7||(14×20⁵⁶⁸−907)/19||[http://factordb.com/index.php?id=1100000003590502516]||[http://factordb.com/cert.php?id=1100000003590502516] |- |20||3310||JCJ₆₂₉||393×20⁶²⁹−1||[http://factordb.com/index.php?id=1100000001559454258]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 is trivially 100% factored |- |20||3311||J₆₅₅05J||20⁶⁵⁸−7881||[http://factordb.com/index.php?id=1100000003590502490]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 has a large prime factor, factordb entry of this prime factor is [http://factordb.com/index.php?id=1100000003591067052], and primality certificate of this prime factor is [http://factordb.com/cert.php?id=1100000003591067052] |- |20||3312||50₁₁₆₃AJ||5×20¹¹⁶⁵+219||[http://factordb.com/index.php?id=1100000003590502412]||[http://factordb.com/cert.php?id=1100000003590502412] |- |20||3313||CD₂₄₄₉||(241×20²⁴⁴⁹−13)/19||[http://factordb.com/index.php?id=1100000002325393915]||[http://factordb.com/cert.php?id=1100000002325393915] |- |20||3314||G0₆₂₆₉D||16×20⁶²⁷⁰+13||[http://factordb.com/index.php?id=1100000003590539457]||[http://factordb.com/cert.php?id=1100000003590539457] |- |22||7984||I7G0₂₅₄H||8882×22²⁵⁵+17||[http://factordb.com/index.php?id=1100000003591372788]||[http://factordb.com/cert.php?id=1100000003591372788] |- |22||7985||D0₂₅₅5EEF||13×22²⁵⁹+60339||[http://factordb.com/index.php?id=1100000003591371932]||[http://factordb.com/cert.php?id=1100000003591371932] |- |22||7986||IK₃₂₂F||(398×22³²³−125)/21||[http://factordb.com/index.php?id=1100000000840384145]||[http://factordb.com/cert.php?id=1100000000840384145] |- |22||7987||C0₃₄₀G9||12×22³⁴²+361||[http://factordb.com/index.php?id=1100000000840384159]||[http://factordb.com/cert.php?id=1100000000840384159] |- |22||7988||77E₃₄₈K7||(485×22³⁵⁰+373)/3||[http://factordb.com/index.php?id=1100000003591369779]||[http://factordb.com/cert.php?id=1100000003591369779] |- |22||7989||J₃₇₉KJ||(19×22³⁸¹+443)/21||[http://factordb.com/index.php?id=1100000003591369027]||[http://factordb.com/cert.php?id=1100000003591369027] |- |22||7990||J₃₈₈EJ||(19×22³⁹⁰−2329)/21||[http://factordb.com/index.php?id=1100000003591367729]||[http://factordb.com/cert.php?id=1100000003591367729] |- |22||7991||DJ₄₀₀||(292×22⁴⁰⁰−19)/21||[http://factordb.com/index.php?id=1100000002325880110]||[http://factordb.com/cert.php?id=1100000002325880110] |- |22||7992||E₄₀₄K7||(2×22⁴⁰⁶+373)/3||[http://factordb.com/index.php?id=1100000003591366298]||[http://factordb.com/cert.php?id=1100000003591366298] |- |22||7993||66F₄₅₃B3||(971×22⁴⁵⁵−705)/7||[http://factordb.com/index.php?id=1100000003591365809]||[http://factordb.com/cert.php?id=1100000003591365809] |- |22||7994||L0₄₅₄B63||21×22⁴⁵⁷+5459||[http://factordb.com/index.php?id=1100000003591365331]||[http://factordb.com/cert.php?id=1100000003591365331] |- |22||7995||L₄₈₃G3||22⁴⁸⁵−129||[http://factordb.com/index.php?id=1100000003591364730]||[http://factordb.com/cert.php?id=1100000003591364730] |- |22||7996||E60₄₉₆L||314×22⁴⁹⁷+21||[http://factordb.com/index.php?id=1100000000632703239]||[http://factordb.com/cert.php?id=1100000000632703239] |- |22||7997||I₆₂₆AF||(6×22⁶²⁸−1259)/7||[http://factordb.com/index.php?id=1100000000632724334]||[http://factordb.com/cert.php?id=1100000000632724334] |- |22||7998||K0₇₆₀EC1||20×22⁷⁶³+7041||[http://factordb.com/index.php?id=1100000000632724415]||[http://factordb.com/cert.php?id=1100000000632724415] |- |22||7999||J0₇₆₇IGGJ||19×22⁷⁷¹+199779||[http://factordb.com/index.php?id=1100000003591362567]||[http://factordb.com/cert.php?id=1100000003591362567] |- |22||8000||7₉₅₉K7||(22⁹⁶¹+857)/3||[http://factordb.com/index.php?id=1100000003591361817]||[http://factordb.com/cert.php?id=1100000003591361817] |- |22||8001||L₂₃₈₅KE7||22²³⁸⁸−653||[http://factordb.com/index.php?id=1100000003591360774]||[http://factordb.com/cert.php?id=1100000003591360774] |- |22||8002||7₃₈₁₅2L||(22³⁸¹⁷−289)/3||[http://factordb.com/index.php?id=1100000003591359839]||[http://factordb.com/cert.php?id=1100000003591359839] |- |24||3400||I0₂₄₁I5||18×24²⁴³+437||[http://factordb.com/index.php?id=1100000002633360037]||[http://factordb.com/cert.php?id=1100000002633360037] |- |24||3401||D0₂₅₉KKD||13×24²⁶²+12013||[http://factordb.com/index.php?id=1100000003593270725]||[http://factordb.com/cert.php?id=1100000003593270725] |- |24||3402||C7₂₉₈||(283×24²⁹⁸−7)/23||[http://factordb.com/index.php?id=1100000002326181235]||[http://factordb.com/cert.php?id=1100000002326181235] |- |24||3403||20₃₁₃7||2×24³¹⁴+7||[http://factordb.com/index.php?id=1100000002355610241]||[http://factordb.com/cert.php?id=1100000002355610241] |- |24||3404||BC0₃₃₁B||276×24³³²+11||[http://factordb.com/index.php?id=1100000002633359842]||[http://factordb.com/cert.php?id=1100000002633359842] |- |24||3405||N₂₆₄₄LLN||24²⁶⁴⁷−1201||[http://factordb.com/index.php?id=1100000003593270089]||[http://factordb.com/cert.php?id=1100000003593270089] |- |24||3406||D₂₆₉₈LD||(13×24²⁷⁰⁰+4403)/23||[http://factordb.com/index.php?id=1100000003593269876]||[http://factordb.com/cert.php?id=1100000003593269876] |- |24||3407||A0₂₉₅₁8ID||10×24²⁹⁵⁴+5053||[http://factordb.com/index.php?id=1100000003593269654]||[http://factordb.com/cert.php?id=1100000003593269654] |- |24||3408||88N₅₉₅₁||201×24⁵⁹⁵¹−1||[http://factordb.com/index.php?id=1100000003593275880]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 is trivially 100% factored |- |24||3409||N00N₈₁₂₉LN||13249×24⁸¹³¹−49||[http://factordb.com/index.php?id=1100000003593391606]||[http://factordb.com/cert.php?id=1100000003593391606] |- |30||2613||AN₂₀₆||(313×30²⁰⁶−23)/29||[http://factordb.com/index.php?id=1100000002327651073]||[http://factordb.com/cert.php?id=1100000002327651073] |- |30||2614||M₂₄₁QB||(22×30²⁴³+3139)/29||[http://factordb.com/index.php?id=1100000003593408295]||[http://factordb.com/cert.php?id=1100000003593408295] |- |30||2615||M0₅₄₇SS7||22×30⁵⁵⁰+26047||[http://factordb.com/index.php?id=1100000003593407988]||[http://factordb.com/cert.php?id=1100000003593407988] |- |30||2616||C0₁₀₂₂1||12×30¹⁰²³+1||[http://factordb.com/index.php?id=1100000000785448736]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], ''N''−1 is trivially 100% factored |- |30||2617||5₄₈₈₂J||(5×30⁴⁸⁸³+401)/29||[http://factordb.com/index.php?id=1100000002327649423]||[http://factordb.com/cert.php?id=1100000002327649423] |- |30||2619||OT₃₄₂₀₅||25×30³⁴²⁰⁵−1||[http://factordb.com/index.php?id=1100000000800812865]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 is trivially 100% factored |} ==Unproven PRPs== {|class=wikitable |base (''b'')||index of this quasi-minimal prime in base ''b'' (assuming the primality of all PRP in base ''b'')||unproven PRP (base-''b'' form)||unproven PRP (algebraic ((''a''×''b''^''n''+''c'')/''d'') form)||factordb entry of this PRP |- |11||1068||57₆₂₆₆₈||(57×11⁶²⁶⁶⁸−7)/10||[http://factordb.com/index.php?id=1100000003573679860] |- |13||3194||C5₂₃₇₅₅C||(149×13²³⁷⁵⁶+79)/12||[http://factordb.com/index.php?id=1100000003590647776] |- |13||3195||80₃₂₀₁₇111||8×13³²⁰²⁰+183||[http://factordb.com/index.php?id=1100000000490878060] |- |16||2345||DB₃₂₂₃₄||(206×16³²²³⁴−11)/15||[http://factordb.com/index.php?id=1100000002383583629] |- |16||2346||4₇₂₇₈₅DD||(4×16⁷²⁷⁸⁷+2291)/15||[http://factordb.com/index.php?id=1100000003615909841] |- |22||8003||BK₂₂₀₀₁5||(251×22²²⁰⁰²−335)/21||[http://factordb.com/index.php?id=1100000003594696838] |- |30||2618||I0₂₄₆₀₈D||18×30²⁴⁶⁰⁹+13||[http://factordb.com/index.php?id=1100000003593967511] |} All these PRPs pass the [[w:Miller–Rabin primality test|Miller–Rabin primality test]] to bases 2, 3, 5, 7, 11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47, 53, 59 and 61, and pass the [[w:Lucas pseudoprime#Strong Lucas pseudoprimes|strong Lucas primality test]] with parameters (''P'', ''Q'') defined by Selfridge's Method ''A'', and [[w:Trial division|trial factored]] to 10¹⁶. (Thus, they pass the [[w:Baillie–PSW primality test|Baillie–PSW primality test]]) ==Proof== ===Base 2=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1) * Case (1,1): ** 11 is prime, and thus the only minimal prime in this family. ===Base 3=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1), (1,2), (2,1), (2,2) * Case (1,1): ** Since 12, 21, 111 are primes, we only need to consider the family 1{0}1 (since any digits 1, 2 between them will produce smaller primes) *** All numbers of the form 1{0}1 are divisible by 2, thus cannot be prime. * Case (1,2): ** 12 is prime, and thus the only minimal prime in this family. * Case (2,1): ** 21 is prime, and thus the only minimal prime in this family. * Case (2,2): ** Since 21, 12 are primes, we only need to consider the family 2{0,2}2 (since any digits 1 between them will produce smaller primes) *** All numbers of the form 2{0,2}2 are divisible by 2, thus cannot be prime. ===Base 4=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1), (1,3), (2,1), (2,3), (3,1), (3,3) * Case (1,1): ** 11 is prime, and thus the only minimal prime in this family. * Case (1,3): ** 13 is prime, and thus the only minimal prime in this family. * Case (2,1): ** Since 23, 11, 31, 221 are primes, we only need to consider the family 2{0}1 (since any digits 1, 2, 3 between them will produce smaller primes) *** All numbers of the form 2{0}1 are divisible by 3, thus cannot be prime. * Case (2,3): ** 23 is prime, and thus the only minimal prime in this family. * Case (3,1): ** 31 is prime, and thus the only minimal prime in this family. * Case (3,3): ** Since 31, 13, 23 are primes, we only need to consider the family 3{0,3}3 (since any digits 1, 2 between them will produce smaller primes) *** All numbers of the form 3{0,3}3 are divisible by 3, thus cannot be prime. ===Base 5=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1), (1,2), (1,3), (1,4), (2,1), (2,2), (2,3), (2,4), (3,1), (3,2), (3,3), (3,4), (4,1), (4,2), (4,3), (4,4) * Case (1,1): ** Since 12, 21, 111, 131 are primes, we only need to consider the family 1{0,4}1 (since any digits 1, 2, 3 between them will produce smaller primes) *** All numbers of the form 1{0,4}1 are divisible by 2, thus cannot be prime. * Case (1,2): ** 12 is prime, and thus the only minimal prime in this family. * Case (1,3): ** Since 12, 23, 43, 133 are primes, we only need to consider the family 1{0,1}3 (since any digits 2, 3, 4 between them will produce smaller primes) *** Since 111 is prime, we only need to consider the families 1{0}3 and 1{0}1{0}3 (since any digit combo 11 between (1,3) will produce smaller primes) **** All numbers of the form 1{0}3 are divisible by 2, thus cannot be prime. **** For the 1{0}1{0}3 family, since 10103 is prime, we only need to consider the families 1{0}13 and 11{0}3 (since any digit combo 010 between (1,3) will produce smaller primes) ***** The smallest prime of the form 1{0}13 is 100000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000013, which can be written as 1(0^93)13 and equal the prime 5^95+8 ([http://factordb.com/index.php?id=1100000000034686071 factordb]) ***** All numbers of the form 11{0}3 are divisible by 3, thus cannot be prime. * Case (1,4): ** Since 12, 34, 104 are primes, we only need to consider the family 1{1,4}4 (since any digits 0, 2, 3 between them will produce smaller primes) *** Since 111, 414 are primes, we only need to consider the families 1{4}4 and 11{4}4 (since any digit combo 11 or 41 between them will produce smaller primes) **** The smallest prime of the form 1{4}4 is 14444. **** All numbers of the form 11{4}4 are divisible by 2, thus cannot be prime. * Case (2,1): ** 21 is prime, and thus the only minimal prime in this family. * Case (2,2): ** Since 21, 23, 12, 32 are primes, we only need to consider the family 2{0,2,4}2 (since any digits 1, 3 between them will produce smaller primes) *** All numbers of the form 2{0,2,4}2 are divisible by 2, thus cannot be prime. * Case (2,3): ** 23 is prime, and thus the only minimal prime in this family. * Case (2,4): ** Since 21, 23, 34 are primes, we only need to consider the family 2{0,2,4}4 (since any digits 1, 3 between them will produce smaller primes) *** All numbers of the form 2{0,2,4}4 are divisible by 2, thus cannot be prime. * Case (3,1): ** Since 32, 34, 21 are primes, we only need to consider the family 3{0,1,3}1 (since any digits 2, 4 between them will produce smaller primes) *** Since 313, 111, 131, 3101 are primes, we only need to consider the families 3{0,3}1 and 3{0,3}11 (since any digit combo 10, 11, 13 between (3,1) will produce smaller primes) **** For the 3{0,3}1 family, we can separate this family to four families: ***** For the 30{0,3}01 family, we have the prime 30301, and the remain case is the family 30{0}01. ****** All numbers of the form 30{0}01 are divisible by 2, thus cannot be prime. ***** For the 30{0,3}31 family, note that there must be an even number of 3's between (30,31), or the result number will be divisible by 2 and cannot be prime. ****** Since 33331 is prime, any digit combo 33 between (30,31) will produce smaller primes. ******* Thus, the only possible prime is the smallest prime in the family 30{0}31, and this prime is 300031. ***** For the 33{0,3}01 family, note that there must be an even number of 3's between (33,01), or the result number will be divisible by 2 and cannot be prime. ****** Since 33331 is prime, any digit combo 33 between (33,01) will produce smaller primes. ******* Thus, the only possible prime is the smallest prime in the family 33{0}01, and this prime is 33001. ***** For the 33{0,3}31 family, we have the prime 33331, and the remain case is the family 33{0}31. ****** All numbers of the form 33{0}31 are divisible by 2, thus cannot be prime. **** All numbers of the form 3{0,3}11 are divisible by 3, thus cannot be prime. * Case (3,2): ** 32 is prime, and thus the only minimal prime in this family. * Case (3,3): ** Since 32, 34, 23, 43, 313 are primes, we only need to consider the family 3{0,3}3 (since any digits 1, 2, 4 between them will produce smaller primes) *** All numbers of the form 3{0,3}3 are divisible by 3, thus cannot be prime. * Case (3,4): ** 34 is prime, and thus the only minimal prime in this family. * Case (4,1): ** Since 43, 21, 401 are primes, we only need to consider the family 4{1,4}1 (since any digits 0, 2, 3 between them will produce smaller primes) *** Since 414, 111 are primes, we only need to consider the families 4{4}1 and 4{4}11 (since any digit combo 14 or 11 between them will produce smaller primes) **** The smallest prime of the form 4{4}1 is 44441. **** All numbers of the form 4{4}11 are divisible by 2, thus cannot be prime. * Case (4,2): ** Since 43, 12, 32 are primes, we only need to consider the family 4{0,2,4}2 (since any digits 1, 3 between them will produce smaller primes) *** All numbers of the form 4{0,2,4}2 are divisible by 2, thus cannot be prime. * Case (4,3): ** 43 is prime, and thus the only minimal prime in this family. * Case (4,4): ** Since 43, 34, 414 are primes, we only need to consider the family 4{0,2,4}4 (since any digits 1, 3 between them will produce smaller primes) *** All numbers of the form 4{0,2,4}4 are divisible by 2, thus cannot be prime. ===Base 6=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1), (1,5), (2,1), (2,5), (3,1), (3,5), (4,1), (4,5), (5,1), (5,5) * Case (1,1): ** 11 is prime, and thus the only minimal prime in this family. * Case (1,5): ** 15 is prime, and thus the only minimal prime in this family. * Case (2,1): ** 21 is prime, and thus the only minimal prime in this family. * Case (2,5): ** 25 is prime, and thus the only minimal prime in this family. * Case (3,1): ** 31 is prime, and thus the only minimal prime in this family. * Case (3,5): ** 35 is prime, and thus the only minimal prime in this family. * Case (4,1): ** Since 45, 11, 21, 31, 51 are primes, we only need to consider the family 4{0,4}1 (since any digits 1, 2, 3, 5 between them will produce smaller primes) *** Since 4401 and 4441 are primes, we only need to consider the families 4{0}1 and 4{0}41 (since any digits combo 40 and 44 between them will produce smaller primes) **** All numbers of the form 4{0}1 are divisible by 5, thus cannot be prime. **** The smallest prime of the form 4{0}41 is 40041 * Case (4,5): ** 45 is prime, and thus the only minimal prime in this family. * Case (5,1): ** 51 is prime, and thus the only minimal prime in this family. * Case (5,5): ** Since 51, 15, 25, 35, 45 are primes, we only need to consider the family 5{0,5}5 (since any digits 1, 2, 3, 4 between them will produce smaller primes) *** All numbers of the form 5{0,5}5 are divisible by 5, thus cannot be prime. ===Base 7=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1), (1,2), (1,3), (1,4), (1,5), (1,6), (2,1), (2,2), (2,3), (2,4), (2,5), (2,6), (3,1), (3,2), (3,3), (3,4), (3,5), (3,6), (4,1), (4,2), (4,3), (4,4), (4,5), (4,6), (5,1), (5,2), (5,3), (5,4), (5,5), (5,6), (6,1), (6,2), (6,3), (6,4), (6,5), (6,6) * Case (1,1): ** Since 14, 16, 41, 61, 131 are primes, we only need to consider the family 1{0,1,2,5}1 (since any digits 3, 4, 6 between them will produce smaller primes) *** Since the digit sum of primes must be odd (otherwise the number will be divisible by 2, thus cannot be prime), there is an odd total number of 1 and 5 in the {} **** If there are >=3 number of 1 and 5 in the {}: ***** If there is 111 in the {}, then we have the prime 11111 ***** If there is 115 in the {}, then the prime 115 is a subsequence ***** If there is 151 in the {}, then the prime 115 is a subsequence ***** If there is 155 in the {}, then the prime 155 is a subsequence ***** If there is 511 in the {}, then the current number is 15111, which has digit sum = 12, but digit sum divisible by 3 will cause the number divisible by 3 and cannot be prime, and we cannot add more 1 or 5 to this number (to avoid 11111, 155, 515, 551 as subsequence), thus we must add at least one 2 to this number, but then the number has both 2 and 5, and will have either 25 or 52 as subsequence, thus cannot be minimal prime ***** If there is 515 in the {}, then the prime 515 is a subsequence ***** If there is 551 in the {}, then the prime 551 is a subsequence ***** If there is 555 in the {}, then the prime 551 is a subsequence **** Thus there is only one 1 (and no 5) or only one 5 (and no 1) in the {}, i.e. we only need to consider the families 1{0,2}1{0,2}1 and 1{0,2}5{0,2}1 ***** For the 1{0,2}1{0,2}1 family, since 1211 is prime, we only need to consider the family 1{0}1{0,2}1 ****** Since all numbers of the form 1{0}1{0}1 are divisible by 3 and cannot be prime, we only need to consider the family 1{0}1{0}2{0}1 ******* Since 11201 is prime, we only need to consider the family 1{0}1{0}21 ******** The smallest prime of the form 11{0}21 is 1100021 ******** All numbers of the form 101{0}21 are divisible by 5, thus cannot be prime ******** The smallest prime of the form 1001{0}21 is 100121 ********* Since this prime has no 0 between 1{0}1 and 21, we do not need to consider more families ***** For the 1{0,2}5{0,2}1 family, since 25 and 52 are primes, we only need to consider the family 1{0}5{0}1 ****** Since 1051 is prime, we only need to consider the family 15{0}1 ******* The smallest prime of the form 15{0}1 is 150001 * Case (1,2): ** Since 14, 16, 32, 52 are primes, we only need to consider the family 1{0,1,2}2 (since any digits 3, 4, 5, 6 between them will produce smaller primes) *** Since 1112 and 1222 are primes, there is at most one 1 and at most one 2 in {} **** If there are one 1 and one 2 in {}, then the digit sum is 6, and the number will be divisible by 6 and cannot be prime. **** If there is one 1 but no 2 in {}, then the digit sum is 4, and the number will be divisible by 2 and cannot be prime. **** If there is no 1 but one 2 in {}, then the form is 1{0}2{0}2 ***** Since 1022 and 1202 are primes, we only need to consider the number 122 ****** 122 is not prime. **** If there is no 1 and no 2 in {}, then the digit sum is 3, and the number will be divisible by 3 and cannot be prime. * Case (1,3): ** Since 14, 16, 23, 43, 113, 133 are primes, we only need to consider the family 1{0,5}3 (since any digits 1, 2, 3, 4, 6 between them will produce smaller primes) *** Since 155 is prime, we only need to consider the family 1{0}3 and 1{0}5{0}3 **** All numbers of the form 1{0}3 are divisible by 2, thus cannot be prime. **** All numbers of the form 1{0}5{0}3 are divisible by 3, thus cannot be prime. * Case (1,4): ** 14 is prime, and thus the only minimal prime in this family. * Case (1,5): ** Since 14, 16, 25, 65, 115, 155 are primes, we only need to consider the family 1{0,3}5 (since any digits 1, 2, 4, 5, 6 between them will produce smaller primes) *** All numbers of the form 1{0,3}5 are divisible by 3, thus cannot be prime. * Case (1,6): ** 16 is prime, and thus the only minimal prime in this family. * Case (2,1): ** Since 23, 25, 41, 61, 221 are primes, we only need to consider the family 2{0,1}1 (since any digits 2, 3, 4, 5, 6 between them will produce smaller primes) *** Since 2111 is prime, we only need to consider the families 2{0}1 and 2{0}1{0}1 **** All numbers of the form 2{0}1 are divisible by 3, thus cannot be prime. **** All numbers of the form 2{0}1{0}1 are divisible by 2, thus cannot be prime. * Case (2,2): ** Since 23, 25, 32, 52, 212 are primes, we only need to consider the family 2{0,2,4,6}2 (since any digits 1, 3, 5 between them will produce smaller primes) *** All numbers of the form 2{0,2,4,6}2 are divisible by 2, thus cannot be prime. * Case (2,3): ** 23 is prime, and thus the only minimal prime in this family. * Case (2,4): ** Since 23, 25, 14 are primes, we only need to consider the family 2{0,2,4,6}4 (since any digits 1, 3, 5 between them will produce smaller primes) *** All numbers of the form 2{0,2,4,6}4 are divisible by 2, thus cannot be prime. * Case (2,5): ** 25 is prime, and thus the only minimal prime in this family. * Case (2,6): ** Since 23, 25, 16, 56 are primes, we only need to consider the family 2{0,2,4,6}6 (since any digits 1, 3, 5 between them will produce smaller primes) *** All numbers of the form 2{0,2,4,6}6 are divisible by 2, thus cannot be prime. * Case (3,1): ** Since 32, 41, 61 are primes, we only need to consider the family 3{0,1,3,5}1 (since any digits 2, 4, 6 between them will produce smaller primes) *** Since 551 is prime, we only need to consider the family 3{0,1,3}1 and 3{0,1,3}5{0,1,3}1 (since any digits combo 55 between (3,1) will produce smaller primes) **** For the 3{0,1,3}1 family, since 3031 and 131 are primes, we only need to consider the families 3{0,1}1 and 3{3}3{0,1}1 (since any digits combo 03, 13 between (3,1) will produce smaller primes, thus for the digits between (3,1), all 3's must be before all 0's and 1's, and thus we can let the red 3 in 3{3}3{0,1}1 be the rightmost 3 between (3,1), all digits before this 3 must be 3's, and all digits after this 3 must be either 0's or 1's) ***** For the 3{0,1}1 family: ****** If there are >=2 0's and >=1 1's between (3,1), then at least one of 30011, 30101, 31001 will be a subsequence. ****** If there are no 1's between (3,1), then the form will be 3{0}1 ******* All numbers of the form 3{0}1 are divisible by 2, thus cannot be prime. ****** If there are no 0's between (3,1), then the form will be 3{1}1 ******* The smallest prime of the form 3{1}1 is 31111 ****** If there are exactly 1 0's between (3,1), then there must be <3 1's between (3,1), or 31111 will be a subsequence. ******* If there are 2 1's between (3,1), then the digit sum is 6, thus the number is divisible by 6 and cannot be prime. ******* If there are 1 1's between (3,1), then the number can only be either 3101 or 3011 ******** Neither 3101 nor 3011 is prime. ******* If there are no 1's between (3,1), then the number must be 301 ******** 301 is not prime. ***** For the 3{3}3{0,1}1 family: ****** If there are at least one 3 between (3,3{0,1}1) and at least one 1 between (3{3}3,1), then 33311 will be a subsequence. ****** If there are no 3 between (3,3{0,1}1), then the form will be 33{0,1}1 ******* If there are at least 3 1's between (33,1), then 31111 will be a subsequence. ******* If there are exactly 2 1's between (33,1), then the digit sum is 12, thus the number is divisible by 3 and cannot be prime. ******* If there are exactly 1 1's between (33,1), then the digit sum is 11, thus the number is divisible by 2 and cannot be prime. ******* If there are no 1's between (33,1), then the form will be 33{0}1 ******** The smallest prime of the form 33{0}1 is 33001 ****** If there are no 1 between (3{3}3,1), then the form will be 3{3}3{0}1 ******* If there are at least 2 0's between (3{3}3,1), then 33001 will be a subsequence. ******* If there are exactly 1 0's between (3{3}3,1), then the form is 3{3}301 ******** The smallest prime of the form 3{3}301 is 33333301 ******* If there are no 0's between (3{3}3,1), then the form is 3{3}31 ******** The smallest prime of the form 3{3}31 is 33333333333333331 **** For the 3{0,1,3}5{0,1,3}1 family, since 335 is prime, we only need to consider the family 3{0,1}5{0,1,3}1 ***** Numbers containing 3 between (3{0,1}5,1): ****** The form is 3{0,1}5{0,1,3}3{0,1,3}1 ******* Since 3031 and 131 are primes, we only need to consider the family 35{3}3{0,1,3}1 (since any digits combo 03, 13 between (3,1) will produce smaller primes) ******** Since 533 is prime, we only need to consider the family 353{0,1}1 (since any digits combo 33 between (35,1) will produce smaller primes) ********* Since 5011 is prime, we only need to consider the family 353{1}{0}1 (since any digits combo 01 between (353,1) will produce smaller primes) ********** If there are at least 3 1's between (353,{0}1), then 31111 will be a subsequence. ********** If there are exactly 2 1's between (353,{0}1), then the digit sum is 20, thus the number is divisible by 2 and cannot be prime. ********** If there are exactly 1 1's between (353,{0}1), then the form is 3531{0}1 *********** The smallest prime of the form 3531{0}1 is 3531001, but it is not minimal prime since 31001 is prime. ********** If there are no 1's between (353,{0}1), then the digit sum is 15, thus the number is divisible by 6 and cannot be prime. ***** Numbers not containing 3 between (3{0,1}5,1): ****** The form is 3{0,1}5{0,1}1 ******* If there are >=2 0's and >=1 1's between (3,1), then at least one of 30011, 30101, 31001 will be a subsequence. ******* If there are no 1's between (3,1), then the form will be 3{0}5{0}1 ******** All numbers of the form 3{0}5{0}1 are divisible by 3, thus cannot be prime. ******* If there are no 0's between (3,1), then the form will be 3{1}5{1}1 ******** If there are >=3 1's between (3,1), then 31111 will be a subsequence. ******** If there are exactly 2 1's between (3,1), then the number can only be 31151, 31511, 35111 ********* None of 31151, 31511, 35111 are primes. ******** If there are exactly 1 1's between (3,1), then the digit sum is 13, thus the number is divisible by 2 and cannot be prime. ******** If there are no 1's between (3,1), then the number is 351 ********* 351 is not prime. ******* If there are exactly 1 0's between (3,1), then the form will be 3{1}0{1}5{1}1 or 3{1}5{1}0{1}1 ******** No matter 3{1}0{1}5{1}1 or 3{1}5{1}0{1}1, if there are >=3 1's between (3,1), then 31111 will be a subsequence. ******** If there are exactly 2 1's between (3,1), then the number can only be 311051, 310151, 310511, 301151, 301511, 305111, 311501, 315101, 315011, 351101, 351011, 350111 ********* Of these numbers, 311051, 301151, 311501, 351101, 350111 are primes. ********** However, 311051, 301151, 311501 have 115 as subsequence, and 350111 has 5011 as subsequence, thus only 351101 is minimal prime. ******** No matter 3{1}0{1}5{1}1 or 3{1}5{1}0{1}1, if there are exactly 1 1's between (3,1), then the digit sum is 13, thus the number is divisible by 2 and cannot be prime. ******** If there are no 1's between (3,1), then the number is 3051 for 3{1}0{1}5{1}1 or 3501 for 3{1}5{1}0{1}1 ********* Neither 3051 nor 3501 is prime. * Case (3,2): ** 32 is prime, and thus the only minimal prime in this family. * Case (3,3): ** Since 32, 23, 43, 313 are primes, we only need to consider the family 3{0,3,5,6}3 (since any digits 1, 2, 4 between them will produce smaller primes) *** If there are >=2 5's in {}, then 553 will be a subsequence. *** If there are no 5's in {}, then the family will be 3{0,3,6}3 **** All numbers of the form 3{0,3,6}3 are divisible by 3, thus cannot be prime. *** If there are exactly 1 5's in {}, then the family will be 3{0,3,6}5{0,3,6}3 **** Since 335, 65, 3503, 533, 56 are primes, we only need to consider the family 3{0}53 (since any digit 3, 6 between (3,5{0,3,6}3) and any digit 0, 3, 6 between (3{0,3,6}5,3) will produce smaller primes) ***** The smallest prime of the form 3{0}53 is 300053 * Case (3,4): ** Since 32, 14, 304, 344, 364 are primes, we only need to consider the family 3{3,5}4 (since any digits 0, 1, 2, 4, 6 between them will produce smaller primes) *** Since 3334 and 335 are primes, we only need to consider the family 3{5}4 and 3{5}34 (since any digits combo 33, 35 between them will produce smaller primes) **** The smallest prime of the form 3{5}4 is 35555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555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with 9234 5's, which can be written as 3(5^9234)4 and equal the prime (23*7^9235-11)/6 ([http://factordb.com/index.php?id=1100000002766595757 factordb]) ([http://factordb.com/cert.php?id=1100000002766595757 primality certificate]) (not minimal prime, since 35555 and 5554 are primes) **** The smallest prime of the form 3{5}34 is 355555555555555555555555555555555555555555555555555555555555555534 (not minimal prime, since 35555, 553, and 5554 are primes) * Case (3,5): ** Since 32, 25, 65, 335 are primes, we only need to consider the family 3{0,1,4,5}5 (since any digits 2, 3, 6 between them will produce smaller primes) *** If there are at least one 1's and at least one 5's in {}, then either 155 or 515 will be a subsequence. *** If there are at least one 1's and at least one 4's in {}, then either 14 or 41 will be a subsequence. *** If there are at least two 1's in {}, then 115 will be a subsequence. *** If there are exactly one 1's and no 4's or 5's in {}, then the family will be 3{0}1{0}5 **** All numbers of the form 3{0}1{0}5 are divisible by 3, thus cannot be prime. *** If there is no 1's in {}, then the family will be 3{0,4,5}5 **** If there are at least to 4's in {}, then 344 and 445 will be subsequences. **** If there is no 4's in {}, then the family will be 3{0,5}5 ***** Since 3055 and 3505 are primes, we only need to consider the families 3{0}5 and 3{5}5 ****** All numbers of the form 3{0}5 are divisible by 2, thus cannot be prime. ****** The smallest prime of the form 3{5}5 is 35555 **** If there is exactly one 4's in {}, then the family will be 3{0,5}4{0,5}5 ***** Since 304, 3545 are primes, we only need to consider the families 34{0,5}5 (since any digits 0 or 5 between (3,4{0,5}5) will produce small primes) ****** All numbers of the form 34{0,5}5 are divisible by 5, thus cannot be prime. * Case (3,6): ** Since 32, 16, 56, 346 are primes, we only need to consider the family 3{0,3,6}6 (since any digits 1, 2, 4, 5 between them will produce smaller primes) *** All numbers of the form 3{0,3,6}6 are divisible by 3, thus cannot be prime. * Case (4,1): ** 41 is prime, and thus the only minimal prime in this family. * Case (4,2): ** Since 41, 43, 32, 52 are primes, we only need to consider the family 4{0,2,4,6}2 (since any digits 1, 3, 5 between them will produce smaller primes) *** All numbers of the form 4{0,2,4,6}2 are divisible by 2, thus cannot be prime. * Case (4,3): ** 43 is prime, and thus the only minimal prime in this family. * Case (4,4): ** Since 41, 43, 14 are primes, we only need to consider the family 4{0,2,4,5,6}4 (since any digits 1, 3 between them will produce smaller primes) *** If there is no 5's in {}, then the family will be 4{0,2,4,6}4 **** All numbers of the form 4{0,2,4,6}4 are divisible by 2, thus cannot be prime. *** If there is at least one 5's in {}, then there cannot be 2 in {} (since if so, then either 25 or 52 will be a subsequence) and there cannot be 6 in {} (since if so, then either 65 or 56 will be a subsequence), thus the family is 4{0,4,5}5{0,4,5}4 **** Since 445, 4504, 544 are primes, we only need to consider the family 4{0,5}5{5}4 (since any digit 4 between (4,5{0,4,5}4) and any digit 0, 4 between (4{0,4,5}5,4) will produce smaller primes) ***** If there are at least two 0's between (4,5{0,4,5}4), then 40054 will be a subsequence. ***** If there is no 0's between (4,5{0,4,5}4), then the family will be 4{5}5{5}4, which is equivalent to 4{5}4 ****** The smallest prime of the form 4{5}4 is 45555555555555554 (not minimal prime, since 4555 and 5554 are primes) ***** If there is exactly one 0's between (4,5{0,4,5}4), then the family will be 4{5}0{5}5{5}4 ****** Since 4504 is prime, we only need to consider the family 40{5}5{5}4 (since any digit 5 between (4,0{5}5{5}4) will produce small primes), which is equivalent to 40{5}4 ******* The smallest prime of the form 40{5}4 is 405555555555555554 (not minimal prime, since 4555 and 5554 are primes) * Case (4,5): ** Since 41, 43, 25, 65, 445 are primes, we only need to consider the family 4{0,5}5 (since any digits 1, 2, 3, 4, 6 between them will produce smaller primes) *** If there are at least two 5's in {}, then 4555 will be a subsequence. *** If there is exactly one 5's in {}, then the digit sum is 20, and the number will be divisible by 2 and cannot be prime. *** If there is no 5's in {}, then the family will be 4{0}5 **** All numbers of the form 4{0}5 are divisible by 3, thus cannot be prime. * Case (4,6): ** Since 41, 43, 16, 56 are primes, we only need to consider the family 4{0,2,4,6}6 (since any digits 1, 3, 5 between them will produce smaller primes) *** All numbers of the form 4{0,2,4,6}6 are divisible by 2, thus cannot be prime. * Case (5,1): ** Since 52, 56, 41, 61, 551 are primes, we only need to consider the family 5{0,1,3}1 (since any digits 2, 4, 5, 6 between them will produce smaller primes) *** If there are at least two 3's in {}, then 533 will be a subsequence. *** If there is no 3's in {}, then the family will be 5{0,1}1 **** Since 5011 is prime, we only need to consider the family 5{1}{0}1 ***** Since 11111 is prime, we only need to consider the families 5{0}1, 51{0}1, 511{0}1, 5111{0}1 (since any digits combo 1111 between (5,1) will produce small primes) ****** All numbers of the form 5{0}1 are divisible by 6, thus cannot be prime. ****** The smallest prime of the form 51{0}1 is 5100000001 ****** All numbers of the form 511{0}1 are divisible by 2, thus cannot be prime. ****** All numbers of the form 5111{0}1 are divisible by 3, thus cannot be prime. *** If there is exactly one 3's in {}, then the family will be 5{0,1}3{0,1}1 **** If there is at least one 1's between (5,3{0,1}1), then 131 will be a subsequence. ***** Thus we only need to consider the family 5{0}3{0,1}1 ****** If there are no 1's between (5{0}3,1), then the digit sum is 12, and the number will be divisible by 3 and cannot be prime. ****** If there are exactly one 1's between (5{0}3,1), then the digit sum is 13, and the number will be divisible by 2 and cannot be prime. ****** If there are exactly three 1's between (5{0}3,1), then the digit sum is 15, and the number will be divisible by 6 and cannot be prime. ****** If there are at least four 1's between (5{0}3,1), then 11111 will be a subsequence. ****** If there are exactly two 1's between (5{0}3,1), then the family will be 5{0}3{0}1{0}1{0}1 ******* Since 5011 is prime, we only need to consider the family 5311{0}1 (since any digit 0 between (5,1{0}1) will produce small primes, this includes the leftmost three {} in 5{0}3{0}1{0}1{0}1, and thus only the rightmost {} can contain 0) ******** The smallest prime of the form 5311{0}1 is 531101 * Case (5,2): ** 52 is prime, and thus the only minimal prime in this family. * Case (5,3): ** Since 52, 56, 23, 43, 533, 553 are primes, we only need to consider the family 5{0,1}3 (since any digits 2, 3, 4, 5, 6 between them will produce smaller primes) *** If there are at least two 1's in {}, then 113 will be a subsequence. *** If there is exactly one 1's in {}, then the digit sum is 12, and the number will be divisible by 3 and cannot be prime. *** If there is no 1's in {}, then the digit sum is 11, and the number will be divisible by 2 and cannot be prime. * Case (5,4): ** Since 52, 56, 14, 544 are primes, we only need to consider the family 5{0,3,5}4 (since any digits 1, 2, 4, 6 between them will produce smaller primes) *** If there are no 5's in {}, then the family will be 5{0,3}4 **** All numbers of the form 5{0,3}4 are divisible by 3, thus cannot be prime. *** If there are at least one 5's and at least one 3's in {}, then either 535 or 553 will be a subsequence. *** If there are exactly one 5's and no 3's in {}, then the digit sum is 20, and the number will be divisible by 2 and cannot be prime. *** If there are at least two 5's in {}, then 5554 will be a subsequence. * Case (5,5): ** Since 52, 56, 25, 65, 515, 535 are primes, we only need to consider the family 5{0,4,5}5 (since any digits 1, 2, 3, 6 between them will produce smaller primes) *** If there are no 4's in {}, then the family will be 5{0,5}5 **** All numbers of the form 5{0,5}5 are divisible by 5, thus cannot be prime. *** If there are no 5's in {}, then the family will be 5{0,4}5 **** All numbers of the form 5{0,4}5 are divisible by 2, thus cannot be prime. *** If there are at least one 4's and at least one 5's in {}, then either 5455 or 5545 will be a subsequence. * Case (5,6): ** 56 is prime, and thus the only minimal prime in this family. * Case (6,1): ** 61 is prime, and thus the only minimal prime in this family. * Case (6,2): ** Since 61, 65, 32, 52 are primes, we only need to consider the family 6{0,2,4,6}2 (since any digits 1, 3, 5 between them will produce smaller primes) *** All numbers of the form 6{0,2,4,6}2 are divisible by 2, thus cannot be prime. * Case (6,3): ** Since 61, 65, 23, 43 are primes, we only need to consider the family 6{0,3,6}3 (since any digits 1, 2, 4, 5 between them will produce smaller primes) *** All numbers of the form 6{0,3,6}3 are divisible by 3, thus cannot be prime. * Case (6,4): ** Since 61, 65, 14 are primes, we only need to consider the family 6{0,2,3,4,6}4 (since any digits 1, 5 between them will produce smaller primes) *** If there is no 3's in {}, then the family will be 6{0,2,4,6}4 **** All numbers of the form 6{0,2,4,6}4 are divisible by 2, thus cannot be prime. *** If there are exactly two 3's in {}, then the family will be 6{0,2,4,6}3{0,2,4,6}3{0,2,4,6}4 **** All numbers of the form 6{0,2,4,6}3{0,2,4,6}3{0,2,4,6}4 are divisible by 2, thus cannot be prime. *** If there are at least three 3's in {}, then 3334 will be a subsequence. *** If there is exactly one 3's in {}, then the family will be 6{0,2,4,6}3{0,2,4,6}4 **** If there is 0 between (6,3{0,2,4,6}4), then 6034 will be a subsequence. **** If there is 2 between (6,3{0,2,4,6}4), then 23 will be a subsequence. **** If there is 4 between (6,3{0,2,4,6}4), then 43 will be a subsequence. **** If there is 6 between (6,3{0,2,4,6}4), then 6634 will be a subsequence. **** If there is 0 between (6{0,2,4,6}3,4), then 304 will be a subsequence. **** If there is 2 between (6{0,2,4,6}3,4), then 32 will be a subsequence. **** If there is 4 between (6{0,2,4,6}3,4), then 344 will be a subsequence. **** If there is 6 between (6{0,2,4,6}3,4), then 364 will be a subsequence. **** Thus the number can only be 634 ***** 634 is not prime. * Case (6,5): ** 65 is prime, and thus the only minimal prime in this family. * Case (6,6): ** Since 61, 65, 16, 56 are primes, we only need to consider the family 6{0,2,3,4,6}6 (since any digits 1, 5 between them will produce smaller primes) *** If there is no 3's in {}, then the family will be 6{0,2,4,6}6 **** All numbers of the form 6{0,2,4,6}6 are divisible by 2, thus cannot be prime. *** If there is no 2's and no 4's in {}, then the family will be 6{0,3,6}6 **** All numbers of the form 6{0,3,6}6 are divisible by 3, thus cannot be prime. *** If there is at least one 3's and at least one 2's in {}, then either 32 or 23 will be a subsequence. *** If there is at least one 3's and at least one 4's in {}, then either 346 or 43 will be a subsequence. ===Base 8=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1), (1,3), (1,5), (1,7), (2,1), (2,3), (2,5), (2,7), (3,1), (3,3), (3,5), (3,7), (4,1), (4,3), (4,5), (4,7), (5,1), (5,3), (5,5), (5,7), (6,1), (6,3), (6,5), (6,7), (7,1), (7,3), (7,5), (7,7) * Case (1,1): ** Since 13, 15, 21, 51, 111, 141, 161 are primes, we only need to consider the family 1{0,7}1 (since any digits 1, 2, 3, 4, 5, 6 between them will produce smaller primes) *** Since 107, 177, 701 are primes, we only need to consider the number 171 and the family 1{0}1 (since any digits combo 07, 70, 77 between them will produce smaller primes) **** 171 is not prime. **** All numbers of the form 1{0}1 factored as 10^n+1 = (2^n+1) * (4^n-2^n+1) (n≥1) (and since if n≥1, 2^n+1 ≥ 2^1+1 = 3 > 1, 4^n-2^n+1 ≥ 4^1-2^1+1 = 3 > 1, this factorization is nontrivial), thus cannot be prime. * Case (1,3): ** 13 is prime, and thus the only minimal prime in this family. * Case (1,5): ** 15 is prime, and thus the only minimal prime in this family. * Case (1,7): ** Since 13, 15, 27, 37, 57, 107, 117, 147, 177 are primes, we only need to consider the family 1{6}7 (since any digits 0, 1, 2, 3, 4, 5, 7 between them will produce smaller primes) *** The smallest prime of the form 1{6}7 is 16667 (not minimal prime, since 667 is prime) * Case (2,1): ** 21 is prime, and thus the only minimal prime in this family. * Case (2,3): ** 23 is prime, and thus the only minimal prime in this family. * Case (2,5): ** Since 21, 23, 27, 15, 35, 45, 65, 75, 225, 255 are primes, we only need to consider the family 2{0}5 (since any digits 1, 2, 3, 4, 5, 6, 7 between them will produce smaller primes) *** All numbers of the form 2{0}5 are divisible by 7, thus cannot be prime. * Case (2,7): ** 27 is prime, and thus the only minimal prime in this family. * Case (3,1): ** Since 35, 37, 21, 51, 301, 361 are primes, we only need to consider the family 3{1,3,4}1 (since any digits 0, 2, 5, 6, 7 between them will produce smaller primes) *** Since 13, 343, 111, 131, 141, 431, 3331, 3411 are primes, we only need to consider the families 3{3}11, 33{1,4}1, 3{3,4}4{4}1 (since any digits combo 11, 13, 14, 33, 41, 43 between them will produce smaller primes) **** All numbers of the form 3{3}11 are divisible by 3, thus cannot be prime. **** For the 33{1,4}1 family, since 111 and 141 are primes, we only need to consider the families 33{4}1 and 33{4}11 (since any digits combo 11, 14 between them will produce smaller primes) ***** The smallest prime of the form 33{4}1 is 3344441 ***** All numbers of the form 33{4}11 are divisible by 301, thus cannot be prime. **** For the 3{3,4}4{4}1 family, since 3331 and 3344441 are primes, we only need to consider the families 3{4}1, 3{4}31, 3{4}341, 3{4}3441, 3{4}34441 (since any digits combo 33 or 34444 between (3,1) will produce smaller primes) ***** All numbers of the form 3{4}1 are divisible by 31, thus cannot be prime. ***** Since 4443 is prime, we only need to consider the numbers 3431, 34431, 34341, 344341, 343441, 3443441, 3434441, 34434441 (since any digit combo 444 between (3,3{4}1) will produce smaller primes) ****** None of 3431, 34431, 34341, 344341, 343441, 3443441, 3434441, 34434441 are primes. * Case (3,3): ** Since 35, 37, 13, 23, 53, 73, 343 are primes, we only need to consider the family 3{0,3,6}3 (since any digits 1, 2, 4, 5, 7 between them will produce smaller primes) *** All numbers of the form 3{0,3,6}3 are divisible by 3, thus cannot be prime. * Case (3,5): ** 35 is prime, and thus the only minimal prime in this family. * Case (3,7): ** 37 is prime, and thus the only minimal prime in this family. * Case (4,1): ** Since 45, 21, 51, 401, 431, 471 are primes, we only need to consider the family 4{1,4,6}1 (since any digits 0, 2, 3, 5, 7 between them will produce smaller primes) *** Since 111, 141, 161, 661, 4611 are primes, we only need to consider the families 4{4}11, 4{4,6}4{1,4,6}1, 4{4}6{4}1 (since any digits combo 11, 14, 16, 61, 66 between them will produce smaller primes) **** The smallest prime of the form 4{4}11 is 44444444444444411 (not minimal prime, since 444444441 is prime) **** For the 4{4,6}4{1,4,6}1 family, we can separate this family to 4{4,6}41, 4{4,6}411, 4{4,6}461 ***** For the 4{4,6}41 family, since 661 and 6441 are primes, we only need to consider the families 4{4}41 and 4{4}641 (since any digits combo 64 or 66 between (4,41) will produce smaller primes) ****** The smallest prime of the form 4{4}41 is 444444441 ****** The smallest prime of the form 4{4}641 is 444641 ***** For the 4{4,6}411 family, since 661 and 6441 are primes, we only need to consider the families 4{4}411 and 4{4}6411 (since any digits combo 64 or 66 between (4,411) will produce smaller primes) ****** The smallest prime of the form 4{4}411 is 444444441 ****** The smallest prime of the form 4{4}6411 is 4444444444444446411 (not minimal prime, since 444444441 and 444641 are primes) ***** For the 4{4,6}461 family, since 661 is prime, we only need to consider the family 4{4}461 ****** The smallest prime of the form 4{4}461 is 4444444461 (not minimal prime, since 444444441 is prime) **** For the 4{4}6{4}1 family, since 6441 is prime, we only need to consider the families 4{4}61 and 4{4}641 (since any digits combo 44 between (4{4}6,1) will produce smaller primes) ***** The smallest prime of the form 4{4}61 is 4444444461 (not minimal prime, since 444444441 is prime) ***** The smallest prime of the form 4{4}641 is 444641 * Case (4,3): ** Since 45, 13, 23, 53, 73, 433, 463 are primes, we only need to consider the family 4{0,4}3 (since any digits 1, 2, 3, 5, 6, 7 between them will produce smaller primes) *** Since 4043 and 4443 are primes, we only need to consider the families 4{0}3 and 44{0}3 (since any digits combo 04, 44 between them will produce smaller primes) **** All numbers of the form 4{0}3 are divisible by 7, thus cannot be prime. **** All numbers of the form 44{0}3 are divisible by 3, thus cannot be prime. * Case (4,5): ** 45 is prime, and thus the only minimal prime in this family. * Case (4,7): ** Since 45, 27, 37, 57, 407, 417, 467 are primes, we only need to consider the family 4{4,7}7 (since any digits 0, 1, 2, 3, 5, 6 between them will produce smaller primes) *** Since 747 is prime, we only need to consider the families 4{4}7, 4{4}77, 4{7}7, 44{7}7 (since any digits combo 74 between (4,7) will produce smaller primes) **** The smallest prime of the form 4{4}7 is 44444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444447, with 220 4's, which can be written as (4^220)7 and equal the prime (4*8^221+17)/7 ([http://factordb.com/index.php?id=1100000000416605822 factordb]) **** The smallest prime of the form 4{4}77 is 4444477 **** The smallest prime of the form 4{7}7 is 47777 **** The smallest prime of the form 44{7}7 is 4477777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777, with 851 7's, which can be written as 44(7^851) and equal the prime 37*8^851-1 ([http://factordb.com/index.php?id=1100000000413677646 factordb]) (not minimal prime, since 47777 is prime) * Case (5,1): ** 51 is prime, and thus the only minimal prime in this family. * Case (5,3): ** 53 is prime, and thus the only minimal prime in this family. * Case (5,5): ** Since 51, 53, 57, 15, 35, 45, 65, 75 are primes, we only need to consider the family 5{0,2,5}5 (since any digits 1, 3, 4, 6, 7 between them will produce smaller primes) *** Since 225, 255, 5205 are primes, we only need to consider the families 5{0,5}5 and 5{0,5}25 (since any digits combo 20, 22, 25 between them will produce smaller primes) **** All numbers of the form 5{0,5}5 are divisible by 5, thus cannot be prime. **** For the 5{0,5}25 family, since 500025 and 505525 are primes, we only need to consider the number 500525 the families 5{5}25, 5{5}025, 5{5}0025, 5{5}0525, 5{5}00525, 5{5}05025 (since any digits combo 000, 055 between (5,25) will produce smaller primes) ***** 500525 is not prime. ***** The smallest prime of the form 5{5}25 is 555555555555525 ***** The smallest prime of the form 5{5}025 is 55555025 ***** The smallest prime of the form 5{5}0025 is 5555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555550025, with 184 5's, which can be written as (5^183)0025 and equal the prime (5*8^187-20333)/7 ([http://factordb.com/index.php?id=1100000002350205912 factordb]) (not minimal prime, since 55555025 and 555555555555525 are primes) ***** The smallest prime of the form 5{5}0525 is 5550525 ***** The smallest prime of the form 5{5}00525 is 5500525 ***** The smallest prime of the form 5{5}05025 is 5555555555555555555555505025 (not minimal prime, since 5550525, 55555025, and 555555555555525 are primes) * Case (5,7): ** 57 is prime, and thus the only minimal prime in this family. * Case (6,1): ** Since 65, 21, 51, 631, 661 are primes, we only need to consider the family 6{0,1,4,7}1 (since any digits 2, 3, 5, 6 between them will produce smaller primes) *** Numbers containing 4: (note that the number cannot contain two or more 4's, or 6441 will be a subsequence) **** The form is 6{0,1,7}4{0,1,7}1 ***** Since 141, 401, 471 are primes, we only need to consider the family 6{0,7}4{1}1 ****** Since 111 is prime, we only need to consider the families 6{0,7}41 and 6{0,7}411 ******* For the 6{0,7}41 family, since 60741 is prime, we only need to consider the family 6{7}{0}41 ******** Since 6777 is prime, we only need to consider the families 6{0}41, 67{0}41, 677{0}41 ********* All numbers of the form 6{0}41 are divisible by 3, thus cannot be prime. ********* All numbers of the form 67{0}41 are divisible by 13, thus cannot be prime. ********* All numbers of the form 677{0}41 are divisible by 3, thus cannot be prime. ******* For the 6{0,7}411 family, since 60411 is prime, we only need to consider the family 6{7}411 ******** The smallest prime of the form 6{7}411 is 67777411 (not minimal prime, since 6777 is prime) *** Numbers not containing 4: **** The form is 6{0,1,7}1 ***** Since 111 is prime, we only need to consider the families 6{0,7}1 and 6{0,7}1{0,7}1 ****** All numbers of the form 6{0,7}1 are divisible by 7, thus cannot be prime. ****** For the 6{0,7}1{0,7}1 family, since 711 and 6101 are primes, we only need to consider the family 6{0}1{7}1 ******* Since 60171 is prime, we only need to consider the families 6{0}11 and 61{7}1 ******** All numbers of the form 6{0}11 are divisible by 3, thus cannot be prime. ******** The smallest prime of the form 61{7}1 is 617771 (not minimal prime, since 6777 is prime) * Case (6,3): ** Since 65, 13, 23, 53, 73, 643 are primes, we only need to consider the family 6{0,3,6}3 (since any digits 1, 2, 4, 5, 7 between them will produce smaller primes) *** All numbers of the form 6{0,3,6}3 are divisible by 3, thus cannot be prime. * Case (6,5): ** 65 is prime, and thus the only minimal prime in this family. * Case (6,7): ** Since 65, 27, 37, 57, 667 are primes, we only need to consider the family 6{0,1,4,7}7 (since any digits 2, 3, 5, 6 between them will produce smaller primes) *** Since 107, 117, 147, 177, 407, 417, 717, 747, 6007, 6477, 6707, 6777 are primes, there cannot be digits combo 00, 10, 11, 14, 17, 40, 41, 47, 70, 71, 74, 77 between them **** If there is 1 between them, then there cannot be 1, 4, 7 before it and cannot be 0, 1, 4, 7 after it, thus the form will be 6{0}17 ***** All numbers of the form 6{0}17 are divisible by 3, thus cannot be prime. **** If there is 7 between them, then there cannot be 1, 4, 7 before it and cannot be 0, 1, 4, 7 after it, thus the form will be 6{0}77 ***** All numbers of the form 6{0}77 are divisible by 3, thus cannot be prime. **** If there is neither 1 nor 7 between them, then the form is 6{0,4}7 ***** Since 6007, 407 at primes, we only need to consider the families 6{4}7 and 60{4}7 (since any digits combo 00, 40 between them will produce smaller primes) ****** All numbers of the form 6{4}7 are divisible by 3, 5, or 15, thus cannot be prime. ****** All numbers of the form 60{4}7 are divisible by 21, thus cannot be prime. * Case (7,1): ** Since 73, 75, 21, 51, 701, 711 are primes, we only need to consider the family 7{4,6,7}1 (since any digits 0, 1, 2, 3, 5 between them will produce smaller primes) *** Since 747, 767, 471, 661, 7461, 7641 are primes, we only need to consider the families 7{4,7}4{4}1, 7{7}61, 7{7}7{4,6,7}1 (since any digits combo 46, 47, 64, 66, 67 between them will produce smaller primes) **** For the 7{4,7}4{4}1 family, since 747, 471 are primes, we only need to consider the family 7{7}{4}1 (since any digits combo 47 between (7,4{4}1) will produce smaller primes) ***** The smallest prime of the form 7{7}1 is 7777777777771 ***** The smallest prime of the form 7{7}41 is 777777777777777777777777777777777777777777777777777777777777777777777777777777741, with 79 7's, which can be written as (7^79)41 and equal the prime 8^81-31 ([http://factordb.com/index.php?id=1100000000294462449 factordb]) (not minimal prime, since 7777777777771 is prime) ***** The smallest prime of the form 7{7}441 is 777777777777777777777777777777777777777777777777777777777777777777777777777777777777441, with 84 7's, which can be written as (7^84)441 and equal the prime 8^87-223 ([http://factordb.com/index.php?id=1100000000294462776 factordb]) (not minimal prime, since 7777777777771 is prime) ***** The smallest prime of the form 7{7}4441 is 777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777774441, with 233 7's, which can be written as (7^233)4441 and equal the prime 8^237-1759 ([http://factordb.com/index.php?id=1100000002352073382 factordb]) (not minimal prime, since 7777777777771 is prime) ***** The smallest prime of the form 7{7}44441 is 7777777777777777777777777777777777777777777777777777777744441, with 56 7's, which can be written as (7^56)44441 and equal the prime 8^61-14047 ([http://factordb.com/index.php?id=1100000002350250002 factordb]) (not minimal prime, since 7777777777771 is prime) ***** All numbers of the form 7{7}444441 are divisible by 7, thus cannot be prime. ***** The smallest prime of the form 7{7}4444441 is 77774444441 ****** Since this prime has just 4 7's, we only need to consider the families with <=3 7's ******* The smallest prime of the form 7{4}1 is 744444441 ******* All numbers of the form 77{4}1 are divisible by 5, thus cannot be prime. ******* The smallest prime of the form 777{4}1 is 777444444444441 (not minimal prime, since 444444441 and 744444441 are primes) * Case (7,3): ** 73 is prime, and thus the only minimal prime in this family. * Case (7,5): ** 75 is prime, and thus the only minimal prime in this family. * Case (7,7): ** Since 73, 75, 27, 37, 57, 717, 747, 767 are primes, we only need to consider the family 7{0,7}7 (since any digits 1, 2, 3, 4, 5, 6 between them will produce smaller primes) *** All numbers of the form 7{0,7}7 are divisible by 7, thus cannot be prime. ===Base 10=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1), (1,3), (1,7), (1,9), (2,1), (2,3), (2,7), (2,9), (3,1), (3,3), (3,7), (3,9), (4,1), (4,3), (4,7), (4,9), (5,1), (5,3), (5,7), (5,9), (6,1), (6,3), (6,7), (6,9), (7,1), (7,3), (7,7), (7,9), (8,1), (8,3), (8,7), (8,9), (9,1), (9,3), (9,7), (9,9) * Case (1,1): ** 11 is prime, and thus the only minimal prime in this family. * Case (1,3): ** 13 is prime, and thus the only minimal prime in this family. * Case (1,7): ** 17 is prime, and thus the only minimal prime in this family. * Case (1,9): ** 19 is prime, and thus the only minimal prime in this family. * Case (2,1): ** Since 23, 29, 11, 31, 41, 61, 71, 251, 281 are primes, we only need to consider the family 2{0,2}1 (since any digits 1, 3, 4, 5, 6, 7, 8, 9 between them will produce smaller primes) *** Since 2221 and 20201 are primes, we only need to consider the families 2{0}1, 2{0}21, 22{0}1 (since any digits combo 22 or 020 between them will produce smaller primes) **** All numbers of the form 2{0}1 are divisible by 3, thus cannot be prime. **** The smallest prime of the form 2{0}21 is 20021 **** The smallest prime of the form 22{0}1 is 22000001 * Case (2,3): ** 23 is prime, and thus the only minimal prime in this family. * Case (2,7): ** Since 23, 29, 17, 37, 47, 67, 97, 227, 257, 277 are primes, we only need to consider the family 2{0,8}7 (since any digits 1, 2, 3, 4, 5, 6, 7, 9 between them will produce smaller primes) *** Since 887 and 2087 are primes, we only need to consider the families 2{0}7 and 28{0}7 (since any digit combo 08 or 88 between them will produce smaller primes) **** All numbers of the form 2{0}7 are divisible by 3, thus cannot be prime. **** All numbers of the form 28{0}7 are divisible by 7, thus cannot be prime. * Case (2,9): ** 29 is prime, and thus the only minimal prime in this family. * Case (3,1): ** 31 is prime, and thus the only minimal prime in this family. * Case (3,3): ** Since 31, 37, 13, 23, 43, 53, 73, 83 are primes, we only need to consider the family 3{0,3,6,9}3 (since any digits 1, 2, 4, 5, 7, 8 between them will produce smaller primes) *** All numbers of the form 3{0,3,6,9}3 are divisible by 3, thus cannot be prime. * Case (3,7): ** 37 is prime, and thus the only minimal prime in this family. * Case (3,9): ** Since 31, 37, 19, 29, 59, 79, 89, 349 are primes, we only need to consider the family 3{0,3,6,9}9 (since any digits 1, 2, 4, 5, 7, 8 between them will produce smaller primes) *** All numbers of the form 3{0,3,6,9}9 are divisible by 3, thus cannot be prime. * Case (4,1): ** 41 is prime, and thus the only minimal prime in this family. * Case (4,3): ** 43 is prime, and thus the only minimal prime in this family. * Case (4,7): ** 47 is prime, and thus the only minimal prime in this family. * Case (4,9): ** Since 41, 43, 47, 19, 29, 59, 79, 89, 409, 449, 499 are primes, we only need to consider the family 4{6}9 (since any digits 0, 1, 2, 3, 4, 5, 7, 8, 9 between them will produce smaller primes) *** All numbers of the form 4{6}9 are divisible by 7, thus cannot be prime. * Case (5,1): ** Since 53, 59, 11, 31, 41, 61, 71, 521 are primes, we only need to consider the family 5{0,5,8}1 (since any digits 1, 2, 3, 4, 6, 7, 9 between them will produce smaller primes) *** Since 881 is prime, we only need to consider the families 5{0,5}1 and 5{0,5}8{0,5}1 (since any digit combo 88 between them will produce smaller primes) **** For the 5{0,5}1 family, since 5051 and 5501 are primes, we only need to consider the families 5{0}1 and 5{5}1 (since any digit combo 05 or 50 between them will produce smaller primes) ***** All numbers of the form 5{0}1 are divisible by 3, thus cannot be prime. ***** The smallest prime of the form 5{5}1 is 555555555551 **** For the 5{0,5}8{0,5}1 family, since 5081, 5581, 5801, 5851 are primes, we only need to consider the number 581 ***** 581 is not prime. * Case (5,3): ** 53 is prime, and thus the only minimal prime in this family. * Case (5,7): ** Since 53, 59, 17, 37, 47, 67, 97, 557, 577, 587 are primes, we only need to consider the family 5{0,2}7 (since any digits 1, 3, 4, 5, 6, 7, 8, 9 between them will produce smaller primes) *** Since 227 and 50207 are primes, we only need to consider the families 5{0}7, 5{0}27, 52{0}7 (since any digits combo 22 or 020 between them will produce smaller primes) **** All numbers of the form 5{0}7 are divisible by 3, thus cannot be prime. **** The smallest prime of the form 5{0}27 is 5000000000000000000000000000027 **** The smallest prime of the form 52{0}7 is 5200007 * Case (5,9): ** 59 is prime, and thus the only minimal prime in this family. * Case (6,1): ** 61 is prime, and thus the only minimal prime in this family. * Case (6,3): ** Since 61, 67, 13, 23, 43, 53, 73, 83 are primes, we only need to consider the family 6{0,3,6,9}3 (since any digits 1, 2, 4, 5, 7, 8 between them will produce smaller primes) *** All numbers of the form 6{0,3,6,9}3 are divisible by 3, thus cannot be prime. * Case (6,7): ** 67 is prime, and thus the only minimal prime in this family. * Case (6,9): ** Since 61, 67, 19, 29, 59, 79, 89 are primes, we only need to consider the family 6{0,3,4,6,9}9 (since any digits 1, 2, 5, 7, 8 between them will produce smaller primes) *** Since 449 is prime, we only need to consider the families 6{0,3,6,9}9 and 6{0,3,6,9}4{0,3,6,9}9 (since any digit combo 44 between them will produce smaller primes) **** All numbers of the form 6{0,3,6,9}9 are divisible by 3, thus cannot be prime. **** For the 6{0,3,6,9}4{0,3,6,9}9 family, since 409, 43, 6469, 499 are primes, we only need to consider the family 6{0,3,6,9}49 ***** Since 349, 6949 are primes, we only need to consider the family 6{0,6}49 ****** Since 60649 is prime, we only need to consider the family 6{6}{0}49 (since any digits combo 06 between {6,49} will produce smaller primes) ******* The smallest prime of the form 6{6}49 is 666649 ******** Since this prime has just 4 6's, we only need to consider the families with <=3 6's ********* The smallest prime of the form 6{0}49 is 60000049 ********* The smallest prime of the form 66{0}49 is 66000049 ********* The smallest prime of the form 666{0}49 is 66600049 * Case (7,1): ** 71 is prime, and thus the only minimal prime in this family. * Case (7,3): ** 73 is prime, and thus the only minimal prime in this family. * Case (7,7): ** Since 71, 73, 79, 17, 37, 47, 67, 97, 727, 757, 787 are primes, we only need to consider the family 7{0,7}7 (since any digits 1, 2, 3, 4, 5, 6, 8, 9 between them will produce smaller primes) *** All numbers of the form 7{0,7}7 are divisible by 7, thus cannot be prime. * Case (7,9): ** 79 is prime, and thus the only minimal prime in this family. * Case (8,1): ** Since 83, 89, 11, 31, 41, 61, 71, 821, 881 are primes, we only need to consider the family 8{0,5}1 (since any digits 1, 2, 3, 4, 6, 7, 8, 9 between them will produce smaller primes) *** Since 8501 is prime, we only need to consider the family 8{0}{5}1 (since any digits combo 50 between them will produce smaller primes) **** Since 80051 is prime, we only need to consider the families 8{0}1, 8{5}1, 80{5}1 (since any digits combo 005 between them will produce smaller primes) ***** All numbers of the form 8{0}1 are divisible by 3, thus cannot be prime. ***** The smallest prime of the form 8{5}1 is 8555555555555555555551 (not minimal prime, since 555555555551 is prime) ***** The smallest prime of the form 80{5}1 is 80555551 * Case (8,3): ** 83 is prime, and thus the only minimal prime in this family. * Case (8,7): ** Since 83, 89, 17, 37, 47, 67, 97, 827, 857, 877, 887 are primes, we only need to consider the family 8{0}7 (since any digits 1, 2, 3, 4, 5, 6, 7, 8, 9 between them will produce smaller primes) *** All numbers of the form 8{0}7 are divisible by 3, thus cannot be prime. * Case (8,9): ** 89 is prime, and thus the only minimal prime in this family. * Case (9,1): ** Since 97, 11, 31, 41, 61, 71, 991 are primes, we only need to consider the family 9{0,2,5,8}1 (since any digits 1, 3, 4, 6, 7, 9 between them will produce smaller primes) *** Since 251, 281, 521, 821, 881, 9001, 9221, 9551, 9851 are primes, we only need to consider the families 9{2,5,8}0{2,5,8}1, 9{0}2{0}1, 9{0}5{0,8}1, 9{0,5}8{0}1 (since any digits combo 00, 22, 25, 28, 52, 55, 82, 85, 88 between them will produce smaller primes) **** For the 9{2,5,8}0{2,5,8}1 family, since any digits combo 22, 25, 28, 52, 55, 82, 85, 88 between (9,1) will produce smaller primes, we only need to consider the numbers 901, 9021, 9051, 9081, 9201, 9501, 9801, 90581, 95081, 95801 ***** 95801 is the only prime among 901, 9021, 9051, 9081, 9201, 9501, 9801, 90581, 95081, 95801, but it is not minimal prime since 5801 is prime. **** For the 9{0}2{0}1 family, since 9001 is prime, we only need to consider the numbers 921, 9201, 9021 ***** None of 921, 9201, 9021 are primes. **** For the 9{0}5{0,8}1 family, since 9001 and 881 are primes, we only need to consider the numbers 951, 9051, 9501, 9581, 90581, 95081, 95801 ***** 95801 is the only prime among 951, 9051, 9501, 9581, 90581, 95081, 95801, but it is not minimal prime since 5801 is prime. **** For the 9{0,5}8{0}1 family, since 9001 and 5581 are primes, we only need to consider the numbers 981, 9081, 9581, 9801, 90581, 95081, 95801 ***** 95801 is the only prime among 981, 9081, 9581, 9801, 90581, 95081, 95801, but it is not minimal prime since 5801 is prime. * Case (9,3): ** Since 97, 13, 23, 43, 53, 73, 83 are primes, we only need to consider the family 9{0,3,6,9}3 (since any digits 1, 2, 4, 5, 7, 8 between them will produce smaller primes) *** All numbers of the form 9{0,3,6,9}3 are divisible by 3, thus cannot be prime. * Case (9,7): ** 97 is prime, and thus the only minimal prime in this family. * Case (9,9): ** Since 97, 19, 29, 59, 79, 89 are primes, we only need to consider the family 9{0,3,4,6,9}9 (since any digits 1, 2, 5, 7, 8 between them will produce smaller primes) *** Since 449 is prime, we only need to consider the families 9{0,3,6,9}9 and 9{0,3,6,9}4{0,3,6,9}9 (since any digit combo 44 between them will produce smaller primes) **** All numbers of the form 9{0,3,6,9}9 are divisible by 3, thus cannot be prime. **** For the 9{0,3,6,9}4{0,3,6,9}9 family, since 9049, 349, 9649, 9949 are primes, we only need to consider the family 94{0,3,6,9}9 ***** Since 409, 43, 499 are primes, we only need to consider the family 94{6}9 (since any digits 0, 3, 9 between (94,9) will produce smaller primes) ****** The smallest prime of the form 94{6}9 is 946669 ===Base 12=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1), (1,5), (1,7), (1,B), (2,1), (2,5), (2,7), (2,B), (3,1), (3,5), (3,7), (3,B), (4,1), (4,5), (4,7), (4,B), (5,1), (5,5), (5,7), (5,B), (6,1), (6,5), (6,7), (6,B), (7,1), (7,5), (7,7), (7,B), (8,1), (8,5), (8,7), (8,B), (9,1), (9,5), (9,7), (9,B), (A,1), (A,5), (A,7), (A,B), (B,1), (B,5), (B,7), (B,B) * Case (1,1): ** 11 is prime, and thus the only minimal prime in this family. * Case (1,5): ** 15 is prime, and thus the only minimal prime in this family. * Case (1,7): ** 17 is prime, and thus the only minimal prime in this family. * Case (1,B): ** 1B is prime, and thus the only minimal prime in this family. * Case (2,1): ** Since 25, 27, 11, 31, 51, 61, 81, 91, 221, 241, 2A1, 2B1 are primes, we only need to consider the family 2{0}1 (since any digits 1, 2, 3, 4, 5, 6, 7, 8, 9, A, B between them will produce smaller primes) *** The smallest prime of the form 2{0}1 is 2001 * Case (2,5): ** 25 is prime, and thus the only minimal prime in this family. * Case (2,7): ** 27 is prime, and thus the only minimal prime in this family. * Case (2,B): ** Since 25, 27, 1B, 3B, 4B, 5B, 6B, 8B, AB, 2BB are primes, we only need to consider the family 2{0,2,9}B (since any digits 1, 3, 4, 5, 6, 7, 8, A, B between them will produce smaller primes) *** Since 90B, 200B, 202B, 222B, 229B, 292B, 299B are primes, we only need to consider the numbers 20B, 22B, 29B, 209B, 220B (since any digits combo 00, 02, 22, 29, 90, 92, 99 between them will produce smaller primes) **** None of 20B, 22B, 29B, 209B, 220B are primes. * Case (3,1): ** 31 is prime, and thus the only minimal prime in this family. * Case (3,5): ** 35 is prime, and thus the only minimal prime in this family. * Case (3,7): ** 37 is prime, and thus the only minimal prime in this family. * Case (3,B): ** 3B is prime, and thus the only minimal prime in this family. * Case (4,1): ** Since 45, 4B, 11, 31, 51, 61, 81, 91, 401, 421, 471 are primes, we only need to consider the family 4{4,A}1 (since any digit 0, 1, 2, 3, 5, 6, 7, 8, 9, B between them will produce smaller primes) *** Since A41 and 4441 are primes, we only need to consider the families 4{A}1 and 44{A}1 (since any digit combo 44, A4 between them will produce smaller primes) **** All numbers of the form 4{A}1 are divisible by 5, thus cannot be prime. **** The smallest prime of the form 44{A}1 is 44AAA1 * Case (4,5): ** 45 is prime, and thus the only minimal prime in this family. * Case (4,7): ** Since 45, 4B, 17, 27, 37, 57, 67, 87, A7, B7, 447, 497 are primes, we only need to consider the family 4{0,7}7 (since any digit 1, 2, 3, 4, 5, 6, 8, 9, A, B between them will produce smaller primes) *** Since 4707 and 4777 are primes, we only need to consider the families 4{0}7 and 4{0}77 (since any digit combo 70, 77 between them will produce smaller primes) **** All numbers of the form 4{0}7 are divisible by B, thus cannot be prime. **** The smallest prime of the form 4{0}77 is 400000000000000000000000000000000000000077 * Case (4,B): ** 4B is prime, and thus the only minimal prime in this family. * Case (5,1): ** 51 is prime, and thus the only minimal prime in this family. * Case (5,5): ** Since 51, 57, 5B, 15, 25, 35, 45, 75, 85, 95, B5, 565 are primes, we only need to consider the family 5{0,5,A}5 (since any digits 1, 2, 3, 4, 6, 7, 8, 9, B between them will produce smaller primes) *** All numbers of the form 5{0,5,A}5 are divisible by 5, thus cannot be prime. * Case (5,7): ** 57 is prime, and thus the only minimal prime in this family. * Case (5,B): ** 5B is prime, and thus the only minimal prime in this family. * Case (6,1): ** 61 is prime, and thus the only minimal prime in this family. * Case (6,5): ** Since 61, 67, 6B, 15, 25, 35, 45, 75, 85, 95, B5, 655, 665 are primes, we only need to consider the family 6{0,A}5 (since any digits 1, 2, 3, 4, 5, 6, 7, 8, 9, B between them will produce smaller primes) *** Since 6A05 and 6AA5 are primes, we only need to consider the families 6{0}5 and 6{0}A5 (since any digit combo A0, AA between them will produce smaller primes) **** All numbers of the form 6{0}5 are divisible by B, thus cannot be prime. **** The smallest prime of the form 6{0}A5 is 600A5 * Case (6,7): ** 67 is prime, and thus the only minimal prime in this family. * Case (6,B): ** 6B is prime, and thus the only minimal prime in this family. * Case (7,1): ** Since 75, 11, 31, 51, 61, 81, 91, 701, 721, 771, 7A1 are primes, we only need to consider the family 7{4,B}1 (since any digits 0, 1, 2, 3, 5, 6, 7, 8, 9, A between them will produce smaller primes) *** Since 7BB, 7441 and 7B41 are primes, we only need to consider the numbers 741, 7B1, 74B1 **** None of 741, 7B1, 74B1 are primes. * Case (7,5): ** 75 is prime, and thus the only minimal prime in this family. * Case (7,7): ** Since 75, 17, 27, 37, 57, 67, 87, A7, B7, 747, 797 are primes, we only need to consider the family 7{0,7}7 (since any digits 1, 2, 3, 4, 5, 6, 8, 9, A, B between them will produce smaller primes) *** All numbers of the form 7{0,7}7 are divisible by 7, thus cannot be prime. * Case (7,B): ** Since 75, 1B, 3B, 4B, 5B, 6B, 8B, AB, 70B, 77B, 7BB are primes, we only need to consider the family 7{2,9}B (since any digits 0, 1, 3, 4, 5, 6, 7, 8, A, B between them will produce smaller primes) *** Since 222B, 729B is prime, we only need to consider the families 7{9}B, 7{9}2B, 7{9}22B (since any digits combo 222, 29 between them will produce smaller primes) **** The smallest prime of the form 7{9}B is 7999B **** The smallest prime of the form 7{9}2B is 79992B (not minimal prime, since 992B and 7999B are primes) **** The smallest prime of the form 7{9}22B is 79922B (not minimal prime, since 992B is prime) * Case (8,1): ** 81 is prime, and thus the only minimal prime in this family. * Case (8,5): ** 85 is prime, and thus the only minimal prime in this family. * Case (8,7): ** 87 is prime, and thus the only minimal prime in this family. * Case (8,B): ** 8B is prime, and thus the only minimal prime in this family. * Case (9,1): ** 91 is prime, and thus the only minimal prime in this family. * Case (9,5): ** 95 is prime, and thus the only minimal prime in this family. * Case (9,7): ** Since 91, 95, 17, 27, 37, 57, 67, 87, A7, B7, 907 are primes, we only need to consider the family 9{4,7,9}7 (since any digit 0, 1, 2, 3, 5, 6, 8, A, B between them will produce smaller primes) *** Since 447, 497, 747, 797, 9777, 9947, 9997 are primes, we only need to consider the numbers 947, 977, 997, 9477, 9977 (since any digits combo 44, 49, 74, 77, 79, 94, 99 between them will produce smaller primes) **** None of 947, 977, 997, 9477, 9977 are primes. * Case (9,B): ** Since 91, 95, 1B, 3B, 4B, 5B, 6B, 8B, AB, 90B, 9BB are primes, we only need to consider the family 9{2,7,9}B (since any digit 0, 1, 3, 4, 5, 6, 8, A, B between them will produce smaller primes) *** Since 27, 77B, 929B, 992B, 997B are primes, we only need to consider the families 9{2,7}2{2}B, 97{2,9}B, 9{7,9}9{9}B (since any digits combo 27, 29, 77, 92, 97 between them will produce smaller primes) **** For the 9{2,7}2{2}B family, since 27 and 77B are primes, we only need to consider the families 9{2}2{2}B and 97{2}2{2}B (since any digits combo 27, 77 between (9,2{2}B) will produce smaller primes) ***** The smallest prime of the form 9{2}2{2}B is 9222B (not minimal prime, since 222B is prime) ***** The smallest prime of the form 97{2}2{2}B is 9722222222222B (not minimal prime, since 222B is prime) **** For the 97{2,9}B family, since 729B and 929B are primes, we only need to consider the family 97{9}{2}B (since any digits combo 29 between (97,B) will produce smaller primes) ***** Since 222B is prime, we only need to consider the families 97{9}B, 97{9}2B, 97{9}22B (since any digit combo 222 between (97,B) will produce smaller primes) ****** All numbers of the form 97{9}B are divisible by 11, thus cannot be prime. ****** The smallest prime of the form 97{9}2B is 979999992B (not minimal prime, since 9999B is prime) ****** All numbers of the form 97{9}22B are divisible by 11, thus cannot be prime. **** For the 9{7,9}9{9}B family, since 77B and 9999B are primes, we only need to consider the numbers 99B, 999B, 979B, 9799B, 9979B ***** None of 99B, 999B, 979B, 9799B, 9979B are primes. * Case (A,1): ** Since A7, AB, 11, 31, 51, 61, 81, 91, A41 are primes, we only need to consider the family A{0,2,A}1 (since any digits 1, 3, 4, 5, 6, 7, 8, 9, B between them will produce smaller primes) *** Since 221, 2A1, A0A1, A201 are primes, we only need to consider the families A{A}{0}1 and A{A}{0}21 (since any digits combo 0A, 20, 22, 2A between them will produce smaller primes) **** For the A{A}{0}1 family: ***** All numbers of the form A{0}1 are divisible by B, thus cannot be prime. ***** The smallest prime of the form AA{0}1 is AA000001 ***** The smallest prime of the form AAA{0}1 is AAA0001 ***** The smallest prime of the form AAAA{0}1 is AAAA1 ****** Since this prime has no 0's, we do not need to consider the families {A}1, {A}01, {A}001, etc. **** All numbers of the form A{A}{0}21 are divisible by 5, thus cannot be prime. * Case (A,5): ** Since A7, AB, 15, 25, 35, 45, 75, 85, 95, B5 are primes, we only need to consider the family A{0,5,6,A}5 (since any digits 1, 2, 3, 4, 7, 8, 9, B between them will produce smaller primes) *** Since 565, 655, 665, A605, A6A5, AA65 are primes, we only need to consider the families A{0,5,A}5 and A{0}65 (since any digits combo 56, 60, 65, 66, 6A, A6 between them will produce smaller primes) **** All numbers of the form A{0,5,A}5 are divisible by 5, thus cannot be prime. **** The smallest prime of the form A{0}65 is A00065 * Case (A,7): ** A7 is prime, and thus the only minimal prime in this family. * Case (A,B): ** AB is prime, and thus the only minimal prime in this family. * Case (B,1): ** Since B5, B7, 11, 31, 51, 61, 81, 91, B21 are primes, we only need to consider the family B{0,4,A,B}1 (since any digits 1, 2, 3, 5, 6, 7, 8, 9 between them will produce smaller primes) *** Since 4B, AB, 401, A41, B001, B0B1, BB01, BB41 are primes, we only need to consider the families B{A}0{4,A}1, B{0,4}4{4,A}1, B{0,4,A,B}A{0,A}1, B{B}B{A,B}1 (since any digits combo 00, 0B, 40, 4B, A4, AB, B0, B4 between them will produce smaller primes) **** For the B{A}0{4,A}1 family, since A41 is prime, we only need consider the families B0{4}{A}1 and B{A}0{A}1 ***** For the B0{4}{A}1 family, since B04A1 is prime, we only need to consider the families B0{4}1 and B0{A}1 ****** The smallest prime of the form B0{4}1 is B04441 (not minimal prime, since 4441 is prime) ****** The smallest prime of the form B0{A}1 is B0AAAAA1 (not minimal prime, since AAAA1 is prime) ***** For the B{A}0{A}1 family, since A0A1 is prime, we only need to consider the families B{A}01 and B0{A}1 ****** The smallest prime of the form B{A}01 is BAA01 ****** The smallest prime of the form B0{A}1 is B0AAAAA1 (not minimal prime, since AAAA1 is prime) **** For the B{0,4}4{4,A}1 family, since 4441 is prime, we only need to consider the families B{0}4{4,A}1 and B{0,4}4{A}1 ***** For the B{0}4{4,A}1 family, since B001 is prime, we only need to consider the families B4{4,A}1 and B04{4,A}1 ****** For the B4{4,A}1 family, since A41 is prime, we only need to consider the family B4{4}{A}1 ******* Since 4441 and BAAA1 are primes, we only need to consider the numbers B41, B441, B4A1, B44A1, B4AA1, B44AA1 ******** None of B41, B441, B4A1, B44A1, B4AA1, B44AA1 are primes. ****** For the B04{4,A}1 family, since B04A1 is prime, we only need to consider the family B04{4}1 ******* The smallest prime of the form B04{4}1 is B04441 (not minimal prime, since 4441 is prime) ***** For the B{0,4}4{A}1 family, since 401, 4441, B001 are primes, we only need to consider the families B4{A}1, B04{A}1, B44{A}1, B044{A}1 (since any digits combo 00, 40, 44 between (B,4{A}1) will produce smaller primes) ****** The smallest prime of the form B4{A}1 is B4AAA1 (not minimal prime, since BAAA1 is prime) ****** The smallest prime of the form B04{A}1 is B04A1 ****** The smallest prime of the form B44{A}1 is B44AAAAAAA1 (not minimal prime, since BAAA1 is prime) ****** The smallest prime of the form B044{A}1 is B044A1 (not minimal prime, since B04A1 is prime) **** For the B{0,4,A,B}A{0,A}1 family, since all numbers in this family with 0 between (B,1) are in the B{A}0{4,A}1 family, and all numbers in this family with 4 between (B,1) are in the B{0,4}4{4,A}1 family, we only need to consider the family B{A,B}A{A}1 ***** Since BAAA1 is prime, we only need to consider the families B{A,B}A1 and B{A,B}AA1 ****** For the B{A,B}A1 family, since AB and BAAA1 are primes, we only need to consider the families B{B}A1 and B{B}AA1 ******* All numbers of the form B{B}A1 are divisible by B, thus cannot be prime. ******* The smallest prime of the form B{B}AA1 is BBBAA1 ****** For the B{A,B}AA1 family, since BAAA1 is prime, we only need to consider the families B{B}AA1 ******* The smallest prime of the form B{B}AA1 is BBBAA1 **** For the B{B}B{A,B}1 family, since AB and BAAA1 are primes, we only need to consider the families B{B}B1, B{B}BA1, B{B}BAA1 (since any digits combo AB or AAA between (B{B}B,1) will produce smaller primes) ***** The smallest prime of the form B{B}B1 is BBBB1 ***** All numbers of the form B{B}BA1 are divisible by B, thus cannot be prime. ***** The smallest prime of the form B{B}BAA1 is BBBAA1 * Case (B,5): ** B5 is prime, and thus the only minimal prime in this family. * Case (B,7): ** B7 is prime, and thus the only minimal prime in this family. * Case (B,B): ** Since B5, B7, 1B, 3B, 4B, 5B, 6B, 8B, AB, B2B are primes, we only need to consider the family B{0,9,B}B (since any digits 1, 2, 3, 4, 5, 6, 7, 8, A between them will produce smaller primes) *** Since 90B and 9BB are primes, we only need to consider the families B{0,B}{9}B **** Since 9999B is prime, we only need to consider the families B{0,B}B, B{0,B}9B, B{0,B}99B, B{0,B}999B ***** All numbers of the form B{0,B}B are divisible by B, thus cannot be prime. ***** For the B{0,B}9B family: ****** Since B0B9B and BB09B are primes, we only need to consider the families B{0}9B and B{B}9B (since any digits combo 0B, B0 between (B,9B) will produce smaller primes) ******* The smallest prime of the form B{0}9B is B0000000000000000000000000009B ******* All numbers of the from B{B}9B is either divisible by 11 (if totally number of B's is even) or factored as 10^(2*n)-21 = (10^n-5) * (10^n+5) (if totally number of B's is odd number 2*n-1 (n≥1)) (and since if n≥1, 10^n-5 ≥ 10^1-5 = 7 > 1, 10^n+5 ≥ 10^1+5 = 15 > 1, this factorization is nontrivial), thus cannot be prime. ***** For the B{0,B}99B family: ****** Since B0B9B and BB09B are primes, we only need to consider the families B{0}99B and B{B}99B (since any digits combo 0B, B0 between (B,99B) will produce smaller primes) ******* The smallest prime of the form B{0}99B is B00099B ******* The smallest prime of the form B{B}99B is BBBBBB99B ***** For the B{0,B}999B family: ****** Since B0B9B and BB09B are primes, we only need to consider the families B{0}999B and B{B}999B (since any digits combo 0B, B0 between (B,999B) will produce smaller primes) ******* The smallest prime of the form B{0}999B is B0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000999B, with 1765 0's, which can be written as B(0^1765)999B and equal the prime 11*12^1769+16967 ([http://factordb.com/index.php?id=1100000002378273165 factordb]) ([http://factordb.com/cert.php?id=1100000002378273165 primality certificate]) (not minimal prime, since B00099B and B0000000000000000000000000009B are primes) ******* The smallest prime of the form B{B}999B is BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB999B, with 245 B's, which can be written as (B^244)999B and equal the prime 12^248-3769 ([http://factordb.com/index.php?id=1100000002378270237 factordb]) (not minimal prime, since BBBBBB99B is prime) == Examples of families which can be ruled out as contain no primes > ''b'' == It is not known if this problem is solvable: Problem: Given strings ''x'', ''y'', ''z'', and a base ''b'', does there exist a prime number whose base-''b'' expansion is of the form ''x''{''y''}''z''? It will be necessary for our algorithm to determine if families of the form ''x''{''y''}''z'' contain a prime > ''b'' or not. We use two different heuristic strategies to show that such families contain no primes > ''b''. In the first strategy, we mimic the well-known technique of “covering congruences”, by finding some finite set ''S'' of primes ''p'' such that every number in a given family is divisible by some element of ''S''. In the second strategy, we attempt to find an algebraic factorization, such as difference-of-squares factorization, difference-of-cubes factorization, and Aurifeuillian factorization for numbers of the form ''x''⁴+4''y''⁴. Examples of first strategy: (we can show that the corresponding numbers are > all elements in ''S'', if ''n'' makes corresponding numbers > ''b'' (i.e. ''n''≥1 for 5{1} in base 9 and 2{5} in base 11 and {4}D in base 16 and {8}F in base 16, ''n''≥0 for other examples), thus these factorizations are nontrivial) * In base 10, all numbers of the form 4{6}9 are divisible by 7 * In base 6, all numbers of the form 4{0}1 are divisible by 5 * In base 15, all numbers of the form 9{6}8 are divisible by 11 * In base 9, all numbers of the form 5{1} are divisible by some element of {2, 5} * In base 11, all numbers of the form 2{5} are divisible by some element of {2, 3} * In base 14, all numbers of the form B{0}1 are divisible by some element of {3, 5} * In base 8, all numbers of the form 6{4}7 are divisible by some element of {3, 5, 13} * In base 13, all numbers of the form 3{0}95 are divisible by some element of {5, 7, 17} * In base 16, all numbers of the form {4}D are divisible by some element of {3, 7, 13} * In base 16, all numbers of the form {8}F are divisible by some element of {3, 7, 13} Examples of second strategy: (we can show that both factors are > 1, if ''n'' makes corresponding numbers > ''b'' (i.e. ''n''≥2 for {1} in base 9, ''n''≥0 for 1{0}1 in base 8 and B{4}1 in base 16, ''n''≥1 for other examples), thus these factorizations are nontrivial) * In base 9, all numbers of the form {1} factored as difference of squares * In base 8, all numbers of the form 1{0}1 factored as sum of cubes * In base 9, all numbers of the form 3{8} factored as difference of squares * In base 16, all numbers of the form 8{F} factored as difference of squares * In base 16, all numbers of the form {F}7 factored as difference of squares * In base 9, all numbers of the form 3{1} factored as difference of squares * In base 16, all numbers of the form {4}1 factored as difference of squares * In base 16, all numbers of the form 1{5} factored as difference of squares * In base 16, all numbers of the from {C}D factored as ''x''⁴+4''y''⁴ * In base 16, all numbers of the form B{4}1 factored as difference of squares Examples of combine of the two strategies: (we can show that for the part of the first strategy, the corresponding numbers are > all elements in S, and for the part of the second strategy, both factors are > 1, if n makes corresponding numbers > b, thus these factorizations are nontrivial) * In base 14, numbers of the form 8{D} are divisible by 5 if ''n'' is odd and factored as difference of squares if ''n'' is even * In base 12, numbers of the form {B}9B are divisible by 13 if ''n'' is odd and factored as difference of squares if ''n'' is even * In base 14, numbers of the form {D}5 are divisible by 5 if ''n'' is even and factored as difference of squares if ''n'' is odd * In base 17, numbers of the form 1{9} are divisible by 2 if ''n'' is odd and factored as difference of squares if ''n'' is even * In base 19, numbers of the form 1{6} are divisible by 5 if ''n'' is odd and factored as difference of squares if ''n'' is even == Bases 2≤''b''≤1024 such that these families can be ruled out as contain no primes > ''b'' == (using A−Z to represent digit values 10 to 35, z−a to represent digit values ''b''−1 to ''b''−26 (e.g. "z" means 1 in base 2, 2 in base 3, 3 in base 4, ..., 8 in base 9, 9 in base 10, A in base 11, B in base 12, ..., Y in base 35, Z in base 36, ...), only consider bases which these families are interpretable, e.g. digit "7" is only interpretable for bases ≥8, and digit "u" (means ''b''−6) is only interpretable for bases ≥7) === 1{0}1 === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' = ''m''^''r'' with odd ''r''>1: Sum-of-''r''th-powers factorization === 1{0}2 === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' == 1 mod 3: Finite covering set {3} === 1{0}3 === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 0 mod 3: Finite covering set {3} === 1{0}4 === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' == 1 mod 5: Finite covering set {5} * ''b'' == 14 mod 15: Finite covering set {3, 5} * ''b'' = ''m''⁴: Aurifeuillian factorization of ''x''⁴+4''y''⁴ === 1{0}5 === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 1 mod 3: Finite covering set {3} * ''b'' == 0 mod 5: Finite covering set {5} === 1{0}6 === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' == 0 mod 3: Finite covering set {3} * ''b'' == 1 mod 7: Finite covering set {7} === 1{0}7 === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 0 mod 7: Finite covering set {7} === 1{0}z === (none) === 1{0}11 (not quasi-minimal prime if there is smaller prime of the form 1{0}1) === * ''b'' == 1 mod 3: Finite covering set {3} === 10{z} (not quasi-minimal prime if there is smaller prime of the form 1{z}) === (none) === 11{0}1 (not quasi-minimal prime if there is smaller prime of the form 1{0}1) === * ''b'' == 1 mod 3: Finite covering set {3} === {1}0z (not quasi-minimal prime if there is smaller prime of the form {1} or {1}z) === * ''b'' such that ''b'' and 2''b''−1 are both squares: Difference-of-squares factorization (such bases are 25, 841) === {1} === * ''b'' = ''m''^''r'' with ''r''>1: Difference-of-''r''th-powers factorization (some bases still have primes, since for the corresponding length this factorization is trivial, but they only have this prime, they are 4 (length 2), 8 (length 3), 16 (length 2), 27 (length 3), 36 (length 2), 100 (length 2), 128 (length 7), 196 (length 2), 256 (length 2), 400 (length 2), 512 (length 3), 576 (length 2), 676 (length 2)) === {1}2 (not quasi-minimal prime if there is smaller prime of the form {1}) === * ''b'' == 0 mod 2: Finite covering set {2} === 1{2} === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' such that ''b'' and 2(''b''+1) are both squares: Difference-of-squares factorization (such bases are 49) === 1{3} === * ''b'' == 0 mod 3: Finite covering set {3} * ''b'' such that ''b'' and 3(''b''+2) are both squares: Difference-of-squares factorization (such bases are 25, 361) * ''b'' == 1 mod 2 such that 3(''b''+2) is square: Combine of finite covering set {2} (when length is even) and difference-of-squares factorization (when length is odd) (such bases are 25, 73, 145, 241, 361, 505, 673, 865) === 1{4} === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' such that ''b'' and 4(''b''+3) are both squares: Difference-of-squares factorization === 1{z} === (none) === 2{0}1 === * ''b'' == 1 mod 3: Finite covering set {3} === 2{0}3 === * ''b'' == 0 mod 3: Finite covering set {3} * ''b'' == 1 mod 5: Finite covering set {5} === 2{1} (not quasi-minimal prime if there is smaller prime of the form {1}) === * ''b'' such that ''b'' and 2''b''−1 are both squares: Difference-of-squares factorization (such bases are 25, 841) === {2}1 === * ''b'' such that ''b'' and 2(''b''+1) are both squares: Difference-of-squares factorization (such bases are 49) === 2{z} === * ''b'' == 1 mod 2: Finite covering set {2} === 3{0}1 === * ''b'' == 1 mod 2: Finite covering set {2} === 3{0}2 === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' == 1 mod 5: Finite covering set {5} === 3{0}4 === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' == 1 mod 7: Finite covering set {7} === {3}1 === * ''b'' such that ''b'' and 3(2''b''+1) are both squares: Difference-of-squares factorization (such bases are 121) === 3{z} === * ''b'' == 1 mod 3: Finite covering set {3} * ''b'' == 14 mod 15: Finite covering set {3, 5} * ''b'' = ''m''²: Difference-of-squares factorization * ''b'' == 4 mod 5: Combine of finite covering set {5} (when length is even) and difference-of-squares factorization (when length is odd) === 4{0}1 === * ''b'' == 1 mod 5: Finite covering set {5} * ''b'' == 14 mod 15: Finite covering set {3, 5} * ''b'' = ''m''⁴: Aurifeuillian factorization of ''x''⁴+4''y''⁴ === 4{0}3 === * ''b'' == 0 mod 3: Finite covering set {3} * ''b'' == 1 mod 7: Finite covering set {7} === {4}1 === * ''b'' such that ''b'' and 4(3''b''+1) are both squares: Difference-of-squares factorization (such bases are 16, 225) === 4{z} === * ''b'' == 1 mod 2: Finite covering set {2} === 5{0}1 === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 1 mod 3: Finite covering set {3} === 5{z} === * ''b'' == 1 mod 5: Finite covering set {5} * ''b'' == 34 mod 35: Finite covering set {5, 7} * ''b'' = 6''m''² with ''m'' == 2 or 3 mod 5: Combine of finite covering set {5} (when length is odd) and difference-of-squares factorization (when length is even) (such bases are 24, 54, 294, 384, 864, 1014) === 6{0}1 === * ''b'' == 1 mod 7: Finite covering set {7} * ''b'' == 34 mod 35: Finite covering set {5, 7} === 6{z} === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 1 mod 3: Finite covering set {3} === 7{0}1 === * ''b'' == 1 mod 2: Finite covering set {2} === 7{z} === * ''b'' == 1 mod 7: Finite covering set {7} * ''b'' == 20 mod 21: Finite covering set {3, 7} * ''b'' == 83, 307 mod 455: Finite covering set {5, 7, 13} (such bases are 83, 307, 538, 762, 993) * ''b'' = ''m''³: Difference-of-cubes factorization === 8{0}1 === * ''b'' == 1 mod 3: Finite covering set {3} * ''b'' == 20 mod 21: Finite covering set {3, 7} * ''b'' == 47, 83 mod 195: Finite covering set {3, 5, 13} (such bases are 47, 83, 242, 278, 437, 473, 632, 668, 827, 863, 1022) * ''b'' = 467: Finite covering set {3, 5, 7, 19, 37} * ''b'' = 722: Finite covering set {3, 5, 13, 73, 109} * ''b'' = ''m''³: Sum-of-cubes factorization * ''b'' = 128: Cannot have primes since 7''n''+3 cannot be power of 2 === 8{z} === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' = ''m''²: Difference-of-squares factorization * ''b'' == 4 mod 5: Combine of finite covering set {5} (when length is even) and difference-of-squares factorization (when length is odd) === 9{0}1 === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 1 mod 5: Finite covering set {5} === 9{z} === * ''b'' == 1 mod 3: Finite covering set {3} * ''b'' == 32 mod 33: Finite covering set {3, 11} === A{0}1 === * ''b'' == 1 mod 11: Finite covering set {11} * ''b'' == 32 mod 33: Finite covering set {3, 11} === A{z} === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 1 mod 5: Finite covering set {5} * ''b'' == 14 mod 15: Finite covering set {3, 5} === B{0}1 === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 1 mod 3: Finite covering set {3} * ''b'' == 14 mod 15: Finite covering set {3, 5} === B{z} === * ''b'' == 1 mod 11: Finite covering set {11} * ''b'' == 142 mod 143: Finite covering set {11, 13} * ''b'' = 307: Finite covering set {5, 11, 29} * ''b'' = 901: Finite covering set {7, 11, 13, 19} === C{0}1 === * ''b'' == 1 mod 13: Finite covering set {13} * ''b'' == 142 mod 143: Finite covering set {11, 13} * ''b'' = 296, 901: Finite covering set {7, 11, 13, 19} * ''b'' = 562, 828, 900: Finite covering set {7, 13, 19} * ''b'' = 563: Finite covering set {5, 7, 13, 19, 29} * ''b'' = 597: Finite covering set {5, 13, 29} === {#}$ (for bases ''b'' == 1 mod 3, # = (''b''−1)/3, $ = (''b''+2)/3) === (none) === {#}$ (for odd bases ''b'', # = (''b''−1)/2, $ = (''b''+1)/2) === * ''b'' = ''m''^''r'' with odd ''r''>1: Sum-of-''r''th-power factorization === #{z} (for even bases b, # = b/2−1) === (none) === y{z} === (none) === {y}z === (none) === z{0}1 === (none) === {z0}z1 (almost cannot be quasi-minimal prime, since this is not simple family) === * ''b'' = ''m''^''r'' with odd ''r''>1: Sum-of-''r''th-power factorization (some bases still have primes, since for the corresponding length this factorization is trivial, but they only have this prime, they are 128 (length 7), 216 (length 3), 343 (length 3), 729 (length 3)) * ''b'' = 4''m''⁴: Aurifeuillian factorization of ''x''⁴+4''y''⁴ (base 4 still have primes, since for the corresponding length this factorization is trivial, but it only have this prime, at length 2) === {z}yz (not quasi-minimal prime if there is smaller prime of the form {z}y) === (none) === {z}1 === (none) === {z}t === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 1 mod 3: Finite covering set {3} * ''b'' == 0 mod 7: Finite covering set {7} === {z}u === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' == 0 mod 3: Finite covering set {3} * ''b'' == 1 mod 5: Finite covering set {5} * ''b'' == 34 mod 35: Finite covering set {5, 7} === {z}v === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 0 mod 5: Finite covering set {5} === {z}w === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' == 1 mod 3: Finite covering set {3} * ''b'' == 14 mod 15: Finite covering set {3, 5} * ''b'' = ''m''²: Difference-of-squares factorization * ''b'' == 4 mod 5: Combine of finite covering set {5} (when length is even) and difference-of-squares factorization (when length is odd) === {z}x === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 0 mod 3: Finite covering set {3} === {z}y === * ''b'' == 0 mod 2: Finite covering set {2} == Large known (probable) primes (length ≥10000) in these families (for bases 2≤''b''≤1024) == Format: base (length) (using A−Z to represent digit values 10 to 35, z−a to represent digit values ''b''−1 to ''b''−26 (e.g. "z" means 1 in base 2, 2 in base 3, 3 in base 4, ..., 8 in base 9, 9 in base 10, A in base 11, B in base 12, ..., Y in base 35, Z in base 36, ...), only consider bases which these families are interpretable, e.g. digit "7" is only interpretable for bases ≥8, and digit "u" (means ''b''−6) is only interpretable for bases ≥7) === 1{0}1 === (none) === 1{0}2 === (none) === 1{0}3 === (none) === 1{0}4 === 53 (13403) 113 (10647) === 1{0}z === 113 (20089) 123 (64371) === 1{0}11 (not quasi-minimal prime if there is smaller prime of the form 1{0}1) === (none) === 10{z} (not quasi-minimal prime if there is smaller prime of the form 1{z}) === 208 (26682) 607 (11032) 828 (19659) === 11{0}1 (not quasi-minimal prime if there is smaller prime of the form 1{0}1) === 201 (31276) 222 (52727) 227 (36323) 327 (135983) 425 (11231) 710 (24112) 717 (37508) 719 (13420) === {1} === 152 (270217) 184 (16703) 200 (17807) 311 (36497) 326 (26713) 331 (25033) 371 (15527) 485 (99523) 629 (32233) 649 (43987) 670 (18617) 684 (22573) 691 (62903) 693 (41189) 731 (15427) 752 (32833) 872 (10093) 932 (20431) === {1}2 (not quasi-minimal prime if there is smaller prime of the form {1}) === (none) === 1{z} === 107 (21911) 170 (166429) 278 (43909) 303 (40175) 383 (20957) 515 (58467) 522 (62289) 578 (129469) 590 (15527) 647 (21577) 662 (16591) 698 (127559) 704 (62035) 845 (39407) 938 (40423) 969 (24097) 989 (26869) === 2{0}1 === 101 (192276) 206 (46206) 218 (333926) 236 (161230) 257 (12184) 305 (16808) 467 (126776) 578 (44166) 626 (174204) 695 (94626) 752 (26164) 788 (72918) 869 (49150) 887 (27772) 899 (15732) 932 (13644) === 2{z} === 432 (16003) === 3{0}1 === (none) === 3{z} === 72 (1119850) 212 (34414) 218 (23050) 270 (89662) 303 (198358) 312 (51566) 422 (21738) 480 (93610) 513 (38032) 527 (46074) 566 (23874) 650 (498102) 686 (16584) 758 (15574) 783 (12508) 800 (33838) 921 (98668) 947 (10056) === 4{0}1 === 107 (32587) 227 (13347) 257 (160423) 355 (10990) 410 (144079) 440 (56087) 452 (14155) 482 (30691) 542 (15983) 579 (67776) 608 (20707) 635 (11723) 650 (96223) 679 (69450) 737 (269303) 740 (58043) 789 (149140) 797 (468703) 920 (103687) 934 (101404) 962 (84235) === 4{z} === 14 (19699) 68 (13575) 254 (15451) 800 (20509) === 5{0}1 === 326 (400786) 350 (20392) 554 (10630) 662 (13390) 926 (40036) === 5{z} === 258 (212135) 272 (148427) 299 (64898) 307 (26263) 354 (25566) 433 (283919) 635 (36163) 678 (40859) 692 (45447) 719 (20552) 768 (70214) 857 (23083) 867 (61411) 972 (36703) === 6{0}1 === 108 (16318) 129 (16797) 409 (369833) 522 (52604) 587 (24120) 643 (164916) 762 (11152) 789 (27297) 986 (21634) === 6{z} === 68 (25396) 332 (15222) 338 (42868) 362 (146342) 488 (33164) 566 (164828) 980 (50878) 986 (12506) 1016 (23336) === 7{0}1 === 398 (17473) 1004 (54849) === 7{z} === 97 (192336) 170 (15423) 194 (38361) 202 (155772) 282 (21413) 283 (164769) 332 (13205) 412 (29792) 560 (19905) 639 (10668) 655 (53009) 811 (31784) 814 (17366) 866 (108591) 908 (61797) 962 (31841) 992 (10605) 997 (15815) === 8{0}1 === 23 (119216) 53 (227184) 158 (123476) 254 (67716) 320 (52004) 410 (279992) 425 (94662) 513 (19076) 518 (11768) 596 (148446) 641 (87702) 684 (23387) 695 (39626) 785 (900326) 788 (11408) 893 (86772) 908 (243440) 920 (107822) 962 (47222) 998 (81240) 1013 (43872) === 8{z} === 138 (35686) 412 (12154) 788 (11326) 990 (23032) === 9{0}1 === 248 (39511) 592 (96870) === 9{z} === 431 (43574) 446 (152028) 458 (126262) 599 (11776) 846 (12781) === A{0}1 === 173 (264235) 198 (47665) 311 (314807) 341 (106009) 449 (18507) 492 (42843) 605 (12395) 708 (17563) 710 (31039) 743 (285479) 744 (137056) 786 (68169) 800 (15105) 802 (149320) 879 (25004) 929 (13065) 977 (125873) 986 (48279) 1004 (10645) === A{z} === 368 (10867) 488 (10231) 534 (80328) 662 (13307) 978 (14066) === B{0}1 === 710 (15272) 740 (33520) 878 (227482) === B{z} === 153 (21660) 186 (112718) 439 (18752) 593 (16064) 602 (36518) 707 (10573) 717 (67707) === C{0}1 === 68 (656922) 219 (29231) 230 (94751) 312 (21163) 334 (83334) 353 (20262) 359 (61295) 457 (10024) 481 (45941) 501 (20140) 593 (42779) 600 (11242) 604 (17371) 641 (26422) 700 (91953) 887 (13961) 919 (45359) 923 (64365) 992 (10300) === {#}$ (for bases ''b'' == 1 mod 3, # = (''b''−1)/3, $ = (''b''+2)/3) === (none) === {#}$ (for odd bases ''b'', # = (''b''−1)/2, $ = (''b''+1)/2) === (none) === #{z} (for even bases b, # = b/2−1) === (none) === y{z} === 38 (136212) 83 (21496) 113 (286644) 188 (13508) 401 (103670) 417 (21003) 458 (46900) 494 (21580) 518 (129372) 527 (65822) 602 (17644) 608 (36228) 638 (74528) 663 (47557) 723 (24536) 758 (50564) 833 (12220) 904 (13430) 938 (50008) 950 (16248) === z{0}1 === 202 (46774) 251 (102979) 272 (16681) 297 (14314) 298 (60671) 326 (64757) 347 (69661) 363 (142877) 452 (71941) 543 (10042) 564 (38065) 634 (84823) 788 (13541) 869 (12289) 890 (37377) 953 (60995) 1004 (29685) === {z0}z1 (almost cannot be quasi-minimal prime, since this is not simple family) === 53 (21942) 124 (16426) 175 (31626) 188 (22036) 316 (48538) 365 (25578) 373 (24006) 434 (10090) 530 (11086) 545 (12346) 560 (15072) 596 (12762) 701 (12576) 706 (10656) 821 (13536) 833 (17116) 966 (14820) 983 (11272) === {z}yz (not quasi-minimal prime if there is smaller prime of the form {z}y) === (none) === {z}1 === (none) === {z}y === 317 (13896) == Bases 2≤''b''≤1024 which have these families as unsolved families == Unsolved families are families which are neither primes (>''b'') found nor can be ruled out as contain no primes > ''b'' (using A−Z to represent digit values 10 to 35, z−a to represent digit values ''b''−1 to ''b''−26 (e.g. "z" means 1 in base 2, 2 in base 3, 3 in base 4, ..., 8 in base 9, 9 in base 10, A in base 11, B in base 12, ..., Y in base 35, Z in base 36, ...), only consider bases which these families are interpretable, e.g. digit "7" is only interpretable for bases ≥8, and digit "u" (means ''b''−6) is only interpretable for bases ≥7) 1{0}1: 38, 50, 62, 68, 86, 92, 98, 104, 122, 144, 168, 182, 186, 200, 202, 212, 214, 218, 244, 246, 252, 258, 286, 294, 298, 302, 304, 308, 322, 324, 338, 344, 354, 356, 362, 368, 380, 390, 394, 398, 402, 404, 410, 416, 422, 424, 446, 450, 454, 458, 468, 480, 482, 484, 500, 514, 518, 524, 528, 530, 534, 538, 552, 558, 564, 572, 574, 578, 580, 590, 602, 604, 608, 620, 622, 626, 632, 638, 648, 650, 662, 666, 668, 670, 678, 684, 692, 694, 698, 706, 712, 720, 722, 724, 734, 744, 746, 752, 754, 762, 766, 770, 792, 794, 802, 806, 812, 814, 818, 836, 840, 842, 844, 848, 854, 868, 870, 872, 878, 888, 896, 902, 904, 908, 922, 924, 926, 932, 938, 942, 944, 948, 954, 958, 964, 968, 974, 978, 980, 988, 994, 998, 1002, 1006, 1014, 1016 (length limit: ≥8388608) 1{0}2: 167, 257, 323, 353, 383, 527, 557, 563, 623, 635, 647, 677, 713, 719, 803, 815, 947, 971, 1013 (length limit: 2000) 1{0}3: 646, 718, 998 (length limit: 2000) 1{0}4: 139, 227, 263, 315, 335, 365, 485, 515, 647, 653, 683, 773, 789, 797, 815, 857, 875, 893, 939, 995, 1007 (length limit: 2000) 1{0}5 1{0}6 1{0}7 1{0}8 1{0}9 1{0}A 1{0}B 1{0}C 1{0}D 1{0}E 1{0}F 1{0}G 1{0}z: 173, 179, 257, 277, 302, 333, 362, 392, 422, 452, 467, 488, 512, 527, 545, 570, 575, 614, 622, 650, 677, 680, 704, 707, 734, 740, 827, 830, 851, 872, 886, 887, 902, 904, 908, 929, 932, 942, 947, 949, 962, 973, 1022 (length limit: 2000) 1{0}11 (not quasi-minimal prime if there is smaller prime of the form 1{0}1): 198, 213, 318, 327, 353, 375, 513, 591, 647, 732, 734, 738, 759, 948, 951, 957, 1013, 1014 (length limit: 2000) 10{z} (not quasi-minimal prime if there is smaller prime of the form 1{z}): 575 (length limit: 247000) 11{0}1 (not quasi-minimal prime if there is smaller prime of the form 1{0}1): 813, 863, 962, 1017 (length limit: ≥100000) {1}0z (not quasi-minimal prime if there is smaller prime of the form {1} or {1}z): 137, 161, 167, 217, 229, 232, 253, 261, 317, 325, 337, 347, 355, 375, 403, 411, 421, 427, 457, 479, 483, 505, 507, 537, 547, 577, 597, 599, 601, 613, 627, 631, 632, 641, 643, 649, 657, 679, 688, 697, 707, 711, 729, 733, 737, 742, 762, 773, 787, 793, 797, 817, 819, 841, 843, 853, 859, 861, 874, 877, 895, 899, 907, 913, 916, 917, 927, 957, 959, 997, 1003, 1009, 1015, 1017 (length limit: 2000) {1}: 185, 269, 281, 380, 384, 385, 394, 452, 465, 511, 574, 601, 631, 632, 636, 711, 713, 759, 771, 795, 861, 866, 881, 938, 948, 951, 956, 963, 1005, 1015 (length limit: ≥100000) 11{z} (not quasi-minimal prime if there is smaller prime of the form 1{z}) {1}2 (not quasi-minimal prime if there is smaller prime of the form {1}): 31, 61, 91, 93, 143, 247, 253, 293, 313, 329, 371, 383, 391, 393, 403, 415, 435, 443, 451, 491, 493, 513, 523, 527, 537, 541, 553, 565, 581, 587, 601, 613, 615, 623, 627, 635, 663, 729, 735, 757, 763, 775, 783, 823, 843, 865, 873, 877, 883, 897, 931, 941, 943, 955, 983, 1013, 1015, 1021, 1023 (length limit: 2000) {1}z 1{2}: 265, 355, 379, 391, 481, 649, 661, 709, 745, 811, 877, 977 (length limit: 2000) 1{3}: 107, 133, 179, 281, 305, 365, 473, 485, 487, 491, 535, 541, 601, 617, 665, 737, 775, 787, 802, 827, 905, 911, 928, 953, 955, 995 1{4}: 83, 143, 185, 239, 269, 293, 299, 305, 319, 325, 373, 383, 395, 431, 471, 503, 551, 577, 581, 593, 605, 617, 631, 659, 743, 761, 773, 781, 803, 821, 857, 869, 897, 911, 917, 923, 935, 983, 1019 (length limit: 2000) 1{z}: 581, 992, 1019 (length limit: ≥100000) 2{0}1: 365, 383, 461, 512, 542, 647, 773, 801, 836, 878, 908, 914, 917, 947, 1004 (length limit: ≥100000) 2{0}3: 79, 149, 179, 254, 359, 394, 424, 434, 449, 488, 499, 532, 554, 578, 664, 683, 694, 749, 794, 839, 908, 944, 982 (length limit: 2000) 2{1} (not quasi-minimal prime if there is smaller prime of the form {1}): 109, 117, 137, 147, 157, 175, 177, 201, 227, 235, 256, 269, 271, 297, 310, 331, 335, 397, 417, 427, 430, 437, 442, 451, 465, 467, 481, 502, 517, 547, 557, 567, 572, 577, 591, 597, 607, 627, 649, 654, 655, 667, 679, 687, 691, 697, 715, 727, 739, 759, 766, 782, 787, 796, 797, 808, 817, 821, 829, 841, 852, 877, 881, 899, 903, 907, 937, 947, 955, 1007, 1011, 1021 (length limit: 2000) {2}1: 106, 238, 262, 295, 364, 382, 391, 397, 421, 458, 463, 478, 517, 523, 556, 601, 647, 687, 754, 790, 793, 832, 872, 898, 962, 1002, 1021 (length limit: 2000) 2{z}: 588, 972 (length limit: ≥100000) 3{0}1: 718, 912 (length limit: ≥100000) 3{0}2: 223, 283, 359, 489, 515, 529, 579, 619, 669, 879, 915, 997 (length limit: 2000) 3{0}4: 167, 391, 447, 487, 529, 653, 657, 797, 853, 913, 937 (length limit: 2000) {3}1: 79, 101, 189, 215, 217, 235, 243, 253, 255, 265, 313, 338, 341, 378, 379, 401, 402, 413, 489, 498, 499, 508, 525, 535, 589, 591, 599, 611, 621, 635, 667, 668, 681, 691, 711, 717, 719, 721, 737, 785, 804, 805, 813, 831, 835, 837, 849, 873, 911, 915, 929, 933, 941, 948, 959, 999, 1013, 1019 (length limit: 2000) 3{z}: 275, 438, 647, 653, 812, 927, 968 (length limit: ≥100000) 4{0}1: 32, 53, 155, 174, 204, 212, 230, 332, 334, 335, 395, 467, 512, 593, 767, 803, 848, 875, 1024 (length limit: ≥100000) 4{0}3: 83, 88, 97, 167, 188, 268, 289, 293, 412, 419, 425, 433, 503, 517, 529, 548, 613, 620, 622, 650, 668, 692, 706, 727, 763, 818, 902, 913, 937, 947, 958 (length limit: 2000) {4}1: 46, 77, 103, 107, 119, 152, 198, 203, 211, 217, 229, 257, 263, 291, 296, 305, 332, 371, 374, 407, 413, 416, 440, 445, 446, 464, 467, 500, 542, 545, 548, 557, 566, 586, 587, 605, 611, 614, 632, 638, 641, 653, 659, 698, 701, 731, 733, 736, 755, 786, 812, 820, 821, 827, 830, 887, 896, 899, 901, 922, 923, 935, 941, 953, 977, 983, 991, 1004 (length limit: 2000) 4{z}: 338, 998 (length limit: ≥100000) 5{0}1: 308, 512, 824 (length limit: ≥100000) 5{z}: 234, 412, 549, 553, 573, 619, 750, 878, 894, 954 (length limit: ≥100000) 6{0}1: 212, 509, 579, 625, 774, 794, 993, 999 (length limit: ≥100000) 6{z}: 308, 392, 398, 518, 548, 638, 662, 878 (length limit: ≥100000) 7{0}1: (none) 7{z}: 321, 328, 374, 432, 665, 697, 710, 721, 727, 728, 752, 800, 815, 836, 867, 957, 958, 972 (length limit: ≥100000) 8{0}1: 86, 140, 182, 263, 353, 368, 389, 395, 422, 426, 428, 434, 443, 488, 497, 558, 572, 575, 593, 606, 698, 710, 746, 758, 770, 773, 824, 828, 866, 911, 930, 953, 957, 983, 993, 1014 (length limit: ≥100000) 8{z}: 378, 438, 536, 566, 570, 592, 636, 688, 718, 830, 852, 926, 1010 (length limit: ≥100000) 9{0}1: 724, 884 (length limit: ≥100000) 9{z}: 80, 233, 530, 551, 611, 899, 912, 980 (length limit: ≥100000) A{0}1: 185, 338, 417, 432, 614, 668, 773, 863, 935, 1000 (length limit: ≥100000) A{z}: 214, 422, 444, 452, 458, 542, 638, 668, 804, 872, 950, 962 (length limit: ≥100000) B{0}1: 560, 770, 968 (length limit: ≥100000) B{z}: 263, 615, 912, 978 (length limit: ≥100000) C{0}1: 163, 207, 354, 362, 368, 480, 620, 692, 697, 736, 753, 792, 978, 998, 1019, 1022 (length limit: ≥100000) C{z} D{0}1 D{z} E{0}1 E{z} F{0}1 F{z} G{0}1 {&#35;}$ (for bases ''b'' == 1 mod 3, # = (''b''−1)/3, $ = (''b''+2)/3): 808, 829, 859, 1006 (length limit: 2000) {&#35;}$ (for odd bases ''b'', # = (''b''−1)/2, $ = (''b''+1)/2): 31, 37, 55, 63, 67, 77, 83, 89, 91, 93, 97, 99, 107, 109, 117, 123, 127, 133, 135, 137, 143, 147, 149, 151, 155, 161, 177, 179, 183, 189, 193, 197, 207, 211, 213, 215, 217, 223, 225, 227, 233, 235, 241, 247, 249, 255, 257, 263, 265, 269, 273, 277, 281, 283, 285, 287, 291, 293, 297, 303, 307, 311, 319, 327, 347, 351, 355, 357, 359, 361, 367, 369, 377, 381, 383, 385, 387, 389, 393, 397, 401, 407, 411, 413, 417, 421, 423, 437, 439, 443, 447, 457, 465, 467, 469, 473, 475, 481, 483, 489, 493, 495, 497, 509, 511, 515, 533, 541, 547, 549, 555, 563, 591, 593, 597, 601, 603, 611, 615, 619, 621, 625, 627, 629, 633, 635, 637, 645, 647, 651, 653, 655, 659, 663, 667, 671, 673, 675, 679, 683, 687, 691, 693, 697, 707, 709, 717, 731, 733, 735, 737, 741, 743, 749, 753, 755, 757, 759, 765, 767, 771, 773, 775, 777, 783, 785, 787, 793, 797, 801, 807, 809, 813, 817, 823, 825, 849, 851, 853, 865, 867, 873, 877, 887, 889, 893, 897, 899, 903, 907, 911, 915, 923, 927, 933, 937, 939, 941, 943, 945, 947, 953, 957, 961, 967, 975, 977, 983, 987, 993, 999, 1003, 1005, 1009, 1017 (length limit: ≥262143) &#35;{z} (for even bases ''b'', # = ''b''/2−1): 108, 278, 296, 338, 386, 494, 626, 920 (length limit: 2000) ${&#35;} (for odd bases ''b'', # = (''b''−1)/2, $ = (''b''+1)/2) x{z} y{z}: 128, 233, 268, 383, 478, 488, 533, 554, 665, 698, 779, 863, 878, 932, 941, 1010 (length limit: ≥200000) z{0}1: 123, 342, 362, 422, 438, 479, 487, 512, 542, 602, 757, 767, 817, 830, 872, 893, 932, 992, 997, 1005, 1007 (length limit: ≥100000) {y}z: 143, 173, 176, 213, 235, 248, 253, 279, 327, 343, 353, 358, 373, 383, 401, 413, 416, 427, 439, 448, 453, 463, 481, 513, 522, 527, 535, 547, 559, 565, 583, 591, 598, 603, 621, 623, 653, 659, 663, 679, 691, 698, 711, 743, 745, 757, 768, 785, 793, 796, 801, 808, 811, 821, 835, 845, 847, 853, 856, 883, 898, 903, 927, 955, 961, 971, 973, 993, 1005, 1013, 1019, 1021 (length limit: 2000) {z0}z1 (almost cannot be quasi-minimal prime, since this is not simple family): 97, 103, 113, 186, 187, 220, 304, 306, 309, 335, 414, 416, 428, 433, 445, 459, 486, 498, 539, 550, 557, 587, 592, 597, 598, 617, 624, 637, 659, 665, 671, 677, 696, 717, 726, 730, 740, 754, 766, 790, 851, 873, 890, 914, 923, 929, 943, 944, 965, 984, 985, 996, 1004, 1005 (length limit: ≥17326) zy{z} (not quasi-minimal prime if there is smaller prime of the form y{z}) {z}yz (not quasi-minimal prime if there is smaller prime of the form {z}y): 215, 353, 517, 743, 852, 899, 913 (length limit: 2000) {z}01 (not quasi-minimal prime if there is smaller prime of the form {z}1) {z}1: 93, 113, 152, 158, 188, 217, 218, 226, 227, 228, 233, 240, 275, 278, 293, 312, 338, 350, 353, 383, 404, 438, 464, 471, 500, 533, 576, 614, 641, 653, 704, 723, 728, 730, 758, 779, 788, 791, 830, 878, 881, 899, 908, 918, 929, 944, 953, 965, 968, 978, 983, 986, 1013 (length limit: 2000) {z}k {z}l {z}m {z}n {z}o {z}p {z}q {z}r {z}s {z}t {z}u {z}v {z}w: 207, 221, 293, 375, 387, 533, 633, 647, 653, 687, 701, 747, 761, 785, 863, 897, 905, 965, 1017 (length limit: 2000) {z}x: (none) {z}y: 305, 353, 397, 485, 487, 535, 539, 597, 641, 679, 731, 739, 755 (length limit: 2000) == List of lengths for quasi-minimal primes in some simple families == [https://docs.google.com/spreadsheets/d/e/2PACX-1vTKkSNKGVQkUINlp1B3cXe90FWPwiegdA07EE7-U7sqXntKAEQrynoI1sbFvvKriieda3LfkqRwmKME/pubhtml list of lengths for quasi-minimal primes in some simple families for bases 2≤''b''≤1024] NB: this family is not interpretable in this base (e.g. family 7{0}1 and 7{z} in bases <=7, family {z}x in bases <=3) (including the case which this family has either leading zeros (leading zeros do not count) or ending zeros (numbers ending in zero cannot be prime > base) in this base) RC: this family can be proven to only contain composite numbers (only count numbers > base) unknown: this family has no primes or PRPs found, nor can this family be proven to only contain composite numbers (only count numbers > base) Background color: red for title (bases or families), green for length > 10000, orange for 2500 < length ≤ 10000, white for length ≤ 2500, cyan for "RC", pink for "NB", yellow for "unknown". Search limit for lengths: ≥8388608 for 1{0}1, ≥200000 for y{z}, ≥100000 for ''d''{0}1 (''d'' = one of digits in {2, 3, 4, 5, 6, 7, 8, 9, A, B, C}) and ''d''{z} (''d'' = one of digits in {1, 2, 3, 4, 5, 6, 7, 8, 9, A, B}) and z{0}1 and {1}, ≥5000 for 1{0}2, {z}y, 1{0}z, {z}1, {y}z, ≥2500 for other families. == References == * [https://mersenneforum.org/showthread.php?t=24972 mersenneforum thread of this problem] * [https://docs.google.com/document/d/e/2PACX-1vQct6Hx-IkJd5-iIuDuOKkKdw2teGmmHW-P75MPaxqBXB37u0odFBml5rx0PoLa0odTyuW67N_vn96J/pub Minimal elements for the base ''b'' representations of the primes which are > ''b'' for bases ''b''≤16] * [https://primes.utm.edu/glossary/xpage/MinimalPrime.html article “minimal prime” in The Prime Glossary] * [https://en.wikipedia.org/wiki/Minimal_prime_(recreational_mathematics article “minimal prime” in Wikipedia] * [https://www.primepuzzles.net/puzzles/puzz_178.htm the puzzle of minimal primes (when the restriction of prime>base is not required) in The Prime Puzzles & Problems Connection] * [https://www.primepuzzles.net/problems/prob_083.htm the problem of minimal primes in The Prime Puzzles & Problems Connection] * [https://github.com/xayahrainie4793/non-single-digit-primes my data for these M(Lb) sets for 2 ≤ b ≤ 16] * [http://www.cs.uwaterloo.ca/~shallit/Papers/minimal5.pdf Shallit’s proof of base 10 minimal primes, when the restriction of prime>base is not required] * [https://scholar.colorado.edu/downloads/hh63sw661 proofs of minimal primes in bases b≤10, when the restriction of prime>base is not required] * [https://cs.uwaterloo.ca/~cbright/reports/mepn.pdf the article for this minimal prime problem in bases b≤30, when the restriction of prime>base is not required] * [https://cs.uwaterloo.ca/~cbright/talks/minimal-slides.pdf the article for this minimal prime problem in bases b≤30, when the restriction of prime>base is not required] * [https://doi.org/10.1080/10586458.2015.1064048 the article for this minimal prime problem in bases b≤30, when the restriction of prime>base is not required] * [https://github.com/curtisbright/mepn-data data for these M(Lb) sets and unsolved families for 2 ≤ b ≤ 30, when the restriction of prime>base is not required, search limits of lengths: 1000000 for b=17, 707000 for b=19, 506000 for b=21, 292000 for b=25, 486000 for b=26, 543000 for b=28, 233000 for b=29] * [https://github.com/RaymondDevillers/primes data for these M(Lb) sets and unsolved families for 2 ≤ b ≤ 50, when the restriction of prime>base is not required, search limits of lengths: 10000 for all b] * [http://www.bitman.name/math/article/730 article for minimal primes, when the restriction of prime>base is not required] * [http://www.bitman.name/math/table/497 data for minimal primes in bases 2 ≤ b ≤ 16, when the restriction of prime>base is not required] * [http://www.prothsearch.com/sierp.html the Sierpinski problem] * [http://www.prothsearch.com/rieselprob.html the Riesel problem] * [https://oeis.org/A076336/a076336c.html the dual Sierpinski problem] * [http://www.noprimeleftbehind.net/crus/Sierp-conjectures.htm generalized Sierpinski conjectures in bases b≤1030, some primes found in these conjectures are minimal primes in base b, especially, all primes for k&lt;b (if exist for a (k,b) combo) are always minimal primes in the base b) (also some examples for simple families contain no primes &gt; b] * [http://www.noprimeleftbehind.net/crus/Riesel-conjectures.htm generalized Riesel conjectures in bases b≤1030, some primes found in these conjectures are minimal primes in base b, especially, all primes for k&lt;b (if exist for a (k,b) combo) are always minimal primes in the base b) (also some examples for simple families contain no primes &gt; b] * [http://www.noprimeleftbehind.net/crus/tab/CRUS_tab.htm list for the status of the generalized Sierpinski conjectures and the generalized Riesel conjectures in bases b≤1030] * [https://www.utm.edu/staff/caldwell/preprints/2to100.pdf article for generalized Sierpinski conjectures in bases b≤100] * [http://www.kurims.kyoto-u.ac.jp/EMIS/journals/INTEGERS/papers/i61/i61.pdf article for the mixed (original+dual) Sierpinski problem] * [http://www.fermatquotient.com/PrimSerien/GenRepu.txt generalized repunit primes (primes of the form (bn−1)/(b−1)) in bases b≤160, the smallest such prime for base b (if exists) is always minimal prime in base b] * [https://web.archive.org/web/20021111141203/http://www.users.globalnet.co.uk/~aads/primes.html generalized repunit primes (primes of the form (bn−1)/(b−1)) in bases b≤1000, the smallest such prime for base b (if exists) is always minimal prime in base b] * [http://jeppesn.dk/generalized-fermat.html generalized Fermat primes (primes of the form b2^n+1) in even bases b≤1000, the smallest such prime for base b (if exists) is always minimal prime in base b] * [http://www.noprimeleftbehind.net/crus/GFN-primes.htm generalized Fermat primes (primes of the form b2^n+1) in even bases b≤1030, the smallest such prime for base b (if exists) is always minimal prime in base b] * [http://www.fermatquotient.com/PrimSerien/GenFermOdd.txt list of generalized half Fermat primes (primes of the form (b2^n+1)/2) sorted by n, the smallest such prime for base b (if exists) is always minimal prime in base b] * [https://harvey563.tripod.com/wills.txt primes of the form (b−1)*bn−1 for bases b≤2049, the smallest such prime for base b (if exists) is always minimal prime in base b] * [https://www.rieselprime.de/ziki/Williams_prime_MM_least the smallest primes of the form (b−1)*bn−1 for bases b≤2049, these primes (if exists) is always minimal prime in base b] * [https://www.rieselprime.de/ziki/Williams_prime_MP_least the smallest primes of the form (b−1)*bn+1 for bases b≤1024, these primes (if exists) is always minimal prime in base b] * [https://www.rieselprime.de/ziki/Riesel_prime_small_bases_least_n the smallest primes of the form k*bn−1 for k≤12 and bases b≤1024, these primes (if exists) is always minimal prime in base b if b>k] * [https://www.rieselprime.de/ziki/Proth_prime_small_bases_least_n the smallest primes of the form k*bn+1 for k≤12 and bases b≤1024, these primes (if exists) is always minimal prime in base b if b>k] * [https://docs.google.com/spreadsheets/d/e/2PACX-1vTKkSNKGVQkUINlp1B3cXe90FWPwiegdA07EE7-U7sqXntKAEQrynoI1sbFvvKriieda3LfkqRwmKME/pubhtml list for the smallest primes in given simple family in bases b≤1024] * [https://www.rose-hulman.edu/~rickert/Compositeseq/ a problem related to this project] * [http://www.worldofnumbers.com/Appending%201s%20to%20n.txt a problem related to this project] * [https://stdkmd.net/nrr/prime/primecount.txt near- and quasi- repdigit (probable) primes sorted by count] * [https://stdkmd.net/nrr/prime/primedifficulty.txt near- and quasi- repdigit (probable) primes sorted by difficulty] * [http://www.prothsearch.com/fermat.html factoring status of Fermat numbers] * [http://www.rieselprime.de/dl/CRUS_pack.zip srsieve, sr1sieve, sr2sieve, pfgw, and llr softwares] * [https://www.bc-team.org/app.php/dlext/?cat=3 srsieve, sr1sieve, sr2sieve, sr5sieve software] * [https://sourceforge.net/projects/openpfgw/ pfgw software] * [http://jpenne.free.fr/index2.html llr software] * [http://www.ellipsa.eu/public/primo/primo.html PRIMO software] * [https://primes.utm.edu/prove/index.html website for primality proving] * [https://primes.utm.edu/curios/page.php?number_id=22380 the largest base 10 minimal prime in Prime Curios!] * [https://oeis.org/A071062 OEIS sequence for base 10 minimal primes, when the restriction of prime>base is not required] * [https://oeis.org/A326609 OEIS sequence for the largest base b minimal prime, when the restriction of prime>base is not required] * [https://primes.utm.edu/primes/lists/all.txt top proven primes] * [http://www.primenumbers.net/prptop/prptop.php top PRPs] * [http://factordb.com online factor database, including many primes which are minimal primes in a small base] d6sluhcwogfabefunwlq7zmc2bl18ht 2408140 2408139 2022-07-20T07:41:52Z 118.170.72.95 /* Base 17 */ sorted wikitext text/x-wiki A '''quasi-minimal prime''' is a [[w:Prime number|prime number]] for which there is no shorter [[w:Subsequence|subsequence]] of its [[w:Numerical digit|digit]]s in a given [[w:Radix|base]] ''b'' that form a prime > ''b''. For example, 857 is a quasi-minimal prime in [[w:Decimal|decimal]] because there is no prime > 10 among the shorter subsequences of the digits: 8, 5, 7, 85, 87, 57. The subsequence does not have to consist of consecutive digits, so 149 is not a quasi-minimal prime in decimal (because 19 is prime and 19 > 10). But it does have to be in the same order; so, for example, 991 is still a quasi-minimal prime in decimal even though a subset of the digits can form the shorter prime 19 > 10 by changing the order. (using A−Z to represent digit values 10 to 35) For the quasi-minimal primes in bases up to 36, I have only solved (found all quasi-minimal primes and proved that these are all such primes) bases 2~12, 14~15, 18, 20, 22, 24, 30 (bases 11, 22, 30 need primality proving of the probable primes). For the remain bases 13, 16~17, 19, 21, 23, 25~29, 31~36, there are some ''x''{''d''}''y'' (with ''x'', ''y'' strings (may be [[w:Empty string|empty]]) with digits in base ''b'', ''d'' digit in base ''b'') families which are not solved (not even a probable prime is known nor can be ruled out as only contain composites (only count the numbers > base (''b'')). I left as a challenge to readers the task of solving (finding all quasi-minimal primes and proving that these are all such primes) bases 13, 16~17, 19, 21, 23, 25~29, 31~36 (this will be a hard problem, e.g. base 23 has a quasi-minimal prime 9E₈₀₀₈₇₃, and base 36 has quasi-minimal prime P₈₁₉₉₃SZ). Proving the set of the quasi-minimal primes in base ''b'' is ''S'', is equivalent to: * Prove that all elements in ''S'', when read as base ''b'' representation, are primes > ''b''. * Prove that all [[w:Proper subset|proper]] subsequence of all elements in ''S'', when read as base ''b'' representation, which are > ''b'', are composite. * Prove that all primes > ''b'', when written in base ''b'', contain at least one element in ''S'' as subsequence (equivalently, prove that all strings not containing any element in ''S'' as subsequence, when read as base ''b'' representation, which are > ''b'', are composite). e.g. proving the set of the quasi-minimal primes in base ''b'' = 10 is {11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47, 53, 59, 61, 67, 71, 73, 79, 83, 89, 97, 227, 251, 257, 277, 281, 349, 409, 449, 499, 521, 557, 577, 587, 727, 757, 787, 821, 827, 857, 877, 881, 887, 991, 2087, 2221, 5051, 5081, 5501, 5581, 5801, 5851, 6469, 6949, 8501, 9001, 9049, 9221, 9551, 9649, 9851, 9949, 20021, 20201, 50207, 60649, 80051, 666649, 946669, 5200007, 22000001, 60000049, 66000049, 66600049, 80555551, 555555555551, 5000000000000000000000000000027}, is equivalent to: * Prove that all of 11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47, 53, 59, 61, 67, 71, 73, 79, 83, 89, 97, 227, 251, 257, 277, 281, 349, 409, 449, 499, 521, 557, 577, 587, 727, 757, 787, 821, 827, 857, 877, 881, 887, 991, 2087, 2221, 5051, 5081, 5501, 5581, 5801, 5851, 6469, 6949, 8501, 9001, 9049, 9221, 9551, 9649, 9851, 9949, 20021, 20201, 50207, 60649, 80051, 666649, 946669, 5200007, 22000001, 60000049, 66000049, 66600049, 80555551, 555555555551, 5000000000000000000000000000027 are primes > 10. * Prove that all proper subsequence of all elements in {11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47, 53, 59, 61, 67, 71, 73, 79, 83, 89, 97, 227, 251, 257, 277, 281, 349, 409, 449, 499, 521, 557, 577, 587, 727, 757, 787, 821, 827, 857, 877, 881, 887, 991, 2087, 2221, 5051, 5081, 5501, 5581, 5801, 5851, 6469, 6949, 8501, 9001, 9049, 9221, 9551, 9649, 9851, 9949, 20021, 20201, 50207, 60649, 80051, 666649, 946669, 5200007, 22000001, 60000049, 66000049, 66600049, 80555551, 555555555551, 5000000000000000000000000000027} which are > 10 are composite. * Prove that all primes > 10 contain at least one element in {11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47, 53, 59, 61, 67, 71, 73, 79, 83, 89, 97, 227, 251, 257, 277, 281, 349, 409, 449, 499, 521, 557, 577, 587, 727, 757, 787, 821, 827, 857, 877, 881, 887, 991, 2087, 2221, 5051, 5081, 5501, 5581, 5801, 5851, 6469, 6949, 8501, 9001, 9049, 9221, 9551, 9649, 9851, 9949, 20021, 20201, 50207, 60649, 80051, 666649, 946669, 5200007, 22000001, 60000049, 66000049, 66600049, 80555551, 555555555551, 5000000000000000000000000000027} as subsequence (equivalently, prove that all numbers > 10 not containing any element in {11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47, 53, 59, 61, 67, 71, 73, 79, 83, 89, 97, 227, 251, 257, 277, 281, 349, 409, 449, 499, 521, 557, 577, 587, 727, 757, 787, 821, 827, 857, 877, 881, 887, 991, 2087, 2221, 5051, 5081, 5501, 5581, 5801, 5851, 6469, 6949, 8501, 9001, 9049, 9221, 9551, 9649, 9851, 9949, 20021, 20201, 50207, 60649, 80051, 666649, 946669, 5200007, 22000001, 60000049, 66000049, 66600049, 80555551, 555555555551, 5000000000000000000000000000027} as subsequence are composite). ==Condensed table== {|class=wikitable |''b''||number of quasi-minimal primes base ''b''||base-''b'' form of largest known quasi-minimal prime base ''b''||length of largest known quasi-minimal prime base ''b''||algebraic ((''a''×''b''^''n''+''c'')/''d'') form of largest known quasi-minimal prime base ''b'' |- |2||1||11||2||3 |- |3||3||111||3||13 |- |4||5||221||3||41 |- |5||22||10₉₃13||96||5⁹⁵+8 |- |6||11||40041||5||5209 |- |7||71||3₁₆1||17||(7¹⁷−5)/2 |- |8||75||4₂₂₀7||221||(4×8²²¹+17)/7 |- |9||151||30₁₁₅₈11||1161||3×9¹¹⁶⁰+10 |- |10||77||50₂₈27||31||5×10³⁰+27 |- |11^*||1068||57₆₂₆₆₈||62669||(57×11⁶²⁶⁶⁸−7)/10 |- |12||106||40₃₉77||42||4×12⁴¹+91 |- |13^*||3195~3197||80₃₂₀₁₇111||32021||8×13³²⁰²⁰+183 |- |14||650||4D₁₉₆₉₈||19699||5×14¹⁹⁶⁹⁸−1 |- |15||1284||7₁₅₅97||157||(15¹⁵⁷+59)/2 |- |16^*||2346~2347||4₇₂₇₈₅DD||72787||(4×16⁷²⁷⁸⁷+2291)/15 |- |17^*||10407~10428||F70₁₈₆₇₆₇1||186770||262×17¹⁸⁶⁷⁶⁸+1 |- |18||549||C0₆₂₆₈C5||6271||12×18⁶²⁷⁰+221 |- |20||3314||G0₆₂₆₉D||6271||16×20⁶²⁷⁰+13 |- |22^*||8003||BK₂₂₀₀₁5||22003||(251×22²²⁰⁰²−335)/21 |- |24||3409||N00N₈₁₂₉LN||8134||13249×24⁸¹³¹−49 |- |30^*||2619||OT₃₄₂₀₅||34206||25×30³⁴²⁰⁵−1 |} ^* Data assumes the primality of the [[w:probable prime|probable prime]]s. Except bases ''b'' = 13, 16, 17, all bases in this table are completely solved (if we allow strong probable primes > 10²⁰⁰⁰⁰), also, except bases ''b'' = 11, 13, 16, 17, 22, 30, all bases in this table are completely solved even if we only allow definitely primes (thus, we can complete the classification of the quasi-minimal primes in these bases, i.e. the “quasi-minimal problems” in these bases are now theorems), for the quasi-minimal primes see the data below. Base ''b'' = 13 has 3195 known quasi-minimal primes (or PRPs), see the data below, and if there are more quasi-minimal primes in base 13, then they must be of the form 9{5} or A{3}A (we are unable to determine if these two families contain a prime or not, i.e. these two families have no known prime members, nor can these two families be ruled out as only containing composites), and must have at least 82000 digits in base 13, besides, since these two families can contain at most one quasi-minimal prime, there are at most 3197 quasi-minimal primes in base 13. (i.e. the quasi-minimal primes in base 13 are the 3195 known quasi-minimal primes in base 13 (they are given in the data section) plus the smallest prime in the family 9{5} in base 13 (if exists) plus the smallest prime in the family A{3}A in base 13 (if exists)) Base ''b'' = 16 has 2346 known quasi-minimal primes (or PRPs), see the data below, and if there are more quasi-minimal primes in base 16, then they must be of the form {3}AF (we are unable to determine if this family contains a prime or not, i.e. this family have no known prime members, nor can this family be ruled out as only containing composites), and must have at least 76000 digits in base 16, besides, since this family can contain at most one quasi-minimal prime, there are at most 2347 quasi-minimal primes in base 16. (i.e. the quasi-minimal primes in base 16 are the 2346 known quasi-minimal primes in base 16 (they are given in the data section) plus the smallest prime in the family {3}AF in base 16 (if exists)) ==Data for quasi-minimal primes== ===Base 2=== 11 ===Base 3=== 12, 21, 111 ===Base 4=== 11, 13, 23, 31, 221 ===Base 5=== 12, 21, 23, 32, 34, 43, 104, 111, 131, 133, 313, 401, 414, 3101, 10103, 14444, 30301, 33001, 33331, 44441, 300031, 100000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000013 ===Base 6=== 11, 15, 21, 25, 31, 35, 45, 51, 4401, 4441, 40041 ===Base 7=== 14, 16, 23, 25, 32, 41, 43, 52, 56, 61, 65, 113, 115, 131, 133, 155, 212, 221, 304, 313, 335, 344, 346, 364, 445, 515, 533, 535, 544, 551, 553, 1022, 1051, 1112, 1202, 1211, 1222, 2111, 3031, 3055, 3334, 3503, 3505, 3545, 4504, 4555, 5011, 5455, 5545, 5554, 6034, 6634, 11111, 11201, 30011, 30101, 31001, 31111, 33001, 33311, 35555, 40054, 100121, 150001, 300053, 351101, 531101, 1100021, 33333301, 5100000001, 33333333333333331 ===Base 8=== 13, 15, 21, 23, 27, 35, 37, 45, 51, 53, 57, 65, 73, 75, 107, 111, 117, 141, 147, 161, 177, 225, 255, 301, 343, 361, 401, 407, 417, 431, 433, 463, 467, 471, 631, 643, 661, 667, 701, 711, 717, 747, 767, 3331, 3411, 4043, 4443, 4611, 5205, 6007, 6101, 6441, 6477, 6707, 6777, 7461, 7641, 47777, 60171, 60411, 60741, 444641, 500025, 505525, 3344441, 4444477, 5500525, 5550525, 55555025, 444444441, 744444441, 77774444441, 7777777777771, 555555555555525, 44444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444447 ===Base 9=== 12, 14, 18, 21, 25, 32, 34, 41, 45, 47, 52, 58, 65, 67, 74, 78, 81, 87, 117, 131, 135, 151, 155, 175, 177, 238, 272, 308, 315, 331, 337, 355, 371, 375, 377, 438, 504, 515, 517, 531, 537, 557, 564, 601, 638, 661, 702, 711, 722, 735, 737, 751, 755, 757, 771, 805, 838, 1011, 1015, 1101, 1701, 2027, 2207, 3017, 3057, 3101, 3501, 3561, 3611, 3688, 3868, 5035, 5051, 5071, 5101, 5501, 5554, 5705, 5707, 7017, 7075, 7105, 7301, 8535, 8544, 8555, 8854, 20777, 22227, 22777, 30161, 33388, 50161, 50611, 53335, 55111, 55535, 55551, 57061, 57775, 70631, 71007, 77207, 100037, 100071, 100761, 105007, 270707, 301111, 305111, 333035, 333385, 333835, 338885, 350007, 500075, 530005, 555611, 631111, 720707, 2770007, 3030335, 7776662, 30300005, 30333335, 38333335, 51116111, 70000361, 300030005, 300033305, 351111111, 1300000007, 5161111111, 8333333335, 300000000035, 311111111161, 544444444444, 2000000000007, 5700000000001, 7270000000007, 88888888833335, 100000000000507, 5111111111111161, 7277777777777777707, 8888888888888888888335, 30000000000000000000051, 1000000000000000000000000057, 56111111111111111111111111111111111111, 7666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666662, 27777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777707, 300000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000011 ===Base 10=== 11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47, 53, 59, 61, 67, 71, 73, 79, 83, 89, 97, 227, 251, 257, 277, 281, 349, 409, 449, 499, 521, 557, 577, 587, 727, 757, 787, 821, 827, 857, 877, 881, 887, 991, 2087, 2221, 5051, 5081, 5501, 5581, 5801, 5851, 6469, 6949, 8501, 9001, 9049, 9221, 9551, 9649, 9851, 9949, 20021, 20201, 50207, 60649, 80051, 666649, 946669, 5200007, 22000001, 60000049, 66000049, 66600049, 80555551, 555555555551, 5000000000000000000000000000027 ===Base 11=== 12, 16, 18, 21, 27, 29, 34, 38, 3A, 43, 49, 54, 56, 61, 65, 67, 72, 76, 81, 89, 92, 94, 98, 9A, A3, 10A, 115, 117, 133, 139, 153, 155, 171, 193, 197, 199, 1AA, 225, 232, 236, 25A, 263, 315, 319, 331, 335, 351, 353, 362, 373, 379, 391, 395, 407, 414, 452, 458, 478, 47A, 485, 4A5, 4A7, 502, 508, 511, 513, 533, 535, 539, 551, 571, 579, 588, 595, 623, 632, 70A, 711, 715, 731, 733, 737, 755, 759, 775, 791, 797, 7AA, 803, 847, 858, 85A, 874, 885, 887, 913, 919, 931, 937, 957, 959, 975, 995, A07, A1A, A25, A45, 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DDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD ===Base 15=== 12, 14, 18, 1E, 21, 27, 2B, 2D, 32, 38, 3E, 41, 47, 4B, 4D, 54, 58, 5E, 67, 6B, 6D, 72, 74, 78, 87, 8B, 92, 94, 9E, A1, A7, AD, B2, B8, BE, C1, CB, CD, D2, D4, E1, ED, 111, 11B, 131, 137, 13B, 13D, 157, 15B, 15D, 171, 177, 197, 19D, 1B7, 1BB, 1D1, 1DB, 1DD, 234, 298, 311, 31B, 337, 33D, 344, 351, 357, 35B, 364, 377, 391, 39B, 39D, 3A4, 3BD, 3C4, 3D7, 3DB, 3DD, 452, 51B, 51D, 531, 53B, 551, 55D, 562, 571, 577, 5A2, 5B1, 5B7, 5BB, 5BD, 5C2, 5D1, 5D7, 634, 652, 681, 698, 717, 71B, 731, 737, 757, 75D, 77D, 79B, 79D, 7B1, 7B7, 7BD, 7D7, 7DD, 801, 852, 88D, 8D8, 91D, 93B, 93D, 95B, 95D, 971, 977, 97B, 97D, 988, 991, 9BD, 9C8, 9D1, A98, AAB, B1D, B31, B3B, B44, B51, B57, B7B, B7D, B97, B9B, BB7, BC4, BD1, BD7, BDD, C07, C34, C52, C7E, C98, CC7, CE7, D0E, D1D, D31, D51, D5B, D68, D77, D7B, D91, D97, DA8, DAE, DCE, DD1, EB4, EEB, 107B, 1091, 10B1, 1107, 110D, 1561, 1651, 1691, 1B01, 2052, 2502, 2522, 303B, 307D, 3097, 30BB, 30D1, 3107, 3361, 3701, 3907, 3B01, 3B0B, 3C97, 4434, 4498, 4834, 4898, 49A8, 4E34, 5037, 507D, 5091, 509B, 5107, 5161, 5202, 53C7, 5552, 570B, 590B, 590D, 59C7, 5A5B, 5C97, 5D0D, 5DAB, 6061, 6151, 6191, 6511, 6601, 6911, 707B, 7091, 7097, 70AE, 70BB, 70CE, 70DB, 7561, 760E, 7691, 76CE, 7907, 7961, 7A0E, 7A3B, 7AEE, 7B0B, 7BAB, 7C0E, 7C77, 7CAE, 7D0B, 7D61, 7DAB, 7E5B, 7E6E, 7E7B, 7EBB, 8098, 811D, 8191, 835D, 853D, 8881, 8908, 8951, 8968, 899D, 8D3D, 8D5D, 8D6E, 8DDD, 8E98, 9011, 9037, 9097, 90D7, 9301, 93C7, 95C7, 9611, 9631, 96A8, 9811, 9851, 989D, 990B, 990D, 998D, 99AB, 99C7, 99D8, 9A08, 9A9B, 9AA8, 9ABB, 9B61, 9BC7, 9D0B, 9DAB, 9DC7, 9DD8, A052, A304, A502, A55B, A9BB, AB04, AB64, B09D, B107, B10B, B161, B1AB, B1C7, B30D, B3C7, B50B, B664, B691, B6A4, B707, B761, B90D, B961, BA5B, BABB, BBAB, BBB4, BC37, BC77, C777, C937, C997, D011, D03D, D05D, D09B, D0B1, D0BD, D101, D10B, D30D, D3AB, D507, D50D, D66E, D761, D7DE, D811, D85D, D86E, D89D, D8C8, D8E8, D9AB, D9D8, DA3B, DA9B, DABB, DB01, DB61, DBAB, DC88, DD07, DD0B, DD7E, DD8D, DDE7, DE6E, E252, E33B, E522, E57B, E7AE, E7CE, E898, E997, E9A8, E9BB, EA34, EB5B, EE98, EEC7, 10017, 10B0D, 170AB, 17A0B, 19001, 19601, 1A09B, 1D0C7, 22E52, 2EA52, 30017, 3001D, 300B1, 301C7, 30334, 30631, 307AB, 3300B, 3333B, 36031, 36301, 37A0B, 37BBB, 39997, 3A30B, 3B0C7, 3D001, 3D601, 40034, 40968, 43334, 49668, 49998, 50022, 5009D, 501C7, 50222, 50507, 505C7, 50611, 50C57, 53007, 53997, 55537, 5555B, 5557B, 5599B, 56101, 56691, 56961, 5700D, 5755B, 59001, 59557, 59997, 5999D, 599DB, 59DDD, 5D99B, 5DD3D, 5DD9D, 60931, 63031, 65691, 66951, 69031, 69361, 69561, 70011, 70051, 7005B, 7006E, 7030D, 703AB, 70501, 70701, 707C7, 71601, 71951, 7300D, 7333B, 75001, 7555B, 75911, 76011, 76051, 766EE, 76EEE, 7700B, 77191, 77661, 7776E, 77771, 777BB, 77911, 77BBB, 79001, 7A05B, 7A66E, 7AA6E, 7AAAE, 7ACCE, 7C6EE, 7CCEE, 7CECE, 7CEEE, 7D3BB, 7E7C7, 7EECE, 80034, 80304, 80434, 809DD, 80A34, 84A34, 850DD, 85961, 86661, 88151, 88331, 88511, 88591, 88898, 890DD, 89998, 89D0D, 8D90D, 8E434, 90017, 90051, 900A8, 900DB, 901C7, 90C57, 90D8D, 91007, 91061, 9199B, 95997, 96068, 96561, 99397, 99537, 9999B, 999B7, 999D7, 999DB, 999DD, 99BBB, 99DBB, 99DD7, 99DDD, 9B007, 9B00B, 9B0AB, 9BB11, 9BBBB, 9D007, 9D08D, 9D537, 9D9BB, 9D9DB, 9DD57, 9DDB7, 9DDDB, 9DDDD, A0A34, A0B5B, A0BBB, A0E34, A2E52, A330B, A8434, A8834, A8E34, A909B, AAA34, AAE52, AB0BB, AB334, ABB34, AE034, AE834, AE99B, AEA52, AEE52, B0011, B0071, B0077, B00B1, B0611, B0A64, B500D, B599D, B6101, B7771, B7911, BA064, BAAA4, BAB34, BB061, BB304, BB53D, BB601, BBB91, BBB9D, BBBBD, BDA0B, BDBBB, D0088, D00D7, D0307, D05C7, D070D, D0888, D0B07, D0BC7, D0C08, D0DC7, D0DD8, D1661, D59DD, D5D3D, D5DDD, D6611, D700D, D8D0D, D900B, D9908, D999D, D9BBB, D9D9D, D9DDB, DB007, DB00D, DB1B1, DB53D, DB59D, DB99D, DBBB1, DD0D8, DD33B, DD3B7, DD3BB, DD57D, DD898, DD9DD, DDB37, DDBDB, DDD08, DDD3D, DDD5D, DDD7D, DDD88, DDD9D, DDDB7, DDDC8, DDDD7, DDE98, DE037, DE998, DEB07, E0098, E00C7, E0537, E0557, E077B, E0834, E0968, E3334, E37AB, E39C7, E4034, E5307, E55AB, E705B, E750B, E766E, E76EE, E8304, E8434, E9608, E9C37, EAE52, EBB0B, EC557, EC597, EC957, 1000BD, 1009AB, 10A90B, 1900AB, 190661, 19099B, 190A0B, 1A900B, 222A52, 2AAA52, 31000D, 330331, 333334, 3733AB, 373ABB, 3BBB61, 430004, 490068, 490608, 5000DB, 500D0B, 505557, 505A0B, 50D00B, 50DDDB, 50DDDD, 522222, 5500AB, 5500C7, 550957, 550A0B, 555A9B, 559057, 560011, 590661, 633331, 666331, 666591, 666661, 7050AB, 705A0B, 706101, 70A50B, 7300AB, 761661, 76666E, 777011, 777101, 77750B, 777A5B, 777CEE, 779051, 791501, 7E7797, 7ECCCE, 7EEE97, 800D9D, 808834, 836631, 83D661, 843004, 856611, 884034, 884304, 888E34, 88A434, 88AE34, 8A4034, 8AEE34, 8E8034, 8E8E34, 8EEE34, 9000BB, 9001AB, 900B07, 900D98, 903661, 905661, 906651, 9080DD, 9099A8, 909D9B, 90A668, 90DD9B, 90DDBB, 910001, 9100AB, 91A00B, 930007, 950001, 956661, 9909A8, 995907, 999068, 999507, 999907, 9B0B1B, 9B0BB1, 9BB01B, 9C5597, 9C5957, 9D09DD, 9D0D9D, 9D800D, 9DB307, 9DD09D, A00034, A0033B, A033B4, A2A252, AAAA52, ABBBBB, B00004, B0001B, B0003D, B00A04, B0555B, B07191, B07711, B07777, B0B911, B0BDBB, B77011, B777C7, BB0001, BB0034, BB035D, BB055B, BB0BDB, BB9101, BBB0DB, BBB50D, BBBB01, BBD0BB, C55397, C55557, C55597, D0003B, D00057, D0007D, D000B7, D000C8, D008DD, D00DAB, D0333B, D05537, D099DD, D09DDD, D0DDBB, D555C7, D5C537, D88008, D88088, D888EE, D909DD, D9D0DD, D9DD0D, DB0BBB, DBBB0B, DBBB0D, DC0008, DC5537, DDDDD8, DDDEBB, DDE99B, DE0808, DE0C57, DE300B, DE5537, DE8888, DEE088, DEE307, DEE888, DEEE37, DEEE57, DEEEC8, E0000B, E007BB, E00A52, E03BC7, E07ABB, E09B07, E0A99B, E0C397, E0E76E, E50057, E55007, E55597, E55937, E730AB, E73A0B, E80E34, E88834, E8E034, E90008, E95557, EA099B, EE4304, EE5057, EE5507, EE8E34, EE9307, EEE434, 100001D, 1000A9B, 1000DC7, 22AA252, 3000BC7, 3033301, 3076661, 333B304, 33B3034, 3B33304, 3D66661, 50007AB, 5005957, 5500597, 5550057, 5559007, 5559597, 5595007, 5966661, 5DDDDDB, 6366631, 7010001, 7066651, 7100061, 733BBBB, 766A6AE, 77505AB, 7776501, 777775B, 777AACE, 777ECCE, 777EEAE, 7CCCCCE, 7E30A0B, 7EEEEAE, 8300004, 8363331, 8693331, 880E834, 8833304, 8888034, 8888434, 888A034, 88A3334, 88E8834, 88EE034, 88EE304, 8AA3334, 8D0009D, 8EE8834, 9000361, 9000668, 9003331, 9005557, 9006008, 9008D0D, 9083331, 9090968, 90BBB01, 90D0908, 9500661, 9555597, 9555957, 9660008, 9900968, 9995597, 9996008, 9999557, 9999597, 9999908, 9A66668, A003B34, A003BB4, AA22252, B00B034, B00B35D, B033334, B0B6661, B0BB01B, B100001, B333304, B777777, B99999D, BA60004, BAA0334, BBB001B, BBB6611, BBBBB11, BBBD00B, BD000AB, D0000DB, D009098, D00CCC8, D00D908, D00D99D, D03000B, D0BB0BB, D0D9008, D0D9998, D1000C7, D800008, D8DDEEE, D90080D, DBBBBBB, DD09998, DDD5557, DDDDBBB, DDDDDBD, DDDE8EE, DECC008, DECCCC8, DEE0CC8, DEEC0C8, E000397, E0003BB, E000434, E00076E, E000937, E007A5B, E00909B, E0090B7, E009307, E00B077, E00E434, E00E797, E00E937, E05999B, E09009B, E0900B7, E0E0937, E0E7E97, E0EAA52, E0EEA52, E555057, E5555C7, E7777C7, E77E797, E88EE34, E999998, EA5999B, EB000BB, EB0BBBB, EE00434, EE0E797, EEE076E, EEE706E, EEE8834, EEEE557, EEEE797, 30333331, 30B66661, 33000034, 33030004, 33B33004, 500575AB, 55000007, 5500075B, 55500907, 55555057, 55555907, 55559507, 60003301, 60033001, 60330001, 7000003D, 70106661, 70666611, 77000001, 7777770B, 777777C7, 77777ACE, 77777EAE, 777E30AB, 777E3A0B, 7CCCC66E, 800005DD, 88AA0834, 90000008, 900008DD, 90099668, 90500557, 90555007, 90666668, 90909998, 90990998, 90996668, 9099999D, 90D00098, 90D90998, 95500057, 99099098, 99555057, 99900998, 99966608, 99966668, 99999668, 99999998, 9D009008, 9D090998, A0803334, A2222252, AAA52222, B00005AB, B000B55B, B0BBBB5B, B3330034, BB0BBB1B, BBAA3334, BBB0BB1B, BBB0BB5B, BBDB000B, D000BBBB, D00100C7, D8888888, D900008D, D9000098, DBB000BB, DC0CCCC8, DCC0CCC8, DCCCC008, DD000908, DD09009D, DDDDDDAB, DDDDDEEE, DDDEEE8E, DDDEEEE8, DEE80008, E0777E97, E0E0E397, E0E77797, E0EE0397, E7777797, E9066668, EE00E397, EE077797, EE0E0397, EEE00797, EEE07E97, EEE0AA52, EEE55397, EEE55557, EEEAAA52, EEEEE834, EEEEEA52, 300003331, 300007661, 300330031, 333000004, 333300001, 333B00034, 3700000AB, 3B3300034, 500000057, 555555007, 555555557, 5DDDDDDDD, 600000331, 7500000AB, 75000A00B, 75A00000B, 761000001, 77000E0C7, 777700EC7, 7777730AB, 7777777AE, 77777EE97, 7777E7E97, 777999997, 7A500000B, 7BBBBBB5B, 88888A834, 900000031, 900666608, 909990098, 90D009998, 950000557, 966666008, 990000007, 990555507, 999999997, A000000B4, A0005999B, AAEEEEE34, B000AA334, BBBBB005B, BBBBBBB5B, D09999998, D0D90009D, D800000DD, D90009998, DCCCC0CC8, DE88EEEEE, DEEEEEE88, E000B7777, E000BBBBB, E003ABBBB, EE0000797, EE0EEE397, EE5555557, EE777EE97, EEEEEE537, EEEEEE937, 2222222252, 3000000071, 3330030001, 3333303001, 3333330001, 500000007B, 5555555097, 7000000071, 77000000C7, 8333333331, 8888883334, 8888888834, 888888AA34, 900000009B, 900000009D, 900000DD9D, 9000099998, 9955555507, 9D0000099D, 9D05555557, AB0000005B, B000000DAB, B00000BBDB, BB00BB0B5B, BB0BB00B5B, D000099998, D00090008D, D0D000909D, D0DDDDDDDB, D300000007, D88EEEEEEE, D900999998, DD00900008, DDD6EEEEEE, DDDDDDD6EE, DDDDDDDDDE, DDDEEEEEEE, DEEEEE8008, E000000797, 7777777CCCE, 88888830004, 90000009D9D, 99955555557, 9999999999D, B00000D00AB, BB000BBB05B, BBBB0000B5B, D000009080D, D000090800D, D090800000D, DDDDDDD999B, DDDDDDDDD9B, EEEEEE00397, EEEEEEE0397, 333000000301, 5000000000DD, 73A00000000B, 9000000000B7, 903333333331, ABB00000000B, D000000001C7, DCCCCCCCCCC8, E0EEEEEEE397, 19A000000000B, 3333333333331, 3BBBBBBBBBBBB, 9333333333331, A00000000099B, B00000000050D, EEEEEEEEEE76E, 1000000000999B, 71000000000001, 908D000000000D, BBBBBBBBBB6661, 77777777777777B, BB00000000BBB5B, DEEEEEEEEEEEEEE, 7777777777777E97, B0BBBBBBBBBBBB1B, BB0000000000DB0B, D000000000000998, D908000000000000D, DDDDDDDDDDDDDDDDB, E9666666666666668, 3330000000000000031, D00000000000000908D, E0BBBBBBBBBBBBBBBBB, 2EEEEEEEEEEEEEEEEE52, 77777777777777777ECE, 5000000000000000005AB, 777777777777777777997, 7BBBBBBBBBBBBBBBBBBBB, BB0000000000000000DBB, DD000000000000000909D, D900000000000000000DDD, DD0000000000000000099D, BBBBBBBBBBBBBBBBBBBBBB1, B00000000000000000000005B, B0700000000000000000000001, B70000000000000000000000001, 705000000000000000000000000B, 633000000000000000000000000001, EBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB, 500000000000000000000000000000000017, 77777777777777777777777777777777777777777777777777777777777CCE, 7777777777777777777777777777777777777777777777777777777777777777777777777CE, 96666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666608, EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE397, 7777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777797 ===Base 16=== 11, 13, 17, 1D, 1F, 25, 29, 2B, 2F, 35, 3B, 3D, 43, 47, 49, 4F, 53, 59, 61, 65, 67, 6B, 6D, 71, 7F, 83, 89, 8B, 95, 97, 9D, A3, A7, AD, B3, B5, BF, C1, C5, C7, D3, DF, E3, E5, E9, EF, F1, FB, 14B, 15B, 185, 199, 1A5, 1BB, 1C9, 1EB, 223, 22D, 233, 241, 277, 281, 287, 28D, 2A1, 2D7, 2DD, 2E7, 301, 337, 373, 377, 38F, 3A1, 3A9, 41B, 42D, 445, 455, 45D, 481, 4B1, 4BD, 4CD, 4D5, 4E1, 4EB, 50B, 515, 51B, 527, 551, 557, 55D, 577, 581, 58F, 5AB, 5CB, 5CF, 5D1, 5D5, 5DB, 5E7, 623, 709, 727, 737, 745, 74B, 755, 757, 773, 779, 78D, 7BB, 7C3, 7C9, 7CD, 7DB, 7EB, 7ED, 805, 80F, 815, 821, 827, 841, 851, 85D, 85F, 8A5, 8DD, 8E1, 8F5, 923, 98F, 99B, 9A9, 9EB, A21, A6F, A81, A85, A99, A9F, AA9, AAB, ACF, B1B, B2D, B7B, B8D, B99, B9B, BB7, BB9, BCB, BDD, BE1, C0B, CB9, CBB, CEB, D01, D21, D2D, D55, D69, D79, D81, D85, D87, D8D, DAB, DB7, DBD, DC9, DCD, DD5, DDB, DE7, E21, E27, E4B, E7D, E87, EB1, EB7, ED1, EDB, EED, F07, F0D, F4D, FD9, FFD, 1069, 1505, 1609, 1669, 16A9, 19AB, 1A69, 1AB9, 2027, 204D, 2063, 207D, 20C3, 20ED, 2221, 22E1, 2327, 244D, 26C3, 274D, 2E01, 2E0D, 2ECD, 3023, 3079, 3109, 3263, 3341, 36AF, 3941, 3991, 39AF, 3E41, 3E81, 3EE1, 3EE7, 3F79, 4021, 40DB, 440B, 444B, 44A1, 44AB, 44DB, 4541, 45BB, 4A41, 4B0B, 4BBB, 4C4B, 4D41, 4DED, 5045, 50A1, 50ED, 540D, 5441, 555B, 556F, 5585, 560F, 56FF, 5705, 574D, 580D, 582D, 5855, 588D, 5A01, 5AA1, 5B01, 5B4B, 5B87, 5BB1, 5BEB, 5C4D, 5CDD, 5CED, 5DD7, 5DDD, 5E0D, 5E2D, 5EBB, 68FF, 6A69, 6AC9, 6C8F, 6CA9, 6CAF, 6F8F, 6FAF, 7033, 7063, 7075, 7087, 70A5, 70AB, 7303, 7393, 74DD, 754D, 7603, 7633, 7663, 7669, 7705, 772D, 775D, 77D5, 7807, 7877, 7885, 7939, 7969, 7993, 79AB, 7A05, 7A69, 7A9B, 7AA5, 7B77, 7BA9, 7D4D, 7D75, 7D77, 8077, 808D, 80D7, 80E7, 8587, 86CF, 8777, 8785, 8885, 88CF, 88ED, 88FD, 8C6F, 8C8F, 8E8D, 8EE7, 8F2D, 8F8D, 9031, 9041, 90AF, 90B9, 9221, 9319, 9401, 944B, 9881, 9931, 9941, 9991, 99AF, 9A0F, 9A1B, 9A4B, 9AFF, 9BA1, 9BB1, 9CAF, 9E81, 9EA1, 9FAF, A001, A05B, A0C9, A105, A10B, A4CB, A55B, A6C9, A88F, A91B, A9B1, A9BB, AA15, AB01, AB0B, AB19, ABBB, AC09, AF09, B041, B04B, B069, B07D, B087, B0B1, B0ED, B1A9, B201, B40B, B40D, B609, B70D, B7A9, B807, B9A1, BA41, BAA1, BB4B, BBB1, BBDB, BBED, BD19, BD41, BDBB, BDEB, BE07, BEE7, C0D9, C203, C24D, C6A9, C88D, C88F, C8CF, C8ED, C9AF, C9CB, CA09, CA4B, CA69, CAC9, CC0D, CC23, CC4D, CC9B, CD09, CDD9, CE4D, CEDD, CFA9, CFCD, D04B, D099, D405, D415, D44B, D4A5, D4DD, D50D, D70B, D74D, D77B, D7CB, D91B, D991, DA05, DA09, DA15, DA51, DB91, DBEB, DD7D, DDA1, DDED, DE0B, DE41, DE4D, DEA1, E02D, E07B, E0D7, E1CB, E2CD, E401, E801, EABB, EACB, EAEB, EBAB, EC4D, ECDD, ED07, EDD7, EE7B, EE81, EEAB, EEE1, F08F, F0A9, F227, F2ED, F3AF, F485, F58D, F72D, F763, F769, F787, F7A5, F7E7, F82D, F86F, F877, F88D, F8D7, F8E7, F8FF, FCCD, FED7, FF85, FF8F, FFA9, 100AB, 10BA9, 1A0CB, 1BA09, 200E1, 2C603, 2CC03, 30227, 303AF, 30AAF, 32003, 32207, 32CC3, 330AF, 33169, 33221, 33391, 33881, 33AFF, 38807, 38887, 3AFFF, 3F203, 3F887, 3FAFF, 400BB, 4084D, 40A4B, 42001, 44221, 44401, 444D1, 4480D, 4488D, 44CCB, 44D4D, 44E8D, 4804D, 4840D, 4A0CB, 4A54B, 4CACB, 4D0DD, 4D40D, 4D44D, 5004D, 50075, 502CD, 5044D, 50887, 50EE1, 5448D, 548ED, 55A45, 55F45, 5844D, 5A4A5, 5AE41, 5B0CD, 5B44D, 5BBCD, 5D4ED, 5E0E1, 5EB4D, 5EC8D, 5ECCD, 5EE41, 5F06F, 5F7DD, 5F885, 5F8CD, 5FC8D, 5FF75, 6088F, 60AFF, 630AF, 633AF, 660A9, 668CF, 669AF, 66A09, 66A0F, 66FA9, 6886F, 6A00F, 6A0FF, 6A8AF, 6AFFF, 7002D, 7024D, 70B0D, 70B7D, 7200D, 73363, 73999, 7444D, 770B7, 777D7, 77B07, 77D7D, 77DD7, 79003, 79999, 7B00D, 7D05D, 7D7DD, 8007D, 800D1, 8074D, 82CCD, 82E4D, 8448D, 8484D, 8704D, 8724D, 87887, 88001, 8800D, 880CD, 88507, 88555, 8866F, 8872D, 8877D, 888D1, 888D7, 88AA1, 88C2D, 88D57, 88D75, 88D77, 8AFAF, 8C2CD, 8C40D, 8C8CD, 8CCED, 8CE2D, 8CFED, 8E007, 8E20D, 8E24D, 8F6FF, 8FAAF, 900CB, 901AB, 90901, 909A1, 90AB1, 90AE1, 90EE1, 910AB, 93331, 940AB, 963AF, 966AF, 99019, 99109, 99A01, 9AAE1, 9B00B, 9B0AB, 9B441, 9BABB, 9BBBB, 9E441, A00BB, A0405, A044B, A08AF, A0A51, A0B91, A0C4B, A1B09, A54A5, A5B41, A6609, A904B, A94A1, A9C4B, A9E01, A9E41, AA0A1, AA441, AA501, AA8AF, AAEE1, AAF45, AAF8F, ABBA1, ACC69, AE0BB, AE0EB, AEAE1, AEE0B, AEEA1, AEECB, AF045, AF4A5, AFA8F, B00A1, B00D7, B044D, B0777, B0A0B, B0A91, B0BBD, B0BCD, B0C09, B0DA9, B0EAB, B2207, B4001, B6669, B7707, B7D07, B8081, B9021, BA091, BA109, BA4BB, BB001, BB0EB, BB8A1, BBBEB, BBE0B, BBEBB, BC009, BCECD, BD0A9, BE44D, BEB0D, BEBBB, BEEBB, C0263, C02C3, C02ED, C040D, C0CA9, C0CCD, C2663, C2CED, C32C3, C3323, C400D, C40ED, C44CB, C44ED, C480D, C484D, C4CAB, C60AF, C686F, C6A0F, C86FF, C8C2D, CAA0F, CAFAF, CBCED, CC0AF, CC44B, CC82D, CC8FF, CCAF9, CCAFF, CCCFD, CCFAF, CD00D, CD4CB, CD4ED, CDDDD, CF2C3, CFC8F, CFE8D, D0045, D07DD, D09BB, D0D4D, D0DD7, D0EBB, D0EEB, D1009, D1045, D10B9, D1BA9, D54BB, D54ED, D5AE1, D5D07, D5EE1, D70DD, D7707, D7777, D77DD, D7DD7, D9441, D9AE1, D9B0B, DA9A1, DA9E1, DAA41, DAAA1, DBB0B, DBBA1, DC4CB, DD227, DD44D, DDDD7, E0081, E00E1, E010B, E088D, E08CD, E0B0D, E0BBD, E100B, E4D0D, E777B, E77AB, E7CCB, E844D, E848D, E884D, E88A1, EB0BB, EBB4D, EBBEB, EBEEB, EC8CD, ECBCD, ECC8D, ED04D, EE001, EE0EB, EE4A1, EEEBB, F0085, F09AF, F0C23, F0CAF, F2663, F2C03, F3799, F3887, F4A05, F4AA5, F506F, F5845, F5885, F5C2D, F5ECD, F5F45, F66A9, F688F, F6AFF, F7399, F777D, F8545, F8555, F8AAF, F8F87, F9AAF, FA0F9, FA405, FA669, FAFF9, FC263, FCA0F, FCAFF, FCE8D, FCF23, FD777, FDDDD, FDEDD, FEC2D, FEC8D, FF545, FF6AF, FF739, FF775, FF9AF, FFC23, 100055, 100555, 10A9CB, 1A090B, 1A900B, 1CACCB, 1CCACB, 20DEE1, 266003, 3000AF, 300A0F, 300AFF, 308087, 308E07, 3323E1, 333A0F, 339331, 33CA0F, 33CF23, 33CFAF, 33F323, 380087, 3A00AF, 3A0F0F, 3AA0FF, 3AAF0F, 3C33AF, 3C3A0F, 3C3FAF, 3CCAAF, 3F0FAF, 3F32C3, 3FF0AF, 3FFAAF, 4004CB, 400A05, 4048ED, 404DDD, 40AA05, 40D04D, 40DD4D, 40E0DD, 40E48D, 440041, 44008D, 44044D, 4404DD, 44440D, 4448ED, 4484ED, 448E4D, 44E44D, 48888D, 4AA005, 4DD00D, 4DD04D, 4DDD0D, 4E048D, 4E448D, 4E880D, 5000DD, 500201, 50066F, 5008CD, 500C2D, 500D7D, 50C20D, 520C0D, 544EDD, 54AA05, 54AAA5, 54ED4D, 566AAF, 57D00D, 580087, 5A5545, 5C20CD, 5C8CCD, 5CC2CD, 5D000D, 5D070D, 5F666F, 5FAA45, 5FFF45, 60008F, 600A0F, 603AAF, 6060AF, 6066AF, 60A0AF, 63AA0F, 6663AF, 66668F, 666AAF, 668A8F, 66AFF9, 68888F, 693AAF, 7007B7, 70404D, 70770B, 70770D, 707BE7, 70DD0D, 733339, 733699, 74004D, 74040D, 77007B, 770CCB, 777B4D, 777BE7, 777CCB, 77ACCB, 77B74D, 77D0DD, 7A0CCB, 7B744D, 7CACCB, 7DDD99, 80044D, 800807, 80200D, 8044ED, 80C04D, 80CC2D, 80E44D, 8404ED, 84888D, 84E04D, 84E40D, 86686F, 8668AF, 8686AF, 86F66F, 86FFFF, 87000D, 87744D, 880807, 886AFF, 88824D, 88870D, 888787, 88884D, 88886F, 88887D, 88888D, 888C4D, 888FAF, 88AA8F, 88CC8D, 88F6AF, 88F8AF, 88FA8F, 88FF6F, 88FF87, 88FFAF, 8A8FFF, 8C0C2D, 8C802D, 8CCFFF, 8CE00D, 8CE0CD, 8CFCCF, 8E00CD, 8E044D, 8E0CCD, 8EC0CD, 8F68AF, 8F88F7, 8FCFCF, 8FF887, 8FFCCF, 8FFF6F, 9002E1, 9004AB, 9008A1, 900919, 900ABB, 900B21, 90B801, 90CCCB, 9332E1, 944441, 94ACCB, 990001, 9900A1, 9A4441, 9A4AA1, 9AA4A1, 9AAA41, 9AAAAF, 9B66C9, 9BBA0B, 9BC0C9, 9BC669, 9BC6C9, 9C4ACB, A0094B, A00ECB, A09441, A0A08F, A0E0CB, A0ECCB, A0F669, A40A05, A4AAA5, A50E41, A5AA45, A60069, A8FAFF, A9AA41, AA5E41, AAA4A5, AAA545, AC6669, ACCC4B, ACCCC9, AEAA41, AFF405, AFF669, AFFA45, AFFFF9, B00921, B00BEB, B00CC9, B00D91, B08801, B0D077, B70077, B70E77, B77E77, B88877, B88881, B94421, BAE00B, BB00AB, BB0DA1, BB444D, BB44D1, BB8881, BBBBBD, BBBC4D, BBCCCD, BC0CC9, BC66C9, BCC669, BCC6C9, BCCC09, BE000D, BE00BD, BE0B4D, BE0CCD, BEA00B, BECCCD, C0084D, C00A0F, C0608F, C0668F, C0844D, C0A0FF, C0AFF9, C0C3AF, C0C68F, C0CAAF, C0CDED, C0D0ED, C0E80D, C0EC2D, C0EC8D, C0FA0F, C0FAAF, C2CC63, C30CAF, C333AF, C3CAAF, C3CCAF, C4048D, C40D4D, C4404D, C4408D, C4440D, C44DDD, C4ACCB, C4DCCB, C4DD4D, C6068F, C66AAF, C68AAF, C6AA8F, C8044D, C8440D, C8666F, CA00FF, CA0FFF, CAAAAF, CAAFFF, CAFF0F, CBE0CD, CC008F, CC0C8F, CC3CAF, CC4ACB, CC608F, CC66AF, CCBECD, CCC4AB, CCCA0F, CCCC8F, CCCE8D, CE0C8D, CF0F23, CF0FAF, CFAFFF, CFCAAF, CFFAFF, D0005D, D00BA9, D05EDD, D077D7, D10CCB, D22207, D4000B, D4040D, D4044D, D40CCB, D70077, D7D00D, D90009, D900BB, DB00BB, DB4441, DD400D, DDD109, DDD1A9, DDD919, DDD941, DED00D, E00D4D, E00EEB, E0AAE1, E0AE41, E0AEA1, E0B44D, E0BCCD, E0BEBB, E0D0DD, E0E441, E4048D, E4448D, E800CD, E8200D, EA0E41, EAA0E1, EBB00B, ECCCAB, EDDDDD, EEBE0B, F00263, F0056F, F00A45, F02C63, F03F23, F05405, F060AF, F08585, F0A4A5, F0F2C3, F0F323, F2CCC3, F33203, F33C23, F5F66F, F5FF6F, F68CCF, F6AA8F, F888AF, FA0F45, FAA045, FAA545, FAFC69, FC0AAF, FC66AF, FCCCAF, FCFFAF, FF0323, FF056F, FF3203, FF7903, FFA045, FFA4A5, FFAA45, FFC0AF, FFF4A5, FFF575, FFFA45, FFFCAF, 10A009B, 20000D1, 2CCC663, 30A00FF, 30CCCAF, 30FA00F, 30FCCAF, 3333C23, 333C2C3, 33C3AAF, 33FCAAF, 33FFFAF, 3A0A00F, 3AAAA0F, 3AF000F, 3AFAAAF, 3C0CA0F, 3CCC3AF, 3CFF323, 3F33F23, 3FAA00F, 3FF3323, 4004441, 400DDD1, 400E00D, 400ED0D, 404404D, 404448D, 404E4DD, 440EDDD, 4440EDD, 44444ED, 4444E4D, 44DDDDD, 4A000A5, 4CCCCAB, 4D0CCCB, 4E4404D, 4E4444D, 4E4DDDD, 5000021, 5004221, 5006AAF, 500FF6F, 5042201, 508CCCD, 5400005, 5400AA5, 5555405, 5808007, 5AA4005, 5C0008D, 5CCC8CD, 5D4444D, 5EEEEEB, 5F40005, 5F554A5, 5F6AAAF, 60000AF, 60006A9, 600866F, 6008AAF, 600AA8F, 600F6A9, 606608F, 606686F, 608666F, 60AA08F, 60AAA8F, 66000AF, 66666A9, 6666AF9, 6866A8F, 6AAAAAF, 70070D7, 70077DD, 700DDDD, 707077D, 707D007, 70D00DD, 770077D, 770400D, 770740D, 7777775, 77777B7, 77777DD, 7777ACB, 77B88E7, 77DD00D, 77DDDDD, 7D0D00D, 7DD0D07, 7DDD00D, 800002D, 8000CED, 80C0E0D, 80CECCD, 840400D, 844000D, 844E00D, 868688F, 880444D, 884404D, 887D007, 8888801, 8888881, 8888E07, 8888F77, 8888FE7, 88A8AFF, 88AAAFF, 88FAFFF, 8A8AAAF, 8A8AAFF, 8AAA8FF, 8C00ECD, 8C8444D, 8E4400D, 8FCCCCF, 900BBAB, 90CC4AB, 9908AA1, 99E0E01, 9B00801, 9B6CCC9, A000FF9, A006069, A00A8FF, A01CCCB, A05F545, A0BEEEB, A0E4AA1, AA0008F, AA08FFF, AA40AA5, AA8FFFF, AAAA405, AE04AA1, AE44441, AE4AAA1, AECCCCB, AF40005, AFA5A45, AFFFC69, B000BAB, B000EBB, B0D0007, B222227, B6CCCC9, B8880A1, BA000EB, BA0BEEB, BAEEEEB, BB000CD, BB00C0D, BB0B00D, BC6CC69, BC6CCC9, BCCCC69, BCCCCED, C0000A9, 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4444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444DD ===Base 17=== 12, 16, 1C, 1E, 23, 27, 29, 2D, 32, 38, 3A, 3G, 43, 45, 4B, 4F, 54, 5C, 5G, 61, 65, 67, 6B, 78, 7C, 81, 83, 8D, 8F, 94, 9A, 9E, A3, A9, AB, B4, B6, BA, BC, C7, D2, D6, D8, DC, E1, E3, ED, F2, F8, FE, FG, G5, G9, GB, 104, 111, 115, 117, 11B, 137, 139, 13D, 14A, 14G, 155, 159, 15F, 171, 17B, 17D, 188, 191, 197, 19F, 1A4, 1A8, 1B3, 1BB, 1BF, 1DB, 1DD, 1F3, 1FD, 1G8, 1GA, 1GG, 20F, 214, 221, 225, 241, 25A, 25E, 285, 2B8, 2C5, 2CF, 2E5, 2EB, 2F6, 30E, 313, 331, 33B, 346, 34C, 351, 35F, 36E, 375, 37B, 391, 39B, 39D, 3B7, 3B9, 3BF, 3D3, 3D5, 3D9, 3DF, 3E4, 3EC, 3F1, 3F7, 407, 418, 447, 44D, 472, 474, 47E, 47G, 489, 49C, 4A1, 4C1, 4CD, 4D4, 4G1, 502, 506, 508, 50E, 519, 522, 528, 52A, 52E, 533, 53F, 551, 55D, 562, 566, 573, 577, 57F, 582, 593, 599, 59B, 59F, 5A6, 5B5, 5D1, 5D3, 5EA, 5EE, 5F9, 60D, 62F, 634, 649, 689, 692, 6CD, 6EF, 6F4, 6FA, 704, 706, 70G, 71D, 726, 737, 739, 73D, 73F, 753, 755, 764, 766, 76G, 771, 77B, 793, 7AA, 7AE, 7B3, 7BB, 7D7, 7E6, 7F3, 7F9, 7FF, 7G2, 7GE, 7GG, 825, 82B, 849, 852, 85E, 869, 876, 87A, 87G, 88B, 892, 898, 89C, 8C5, 8E7, 8G7, 908, 90G, 913, 91F, 92C, 935, 937, 93B, 951, 953, 957, 95D, 968, 96G, 979, 97B, 98C, 98G, 99D, 9B1, 9B3, 9B9, 9BD, 9BF, 9DB, 9DF, 9F1, 9F5, 9G6, A07, A0D, A1A, A2F, A4D, A72, A7A, A7E, AA1, AA7, ACF, ADA, AG1, AG7, B02, B08, B17, B1D, B28, B2G, B57, B71, B73, B79, B7F, B88, B8E, B8G, B9B, B9F, BB5, BB7, BD7, BDD, BEG, BFF, BGG, C01, C2F, C3E, C56, C6D, C89, C92, C9G, CA5, CBG, CC1, CC5, CF4, CFA, D04, D0A, D15, D3D, D3F, D55, D59, D5B, D71, D75, D7D, D91, D97, D99, D9D, DA4, DAG, DB3, DDB, DF1, DF7, DF9, DFF, E05, E0B, E2B, E52, E58, E69, E92, E9C, EAF, EB8, EC9, ECB, EE5, F04, F15, F1B, F35, F3B, F46, F51, F53, F64, F6A, F73, F79, F95, FAC, FB1, FCA, FD5, FDB, FF1, FF7, FFD, G0D, G0F, G18, G1A, G1G, G2F, G34, G63, G7G, GA7, GC3, GDG, GEF, GFA, GG7, GGD, 1013, 101D, 1033, 1035, 1051, 105B, 105D, 1077, 108A, 109B, 10AG, 10B1, 10B7, 10BD, 10FB, 1149, 1189, 11AF, 11G3, 1303, 130B, 1314, 1341, 1479, 14D9, 1501, 1503, 15A1, 15B8, 1734, 1749, 17AF, 17G3, 1844, 185B, 1875, 1877, 18AG, 18B5, 1903, 1909, 1958, 19BG, 19G3, 1A5D, 1A75, 1A7F, 1ADF, 1AF1, 1B01, 1B09, 1B18, 1B85, 1B89, 1BDG, 1BGD, 1D07, 1D49, 1D9G, 1DF4, 1F09, 1F47, 1F5A, 1F74, 1F7A, 1FA1, 1FAF, 2018, 201G, 202B, 208B, 20G1, 215B, 218G, 21AG, 21B1, 222F, 22AF, 22BG, 22EF, 22F4, 22GF, 251B, 2526, 25F1, 266F, 26FC, 280B, 2A05, 2A58, 2AFC, 2AGF, 2B1B, 2B1F, 2BGE, 2C1G, 2C2B, 2C8B, 2CG1, 2E2F, 2EGF, 2F0C, 2F55, 2FAA, 2FC4, 2FFF, 2GA1, 2GFC, 2GG1, 2GGF, 301B, 301F, 3037, 3053, 3057, 3079, 3095, 30B3, 30BD, 30C4, 31F4, 330D, 3334, 333E, 3349, 3376, 337E, 33CD, 33EF, 3411, 3417, 3499, 3503, 3505, 3509, 353E, 35E5, 35EB, 3604, 36FD, 3701, 3741, 374D, 376F, 3796, 37D4, 37F4, 3956, 3B03, 3B05, 3B0B, 3BBE, 3C04, 3C15, 3C19, 3C4E, 3C59, 3C64, 3CB3, 3CDB, 3CE6, 3D07, 3D14, 3DDE, 3E77, 3E79, 3E7F, 3E99, 3EEE, 3EFB, 3F05, 3F0D, 3FCB, 3FF4, 4009, 4021, 4069, 4098, 40DG, 40GD, 419D, 4201, 4401, 4492, 46AD, 46C9, 46DA, 4719, 476A, 4779, 479D, 47A6, 4906, 4911, 4917, 4919, 491D, 492G, 4982, 4988, 49D7, 49D9, 49GG, 4ADE, 4AE7, 4C49, 4C96, 4CC9, 4D79, 4DAE, 4DEG, 4E7A, 4E96, 4EG7, 4G6D, 4G87, 501B, 5037, 5059, 507D, 50BB, 50BF, 50D7, 50DD, 50F1, 5105, 51A7, 51AD, 521B, 525F, 52FB, 5307, 5356, 53BE, 53DE, 53E9, 5507, 550B, 5587, 5598, 55EF, 560A, 568E, 56AA, 56F3, 5709, 5725, 572B, 575A, 575E, 5769, 57A1, 57B2, 5868, 586E, 58AE, 58B9, 590D, 5918, 5952, 5958, 596D, 5A17, 5A1F, 5ADD, 5ADF, 5AE8, 5B07, 5B21, 5B2F, 5B3E, 5BEF, 5DA7, 5DEB, 5E57, 5E5F, 5E86, 5E97, 5EB9, 5EBF, 5EF5, 5F01, 5F1A, 5F6F, 5FA7, 5FDA, 60AF, 60G3, 64AD, 64DE, 64DG, 663E, 666D, 66AF, 693D, 69CG, 69D3, 69D9, 69G8, 69GC, 6ADE, 6AGD, 6C98, 6D33, 6D4E, 6D93, 6D9F, 6DDD, 6DEE, 6DF3, 6DFD, 6DGE, 6E09, 6G36, 6G4D, 6G6D, 6GD4, 6GDE, 6GFC, 702E, 7057, 705B, 7073, 7079, 7095, 70B5, 70BD, 70D1, 70E2, 70F5, 7107, 7149, 719G, 71BG, 71F4, 724E, 724G, 725F, 72A2, 72BF, 72EE, 72GA, 7314, 733E, 7341, 7363, 73EB, 7419, 742A, 742G, 7442, 74EG, 7501, 750F, 751A, 756D, 757E, 75A1, 75A7, 75BE, 75DA, 75E9, 75F6, 7622, 769F, 76EA, 7734, 773E, 776D, 779G, 77AF, 7905, 790B, 7976, 79B2, 79F6, 79GD, 7A1F, 7A5D, 7AD5, 7ADF, 7AF1, 7AFD, 7B01, 7B09, 7B2F, 7B52, 7B72, 7BE5, 7D01, 7D05, 7D9G, 7DAF, 7DBG, 7E0A, 7E75, 7EA2, 7EA4, 7EB5, 7EBF, 7EE2, 7EF7, 7EG4, 7F0B, 7F14, 7F5A, 7F76, 7FA7, 7G1F, 7G46, 7GA6, 7GD3, 7GDF, 8009, 8058, 80B8, 80E9, 84A7, 850A, 8557, 857B, 85A8, 870E, 8744, 8777, 879B, 87B5, 87B7, 87EE, 8805, 8872, 8887, 8889, 88E9, 8906, 8959, 8966, 89GG, 8A87, 8AE5, 8B0G, 8B59, 8B95, 8B97, 8CB2, 8CB8, 8CE9, 8E56, 8EE9, 9026, 9031, 903D, 907F, 9091, 909B, 90FB, 9101, 910D, 9118, 917G, 9185, 9189, 91B8, 9202, 9288, 92B5, 92FB, 92GG, 93C1, 9505, 950B, 950F, 952B, 956F, 9592, 9596, 9598, 9602, 96D9, 96FD, 971G, 9725, 9752, 97DG, 9855, 9862, 9895, 9899, 98B7, 98BB, 9901, 990B, 9921, 992F, 99G3, 9B0B, 9B2B, 9B8B, 9BB8, 9BBG, 9C19, 9C1B, 9C31, 9C59, 9C95, 9CD5, 9CFB, 9CGC, 9D03, 9D07, 9D7G, 9DG1, 9DGD, 9F0B, 9F76, 9FCB, 9G11, 9G1D, 9G28, 9G3F, 9G7D, 9GCC, 9GD7, 9GF7, 9GFD, 9GG8, A025, A041, A058, A0C5, A0F6, A0GF, A11F, A184, A1F7, A21G, A258, A401, A421, A476, A511, A517, A57D, A5A8, A5E8, A6AD, A6FC, A6GF, A751, A77F, A7F5, A7FD, A7G6, A847, AACD, AC1G, AC41, AC58, AC5E, ACGD, AD0E, AD0G, AD1F, AD51, ADD5, ADE4, ADF5, ADGE, AE56, AE74, AEF6, AEFA, AF77, AF7D, AFA4, AFCC, AFD7, AFDD, AGAF, AGF4, B00G, B037, B055, B05B, B075, B0D5, B0FD, B10F, B198, B25F, B2F1, B2F5, B307, B309, B35E, B3EF, B50D, B589, B7BE, B7BG, B7E7, B875, B952, B958, B97G, B99G, B9G7, B9GD, BB01, BB2F, BB3E, BB89, BB98, BBDE, BD03, BD09, BD5E, BDE5, BDEB, BDG1, BE5F, BF01, BF0D, BG13, BG1F, BG3F, BGD1, BGE2, BGE8, C00B, C034, C05A, C0AF, C0EF, C0GF, C153, C15B, C199, C1B9, C1D1, C1D5, C1F9, C205, C21A, C21G, C252, C258, C2B2, C335, C33D, C35D, C364, C395, C3B3, C3F5, C3FB, C3FD, C414, C41A, C469, C496, C4DA, C4GD, C535, C55B, C5B1, C5BD, C5D9, C5DF, C5E8, C5F3, C5F5, C6E9, C85A, C885, C8B8, C8BE, C8CB, C8E5, C919, C931, C959, C95F, C9D3, CA0F, CA18, CA1G, CAD4, CADE, CAEF, CAGD, CB22, CB33, CB35, CB3F, CB5D, CB82, CB99, CBB1, CBFB, CC49, CCCB, CCDE, CD11, CD1D, CD39, CD4A, CD53, CD93, CDAE, CDD5, CDF3, CDFD, CDG4, CE49, CE5A, CE8B, CF13, CF19, CF5D, CF5F, CFB9, CFBF, CFD9, CFDF, CG14, CG41, CG6F, CGCF, CGF6, CGG1, D01F, D039, D079, D09B, D09F, D0B7, D0BB, D0D1, D0EG, D0GG, D10D, D19G, D1G3, D30B, D347, D3BE, D4E4, D50D, D57E, D5AD, D5FA, D707, D73E, D7E7, D7GF, DA1F, DA57, DAAE, DB01, DB09, DB0D, DB7E, DB9G, DD05, DD7E, DDA5, DDFA, DDG3, DE0G, DE44, DE4A, DE77, DEAE, DEB9, DEBB, DF03, DF05, DG0E, DGDF, E009, E06F, E072, E07G, E089, E0CF, E0E9, E0G7, E47A, E498, E4E7, E50A, E559, E55F, E575, E5B9, E5BF, E5F5, E5F7, E6FC, E722, E724, E72A, E72E, E744, E746, E75B, E76E, E79B, E7A4, E7A6, E7AG, E7B5, E7B7, E7EG, E7G4, E887, E89G, E8E9, E906, E955, E95B, E95F, E988, E99F, E9F9, E9G8, E9GG, EA25, EA7G, EAC5, EAE7, EB7B, EBF5, EBF7, EBFB, EC6F, ECCF, ECEF, EE72, EE76, EE89, EE9G, EF0A, EF44, EF77, EF97, EFA4, EFB5, EFC6, EFFF, EG6F, EG74, EGE7, EGFC, EGGF, F019, F01F, F075, F091, F09B, F0BF, F0FB, F10F, F1A7, F1AD, F1D4, F376, F3CD, F3F4, F40A, F411, F444, F44A, F497, F499, F49D, F4D7, F509, F57A, F5AD, F5F6, F6D3, F6D9, F70D, F741, F747, F76D, F7F6, F7FA, F907, F976, F9CB, FA11, FA7D, FADD, FB09, FC4C, FC5D, FC5F, FC91, FCB9, FD1A, FD41, FD47, FDF4, FF0B, FF56, G021, G07A, G0A1, G0E7, G11F, G17F, G1DF, G1F1, G1F7, G201, G2A1, G306, G311, G36C, G377, G37F, G3CC, G3CE, G3D1, G476, G487, G4DE, G6AF, G6D4, G6F6, G6GF, G713, G724, G731, G742, G74E, G76E, G7A2, G872, G874, GA21, GAC1, GC6F, GCAF, GCD4, GCDA, GCG1, GD73, GD7F, GDAE, GDDF, GDEA, GDFD, GE47, GE7E, GF13, GF33, GF3F, GF4C, GF71, GF7F, GFDD, GG01, GG21, GGAF, GGC1, 1000G, 10053, 100AA, 100B9, 100F1, 100FF, 10301, 10587, 10705, 1075A, 107GF, 10895, 108B9, 10985, 1099G, 10B98, 10B9G, 10D03, 10D0F, 10D7A, 10DG3, 10DG7, 10G1F, 10G3F, 110GF, 1140D, 11D93, 11DG4, 11F0A, 11G4D, 11GD4, 13333, 133FF, 13F44, 14109, 14499, 150A7, 153B1, 1570A, 17005, 17799, 177AG, 17995, 17A7G, 17G47, 18079, 18507, 185A7, 18B07, 18B9G, 19333, 199B5, 1A00A, 1A00G, 1A0F5, 1AAAA, 1AAAG, 1AF05, 1AFFA, 1B07G, 1B10G, 1B807, 1D001, 1D1AA, 1D7G4, 1DG03, 1DG41, 1F001, 1F00F, 1F01A, 1F0A7, 1F199, 1F1F9, 1F414, 1F449, 1F7F5, 1F999, 1FF0A, 1FFAA, 1FFB5, 1G073, 1G14D, 1G1F4, 1G301, 1G477, 1GD01, 1GD47, 1GF07, 1GFF4, 20005, 200A1, 2010A, 20586, 20588, 20A01, 20B11, 20B15, 20BEE, 20C1A, 20CBE, 210B5, 21A1F, 21A51, 21F1A, 21G1F, 21GFF, 222BE, 228B2, 228BE, 22BE2, 22C0B, 22F0A, 252BB, 25505, 25552, 26GAF, 2A001, 2A1FF, 2A55F, 2AEEF, 2AF44, 2B051, 2B20E, 2BB2B, 2BBBG, 2BE22, 2BEE2, 2BEEE, 2BF0B, 2C0BE, 2C18A, 2F101, 2F1FA, 2F44C, 2FCBB, 2G1FF, 2GA6F, 2GF44, 30035, 300B1, 300FB, 30101, 303C5, 30444, 30497, 304D1, 304D7, 30703, 30714, 30734, 30763, 30774, 30CF5, 30CFD, 30D41, 30FC5, 3100B, 31779, 31F5B, 31FB5, 31FFF, 330C5, 330F4, 33357, 33373, 33379, 33555, 33557, 33777, 3379F, 337FD, 33997, 33D44, 33D4E, 33F3D, 33FF5, 34019, 34044, 340D1, 353DD, 35535, 355B3, 355E6, 35BB3, 35DDD, 3636D, 364DD, 3663D, 36DD4, 37003, 3700F, 3717F, 373EE, 37609, 3774E, 37773, 37797, 37977, 3797F, 37EEF, 39007, 390C5, 39777, 39973, 3B355, 3B553, 3BBDB, 3BDB1, 3C03D, 3C0F5, 3C10F, 3C141, 3C444, 3CBE5, 3CD0D, 3CE5B, 3CEBB, 3CEF9, 3D401, 3DEBE, 3E006, 3E066, 3E57E, 3E5E9, 3E666, 3E90F, 3EF6F, 3F33D, 3F3C4, 3F5BB, 3FB33, 3FDDD, 3FF59, 4006D, 400DE, 4011D, 401D9, 40414, 4041G, 404C9, 40966, 40D11, 40D19, 40D1D, 40E49, 41019, 411DA, 41AAG, 4210A, 44049, 4410G, 44144, 441G4, 44441, 444E9, 446E9, 44986, 44E49, 4609G, 460E9, 466DE, 469DD, 46E9G, 4711A, 476D9, 4770D, 47A77, 47D09, 49099, 490D1, 49226, 49622, 49699, 496DD, 49996, 4999G, 499G7, 49G22, 49G77, 4A7DD, 4AA6D, 4ADD7, 4C0E9, 4C999, 4D1DA, 4DADD, 4DD01, 4DD1G, 4DD7A, 4DDA7, 4DDE9, 4DG0G, 4DGAA, 4DGGA, 4DGGE, 4E049, 4E449, 4E49G, 4E4E9, 4E797, 4G7DD, 4GDAA, 4GDD7, 50011, 50079, 50095, 500B1, 500F3, 501A5, 501AF, 50503, 507A5, 50AF7, 50F03, 50F7A, 510A1, 510DA, 511AA, 511DF, 5135B, 515B7, 5180B, 51A0F, 51F0A, 520B1, 53005, 531BD, 53559, 53609, 53B11, 55205, 55357, 553E6, 5555B, 5556E, 55588, 5558A, 555F3, 555FB, 556AF, 556E9, 55759, 5575B, 55805, 55885, 55896, 558B8, 55926, 55BE2, 55E8B, 55F57, 560FF, 5700D, 570A5, 570DA, 575B9, 576AD, 576DA, 579D5, 57A05, 57A52, 57B9D, 57DBD, 58057, 58509, 5855A, 585A7, 587EB, 58857, 588E8, 58A75, 58B0B, 58B87, 58BBE, 58BEB, 58E5B, 591D5, 59201, 59256, 59715, 59807, 5A88A, 5AA88, 5AFAD, 5B001, 5B00B, 5B1F1, 5B31B, 5B7E2, 5B80B, 5BB13, 5BBE8, 5BBFB, 5BE87, 5BE8B, 5BF37, 5BFBD, 5D00F, 5DA05, 5DA5A, 5DAE5, 5DBBD, 5DD95, 5DDAA, 5DFDD, 5E879, 5E8B7, 5E8BB, 5F07A, 5F0AD, 5F37D, 5F70A, 5F7BD, 5FB7B, 5FBBB, 5FBF3, 5FFF3, 6003E, 60098, 603E6, 606GF, 60986, 609C8, 60G6F, 60GCF, 6336D, 633E9, 63CCE, 63E06, 63E66, 6609G, 660E9, 66AD4, 66D4A, 66DG4, 66DGG, 66E98, 66FD9, 66GF6, 69806, 69866, 69C86, 69CC8, 6A66F, 6AAGF, 6AF06, 6AF66, 6AGGF, 6C6G3, 6C6GF, 6CCGF, 6CG03, 6DA0E, 6DAEA, 6DD9G, 6DDE9, 6DEGA, 6DGD3, 6E986, 6EEE9, 6F69D, 6F6DF, 6F96D, 6FD03, 6FD09, 6G003, 6G3F3, 6G3FF, 6G6CF, 6GAAF, 6GCCF, 70031, 70099, 700BF, 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IIIIIIIIIBIII3, J0000000000GJJ, JJJJJJJE00000J, K00000000006GD, K0000000000CFF, K0000000000JI7, K000000000B055, K00000000K0KB5, K022222222222D, K0KKKKKKK00045, K0KKKKKKKKK545, K6CCCCCCCCCCCF, KEEEEEEEEEEE07, KKKKKKKKKKK0B5, L0LLLLLLLLLK77, L88888888888EJ, LK0000000000FF, LLLLLLLLLK00E7, LLLLLLLLLL9G33, LLLLLLLLLLGI33, LLLLLLLLLLL3G3, LLLLLLLLLLL9EL, LLLLLLLLLLLGI3, 200000000000JJ7, 2A0000000000001, 2CCCCCCCCCCCCCL, 2K00000000000K5, 3000000000009G9, 4HHHHHHHHHHHEEH, 50000000000010D, 500000000000KB5, 50E0000000000I7, 700000077777II7, 700777777777II7, 7700000000007I7, 7700700000000I7, 7707000000000I7, 777777777777727, 7IIIIIIIIIIIIIF, 7LLLIIIIIIIIIIF, 80008888888888J, 80088888888888J, 80D00000000000D, 89000000000080J, A0000000000I4IH, B00000000000HEH, B000000000BBEBD, B0BBBBBBBBBBBB5, BBBBBBBBBBBBBB1, BBBBE000000000D, C00000000000LEL, CEEEEEEEE0EEE0L, D555555555550A5, DHHHHHHHHHHHHHH, EKEEEEEEEEEEEE7, FFFFFFFFFFFFG45, FFFFFFFFFFFIIAF, G000000000000B5, G0GGGGGGGGGGGG3, GG000000000002J, H000000000000B1, I77777777777777, K000000000K0BK5, K0000000KKKKK25, K000EEEEEEEEEE7, K05555555555KB5, KEEEEEEEEEEE7E7, KEKEEEEEEEEEEE7, KK00000000005EF, KK0K000000000B5, L000000000006B3, L0000000000ILB3, L0000000000LIB3, LCLEEEEEEEEEEEL, LLLLLLLLLL00KE7, LLLLLLLLLLILLB3, LLLLLLLLLLLK0E7, LLLLLLLLLLLL4G3, 20000000000000K7, 3AF000000000000F, 4000000000000IEH, 4IIIIIIIIIIIII33, 500000000000IJG9, 509B00000000000J, 59000000000000BJ, 6000000000008KK1, 60I00000000000B3, 6GGGGGGGGGGGGGED, 70000000000000I7, 700000000000EKE7, 7070000000007II7, 70777777777777I7, 7077777777777II7, 77000007000000I7, 80000000000000DD, 80000000000000E1, 888888888888888J, 900000000000088J, 988000000000000J, A000000000000001, A000000000000015, A0000000000002A1, BBBB0000000000ED, BH00000000000001, CLEEEEEEEEEEEEEL, D055555555555555, DDDHHHHHHHHHHHHH, EEEEEEEEEEEEEEEH, EELLLLLLLLLLLLB7, EHHHHHHHHHHHHHHH, GI0G00000000000H, HEEEEEEEEEBEEEEH, HHHHHHHHHHHHHH2D, I0000000000000B3, IEEEEEEEEEEEE7E7, J0000000000000GH, J000000000000JBJ, J00000000000JIJJ, JJ00000000000IJJ, JJJJE0000000000J, K000000000000K25, KFFFFFFFFFFFFCFF, L00000000000000J, LLLLLLLLLLL0LIB3, LLLLLLLLLLLECLLL, LLLLLLLLLLLLILB3, LLLLLLLLLLLLLG33, LLLLLLLLLLLLLKFF, 2KK00000000000005, 44EHHHHHHHHHHHHHH, 55555555555555BB5, 5B0BBBBBBBBBBBBBD, 7000000000000I40H, 707777777777777K7, 77000000000000I77, 8000000000000008D, A0000000000000CB1, A0000000000000EEH, B00000000000000D1, BAA55555555555555, BIIIIIIIIIIIIII63, C00000000000002IL, C0000000000000CEL, CCEEEEEEEEEEEEEEL, CEEEEEEEEEE0EEEEL, CEEEEEEEEEEEE0EEL, D000002222222222D, D5555505555555555, D5555555555505555, DGGGGGGGGGGGGGEED, F0000000000000EBD, F000000000000262D, F000000000000E0BD, F000000000000F6B3, F000000000000K6FF, F000000F6000000B3, GGGGGGGGGGGGGGGGD, HHEEBEEEEEEEEEEEH, HHHHHHHHHHHHH2GGD, HHHHHHHHHHHHHGBBD, JJE0000000000000J, JJJJJJJJJJJJJK00J, K0000000000000B55, K80000000000000I7, L0000000000000IB3, L0000000000009E2J, LLLLLLLLLLEB00007, LLLLLLLLLLLLLBGG3, 2D0000000000000001, 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5IIIIIIIIIIIIIIIIIIIIIIIIIIF, D555555555555555555555550555, EEAAAAAAAAAAAAAAAAAAAAAAAAAF, HHHHHHHHHHHHHHHHHHHHHHHHEEBH, K66666666666666666666666666F, LLLLLLLLLLLLLLLLLLLLLLLLEEB7, D5555555555555555555555555A55, GGGGGGGGGGGGGGGGGGGGGGGGGGGG3, GIG0000000000000000000000000H, HH00000000000000000000000001H, K0000000000000000000000005KEF, 5BBBBBBBBBBBBBBBBBBBBBBBBBBBBD, HB0000000000000000000000000001, K000000000000000000000000505EF, L7777777777777777777777777772L, 2000000000000000000000000000CB1, C8CCCCCCCCCCCCCCCCCCCCCCCCCCCC9, IKKKKKKKKKKKKKKKKKKKKKKKKKKKKFF, JE0000000000000000000000000000J, K000000000000000000000000000261, A0000000000000000000000000004I4H, HD000000000000000000000000000001, K000000000000000000000000000EC01, K0FFFFFFFFFFFFFFFFFFFFFFFFFFFFCF, D0002222222222222222222222222222D, FFFFFFFFFFFFFFFFFFFFFFFFFFFFFFL2L, I700000000000000000000000000000GH, K00000000000000000000000000000E61, 20000000000000000000000000000000JJ, DD5KKKKKKKKKKKKKKKKKKKKKKKKKKKKKKF, 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6000000000000000000000000000000000000000000000000000000000000000000000000000000043, KKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKB5, HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHEEH, 4HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHEH, 50000000000000000000000000000000000000000000000000000000000000000000000000000000002C1, K0000000000000000000000000000000000000000000000000000000000000000000000000000000000055EF, H700000000000000000000000000000000000000000000000000000000000000000000000000000000000000000H, 80000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000K1, EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE0I7, HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHEH, 5000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000BB5, J000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000BIJ, C4IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII3, F0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000066B3, G0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000A5, D5KKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKF, HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHBH, L0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000IKF, 4IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII3, A400000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000H, DKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKF, 4HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH, E0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000071, 7LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLIL, LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLK77, EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEI7, LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLIB3, I7G00000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000H, 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77EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEK7, JJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJKJ, 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LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLKE7, 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BKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKK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80BN, 80FH, 80LN, 80MN, 840N, 848N, 866B, 86FB, 880B, 880N, 884N, 88CB, 88FB, 88LN, 88MN, 8BBB, 8BLB, 8C6B, 8CCH, 8CFH, 8F0B, 8FHH, 8FLB, 8H0H, 8HCH, 8IGN, 8ILN, 8KKH, 8L8B, 8LBB, 8LFB, 8LIN, 8M8N, 8MLN, 8N0N, 8NGN, 8NLN, 9061, 9091, 90EJ, 90F1, 90GJ, 90K1, 940J, 9501, 95F1, 9CC1, 9E0J, 9E95, 9F61, 9FI5, 9G3J, 9II5, 9K01, 9KK1, 9M01, A007, A05D, A0AD, A33D, A3AD, A3F5, A44J, A727, A9EJ, AA0D, AAAD, AAAJ, ACM7, AD8D, ADKD, AE27, AE9J, AEAJ, AEE7, AIAD, AIDD, AIID, AJ9J, AK5D, AM07, AM27, AM35, AMK5, B08B, B0CB, B0GB, B18B, B1CB, B80B, B8CB, BB21, BB4N, BBCB, BBF1, BBFB, BBK1, BC8B, BCF1, BCLB, BF1B, BF8B, BFB1, BFM1, BGC1, BGF1, BK21, BL8B, BLFB, BM1B, BM3N, BMB1, BMMN, BNF1, C00D, C06B, C077, C0D7, C0H7, C0L7, C0LB, C0M1, C60H, C6LB, C76H, C7E7, CAID, CC01, CCFH, CCKH, CDLB, CGE7, CH07, CHE7, CI8D, CIAD, CK0D, CL8B, CLDB, CLE7, CM01, CM07, CME7, CMM1, D007, D08D, D0C7, D0HH, D0LN, D0M7, D0NN, D207, D2KH, D2M7, D777, D7E7, D80H, D8LD, DA27, DAC7, DAM7, DBFB, DBMB, DC77, DCLB, DDL7, DE77, DF0H, DF2H, DFFH, DFMB, DH27, DH8H, DHC7, DHHH, DILN, DK0H, DK2H, DK8H, DKHH, DLIN, DLL7, DLM7, DLMB, DM07, DMH7, DMMB, DNGN, E07J, E09J, E335, E355, E555, E5A5, E5K5, E79J, E93J, E995, EA35, EE95, EKE5, F00B, F00H, F06H, F08B, F0I5, F11B, F18B, F1L1, F20H, F26H, F2FH, F355, F661, F6K1, F80B, F86B, F8BB, FBGB, FBK1, FBLB, FC0B, FC6H, FCLB, FEK5, FGB1, FH05, FH0H, FH35, FH6H, FHCH, FHF5, FHHH, FI05, FK91, FKK1, FL1B, FLB1, FLBB, FM61, FMBB, FMK1, G00J, G021, G027, G0EJ, G0JJ, G0M1, G0M7, G1CB, G2E7, G40J, G4AJ, G4IJ, G4JJ, G6C1, G701, G94J, G9IJ, GAEJ, GAJJ, GB21, GBM1, GC01, GCF1, GCLB, GE0J, GEAJ, GEE7, GEG7, GEIJ, GEL7, GFM1, GGE7, GGMB, GI0J, GIIJ, GIIN, GJ9J, GM27, GMB1, GNM7, H005, H0K5, H0M5, H207, H2E7, H335, H3I5, H595, H5K5, H60H, H68H, H76H, H80H, H8HH, HAAJ, HE7J, HEC7, HGE7, HGM7, HH35, HI55, HIM5, I00J, I035, I08D, I0CD, I4JJ, IC0D, ICID, II0D, II0J, II35, IIAD, IILD, IIM5, IIMN, IJ9J, ILCD, IM05, IM35, IMNN, INLD, J03J, J0HJ, J0JH, J2CH, J39J, J3ID, J60H, J62H, J8CH, J9IJ, JGAJ, JGJJ, JH9J, JI0J, JIDD, JJ0H, JJCD, JJJD, JJLD, JL3D, JLCD, K0E5, K0I5, K0K1, K0KH, K191, K211, K2F1, K2G1, K591, K5AD, K6F1, K6G1, K9I5, KA0D, KAAD, KAM5, KCCH, KCHH, KD8D, KDDD, KFI5, KG01, KG61, KH0H, KHHH, KI55, KIDD, KK21, KK8H, KKF1, KKK1, KKKD, KM8H, KMHH, KMK5, L027, L0M7, L1C1, L1MB, L211, L727, L8BB, L8BN, L8FB, L8LN, L9C1, L9M1, LB8B, LBC1, LBM1, LCAD, LD77, LDIN, LDL7, LDM7, LF8B, LG21, LIIN, LLLN, LLN7, LM07, LM1B, LM77, LMG1, LN77, LNM1, M00N, M01B, M03N, M055, M077, M08B, M0B1, M0C1, M0GB, M0K1, M0M7, M0N7, M18B, M1BB, M1MB, M26H, M335, M3GN, M3M5, M3MN, M3NN, M501, M53N, M5M1, M5NN, M6BB, M6C1, M6G1, M6KH, M88B, M88N, M8BB, M8NN, MBB1, MC01, MCC1, MCKH, MCM1, ME07, ME35, MEK5, MGGB, MGMB, MH35, MH8H, MHE7, MHM5, MK8H, MKC1, MKG1, MKHH, MKK5, ML8N, MM01, MM8B, MMC1, MMLN, MMM5, MMMN, MMN1, MN0N, MN27, MNGN, MNLN, N007, N027, N077, N0C7, N0DN, N0IN, N1M1, N227, N2M7, N661, N707, N727, N8LD, NA27, NA3D, NC07, ND0D, ND0N, NDLD, NF11, NF61, NGG7, NILN, 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5M0M1, 5MNNN, 5N03D, 5N3LD, 5NA8D, 5NADD, 5NDGN, 5NNGN, 600KH, 61661, 616L1, 61MM1, 66161, 66611, 666B1, 666L1, 666LB, 66BB1, 66BG1, 66BLB, 66G61, 66KF1, 66LBB, 66LG1, 6BBBB, 6BFCB, 6CC11, 6F1M1, 6F66B, 6F6B1, 6F6L1, 6FBCB, 6FLMB, 6FMCB, 6FMM1, 6FMMB, 6GCM1, 6GM61, 6GMC1, 6K1C1, 6K1K1, 6KK11, 6KKL1, 6KL11, 6L1G1, 6LBFB, 6LCC1, 6LFMB, 6MM61, 6MM6B, 70291, 702C1, 702G1, 72CF1, 72EE7, 7433J, 7443J, 77A07, 79901, 799F1, 7AAEJ, 7EE27, 7H9EJ, 7K2KH, 7KK2H, 7KKKH, 7KKMH, 7L2C1, 800NN, 806BB, 808BB, 808LB, 80F8B, 80IIN, 833ID, 860KH, 8886B, 888NN, 8BG4N, 8CH6H, 8CKHH, 8FC0H, 8FFCH, 8HHHH, 8IIIN, 8K0HH, 8LL4N, 8M0NN, 8MNNN, 8NNND, 9000J, 900M1, 9034J, 90IIJ, 94IIJ, 96CM1, 96KF1, 96MM1, 990C1, 990M1, 99591, 99961, 999C1, 99F91, 99FM1, 99KF1, 99M61, 99MK1, 9AAA5, 9FEE5, 9FFA5, 9FFF5, 9II4J, 9K6C1, 9K9C1, 9K9F1, 9KF91, 9M6M1, 9MK61, A02M7, A0A35, A0AM5, A0C77, A0D0D, A0DDD, A0EC7, A0M55, A0MM7, A2ME7, A3335, A33M5, A3555, A3MM5, A550D, A58ID, A5D0D, A5DDD, A74AJ, A7E07, AA0M5, AA3ID, AA3M5, AA83D, AA8ID, AAAM5, AACID, AAICD, AAM05, AC08D, AC0ID, AC0KD, AC8ID, ACA8D, AFA35, AIC8D, AJAJJ, AK0KD, AKI0D, AKKM5, AKM05, AM505, B00FB, B00LB, B0LBB, B1MBB, B1MMB, B2GM1, B3MGN, B88BB, BB3MN, BBB3N, BBB8B, BBBBN, BBBMN, BBCC1, BBGB1, BBGLB, BBMC1, BBMGB, BBNM1, BFB0B, BFBMB, BFGLB, BFGMB, BGGLB, BGMM1, BLMMB, BMC0B, BMGM1, BMMK1, BMNM1, C006H, C00CH, C00M7, C0C11, C0CC1, C0E07, C0F6H, C0GG7, C0K8D, C0KDH, C0KHH, C1CC1, C1CM1, C1MC1, C70F1, C886B, CC06H, CCCCH, CCCF1, CCCM1, CDHH7, CE707, CE7L7, CEE77, CEEG7, CEL07, CFFHH, CGLL7, CHC6H, CHCCH, CHH7H, CHHH7, CHHM7, CI0LD, CK0HH, CKHCH, CL007, CLD07, CLLL7, CM777, CMMM7, D008H, D07L7, D0DE7, D0EL7, D0L77, D0M8H, D0NA7, D22E7, D70A7, D7227, DBLBB, DCL07, DD7A7, DDAE7, DDD8D, DDE07, DDK0D, DDM77, DEE27, DKK8D, DL227, DL707, DLBBB, DLDFB, DLE27, DM2E7, DMM77, DMME7, DN0A7, DNIIN, DNLLN, E000J, E0227, E02E7, E0AAJ, E0GL7, E0I0J, E2E07, E7AAJ, E7E27, EAA55, EAK55, EC777, ECEE7, ECEL7, ECGL7, ECL77, EEC77, EECL7, EEEC7, EEG27, EEGG7, EG0E7, EG0L7, EG207, EGE07, EGG07, EGG27, EGL07, EI9IJ, F02HH, F06LB, F0C6B, F0CCH, F0CHH, F0E55, F0EA5, F0FH5, F0GGB, F0M2H, F0MGB, F0MMB, F1BMB, F3FF5, F3I35, F3II5, F6BCB, FA035, FB1MB, FBBM1, FBBMB, FBM8B, FC0HH, FC88B, FCFHH, FFC0H, FFCFH, FFCHH, FFF0H, FFF6H, FFFH5, FFHI5, FFI55, FG1MB, FGGCB, FGM1B, FHK55, FI5I5, FKEA5, FKKI5, FKL11, FM16B, FM1CB, FM62H, FM6CB, FMBG1, FMM0B, G0001, G00E7, G039J, G06F1, G07C1, G07F1, G0A9J, G0G07, G0GG7, G0I4J, G0I9J, G0LL7, G22M7, G2M07, G339J, G433J, G62M1, G6M61, G6MM1, G903J, G933J, GAA9J, GBCC1, GE007, GGGGB, GGGL7, GJ0IJ, GL007, GL2M7, GLL07, GLLM7, GMGCB, GMM07, GMM1B, H007H, H05I5, H0CCH, H0CM7, H0GG7, H0H27, H0H8H, H0HC7, H0HH5, H0I35, H0MM7, H3555, H35F5, H3F55, H3FF5, H5055, H50F5, H7HEJ, H9995, H9GEJ, HCC0H, HCC6H, HCGG7, HCHM7, HE027, HE0G7, HEE07, HEEG7, HEG27, HF0F5, HF505, HF555, HFF05, HFKF5, HG0G7, HH06H, HH08H, HH0H5, HH5I5, HH7HJ, HH9EJ, HH9I5, HHCHH, HHE07, HHGG7, HHH05, HHH7H, HHH9J, HHKI5, HHM05, HHM07, HHM27, HI0I5, HJ86H, HJC0H, HK055, HK9F5, HKF05, HKFF5, HKFK5, HKII5, HKK95, HM2M7, HME27, HMKM5, HMM05, HMM27, HMM55, HMMM7, I00DD, I00M5, I044J, I0505, I09IJ, I0AAD, I0D0D, I0DDD, I0I05, I0IDD, I0II5, I0IJJ, I0JIJ, I33M5, I4I4J, I5INN, I888N, I8NND, I8NNN, I904J, I94IJ, IA8ID, IAADD, IAI8D, IDDDD, IDINN, II88N, II8NN, IID8D, IIDIN, III8N, IIIDD, IIIID, IIIIN, IIIND, IIN8D, IINDD, IJJ0J, IJJJJ, ILILN, ILLIN, IMM8N, INA0D, INDNN, INGIN, INNDN, INNND, J000H, J002H, J00AJ, J00GJ, J00KH, J02KH, J068H, J080H, J090J, J0A9J, J0AAJ, J0C0H, J0G0J, J0IIJ, J0JGJ, J0JIJ, J0K8H, J2K0H, J2KKH, J6K8H, J86KH, JC00H, JC0KH, JCCCH, JCK0H, JCKCH, JDDLD, JG93J, JIIJJ, JJ0IJ, JJ2KH, JJ9GJ, JJCCH, JJG9J, JJGIJ, JJJ9J, JJJJH, JJK8H, JK08H, JK0CH, JK8KH, JKC0H, JKKKH, K0001, K0091, K020H, K02C1, K03ID, K0611, K06L1, K083D, K08HH, K0961, K09C1, K0CF1, K0F91, K0KM5, K0LG1, K1G21, K20HH, K29K1, K2KHH, K5001, K500D, K58ID, K5D0D, K5L11, K6621, K6C11, K6LC1, K8CKH, K8KCH, K96C1, K99E5, K9F91, K9FA5, K9FE5, K9K91, KA55D, KC011, KCF11, KD02H, KD0MH, KD20H, KDM2H, KEA55, KEAA5, KEK95, KEKK5, KF1G1, KF1K1, KF611, KF6L1, KFEA5, KH8CH, KI005, KIMM5, KK05D, KK0AD, KK0DH, KK2CH, KK2KH, KK33D, KK961, KK9C1, KKA5D, KKD0D, KKE55, KKI0D, KKIID, KKIM5, KKK0H, KKKM5, KLGC1, KMK2H, L188B, L1991, L2007, L22M7, L2EE7, L2MM7, L333D, L3LIN, L7291, L72G1, L88IN, L8C8B, L9991, LBB1B, LBBBB, LBBBN, LD0E7, LDBBN, LE207, LFMCB, LGCC1, LL227, LL3IN, LL48N, LLM27, LLMM7, LMBCB, LME27, LMMBB, LMMM7, LN33D, LN3AD, LNAAD, LNACD, M0007, M0061, M00K5, M0207, M066B, M0BCB, M0EE5, M0G01, M0GM1, M0M8N, M27KH, M2E27, M2M07, M2M27, M5005, M5555, M66CB, M66K1, M6K61, M6MCB, M7007, M7EE7, M8C0B, M8KCH, M8MGN, MBBGB, MBGM1, MCCCH, MCHCH, MEE55, MGBC1, MGMM1, MH227, MH2M7, MHH7H, MKM55, ML3LN, MM0CB, MM16B, MM227, MM661, MM6K1, MME55, MMEE7, MMKE5, MMM07, MMM6B, MMMB1, MMMGB, MMMM7, MNM61, MNN3N, N00CD, N00KD, N03LN, N0A8D, N0AM7, N0D8D, N0KKD, N0L3N, N0LAD, N0NDD, N16L1, N3GIN, N3LAD, N3LIN, N3NNN, N61L1, N96M1, N9M61, NA0CD, NAK0D, NAKKD, NCA8D, NCM77, NDGIN, NDIIN, NDLLN, NF991, NGM07, NIIIN, NINNN, NKKDD, NLNAD, NN0LN, NN191, NN3NN, NN6L1, NN83D, NNAAD, NNDIN, NNGIN, NNL3N, NNLND, NNM61, NNNIN, 166G21, 16G621, 19MMM1, 1BBBMB, 1BBGM1, 1GCCC1, 1GCCM1, 1MMM1B, 200E27, 2E0027, 2HH0HH, 2HHC0H, 2KK0HH, 2M0E27, 2M22E7, 30NNNN, 3333M5, 333AID, 333I35, 33I555, 3F5FF5, 3I3MM5, 3I88GN, 3II8LN, 3IIII5, 400IJJ, 40J00J, 40JJ3J, 40JJJJ, 44403J, 444I0J, 44IJJJ, 44J0JJ, 44JJIJ, 48I8IN, 4I440J, 4II8IN, 4IJ0IJ, 4JIIIJ, 4JJ0JJ, 4JJJ0J, 50033D, 5003AD, 5008ID, 500D8D, 500G01, 500L11, 500LAD, 500MG1, 503LAD, 508ILD, 50DDLD, 50ILAD, 50M001, 516G61, 519MM1, 538NNN, 53NNNN, 55005D, 5508ID, 550D8D, 558ILD, 55F5I5, 56G661, 58333D, 58NNNN, 5999F5, 59AAF5, 5DNNNN, 5F55I5, 5FMMM1, 5G6661, 5K9AA5, 5KK9F5, 5KKK95, 5M0001, 5NDD8D, 5NDINN, 5NN33D, 5NNLAD, 5NNNAD, 5NNNDN, 608K0H, 61CCM1, 61G621, 661G21, 666621, 6666CB, 6666F1, 66K661, 6BCCC1, 6BKKC1, 6F6BBB, 6G6621, 6GCCC1, 6GMMM1, 6K6K61, 6M666B, 70A077, 70L991, 7722E7, 772E27, 7772E7, 777A27, 777L27, 77A777, 77EL27, 7A7077, 7A7777, 7E7227, 7L2E27, 7LEL27, 7LL2E7, 7LLE27, 7LLL27, 800GIN, 80NINN, 80NNNN, 8BBMGN, 8C888B, 8C88LB, 8MM0GN, 900001, 90043J, 959MM1, 96K661, 9999F1, 9999K1, 999AF5, 999FF5, 99EEE5, 99K991, 99MMM1, 9AAFF5, 9EIIIJ, 9F9991, 9F9MM1, 9FEAA5, 9G444J, 9K9991, 9M6661, A000CD, A000KD, A000M5, A0083D, A00I0D, A00M05, A022E7, A07E77, A0FF35, A0K3ID, A0K83D, A4AJJJ, A77777, AA0035, AA0355, AAA035, ADDD0D, ADDDDD, AF0035, AFFF35, AKK8ID, AM0M05, AM7777, B0F0MB, BBBBM1, BBLBMB, BFBBBB, BFM0MB, BFMMMB, BLBBMB, BLMBBB, C00071, C000E7, C007C1, C00G07, C07KKH, C0CC6H, C0CH6H, C0EEE7, C0HHHH, C777L7, C77L77, C7L777, C7LL07, C8088B, CAAK8D, CAKKAD, CC000H, CC0CHH, CD000H, CD0KKH, CE0007, CEE0E7, CELL77, CG0007, CGGL07, CH0CHH, CHCH0H, CHHH6H, CK0C0H, CKAK8D, CKKA8D, CL7707, D002FH, D0D0KD, D0DA77, D0DKKD, D0IIIN, D0K0DD, D0KDKD, D0KKDD, D0KKKH, DC0EE7, DCEEE7, DD0227, DD0D27, DD0DKD, DD0KKD, DD2E27, DDD0D7, DDD0LD, DDD227, DDDA77, DDDBCB, DDDCE7, DDDDFB, DDDMM7, DDEEE7, DDMBCB, DEEC07, DH000H, DHMEE7, DIIIGN, DK0KDD, DKMKKH, DMBBBB, DMEEE7, DMMM27, E00G27, E07727, E0C707, E0CE77, E0E027, E0EEG7, E0EGE7, E0EL27, E0GE27, E0L207, E0LE27, E0LL27, E2E2E7, E7L2E7, E900IJ, E9EEE5, EAAKK5, EC00E7, EC0G07, EC7007, ECEG07, EE0G07, EE0GE7, EE72E7, EE7L27, EECE07, EECEG7, EEEEE5, EEEK55, EEEKA5, EEEL27, EEGLL7, EELE27, EGLLL7, EKK595, EKKA55, EKKAK5, EKKKK5, F000E5, F0AA35, F0F035, F0FFFH, F0HKK5, F0KKE5, F16BB1, F16MM1, F1BBBB, F1MC6B, F666BB, F66BBB, F6GMM1, FB0BBB, FB1BBB, FBBB0B, FBMMG1, FC0FFH, FCFCCH, FEEE55, FEEEA5, FF03F5, FF0FFH, FF3F35, FFEE35, FFF2CH, FFFCCH, FFFFE5, FFI335, FFKFE5, FGLMMB, FK55I5, FKFE55, FLM8CB, FMC66B, FMMC6B, G0AA4J, G0CCC1, G0LE07, G666F1, GG0007, GG00G7, GG0L07, GGLLL7, GGLMM7, GI444J, GJJ33J, GLLE27, GLMMCB, GM0661, GMMM61, H00G07, H05555, H09FF5, H0C0E7, H0CE07, H0CEE7, H0E227, H0H007, H0H5F5, H0H995, H0HHE7, H0HHH7, H55505, H55II5, H5FII5, H99FF5, HEG007, HFFK55, HH0007, HH02M7, HH0C0H, HH7AEJ, HHC0E7, HHE227, HHH0C7, HHH0M7, HHH995, HHHC0H, HHHE27, HHHEAJ, HHHH07, HHHH8H, HHHHE7, HHHHI5, HHHHJH, HHHJ8H, HHHJCH, HHJ00H, HHK095, HHKKM5, HKK0F5, HKK5F5, HKKK55, HKKKK5, HKM555, HMEEE7, I00555, I05555, I0I94J, I333I5, I33555, I444IJ, I55055, I55505, I55555, IAAC8D, ID000D, IDD0LD, II9I4J, III4IJ, III505, IIIC8D, IIJIJJ, IJIIIJ, IM8LLN, IN00AD, INAACD, INCAAD, ININGN, J00CCH, J0IJJJ, J0J09J, J3333D, JIJIIJ, JJ68KH, JJIJIJ, JJJAJJ, JJJHGJ, JJJJAJ, JJJJGJ, JJJJIJ, K0008H, K00161, K001G1, K001L1, K002CH, K002HH, K00521, K00AKD, K00C0H, K00GF1, K00I0D, K00K95, K00M05, K01621, K05021, K0505D, K051G1, K059F5, K05K95, K0C0C1, K0L291, K0M005, K0M505, K1K661, K2CK0H, K33IAD, K3IIID, K5550D, K56121, K59AA5, K612K1, K61CC1, K66661, K6K611, K900C1, K99661, K9AFF5, K9C001, KAKI8D, KC00C1, KDK00D, KF9991, KI0IID, KK000D, KK01L1, KK0661, KK0I8D, KK0L11, KK0M2H, KK5661, KK59F5, KK61C1, KK9995, KK9EE5, KKA3ID, KKA83D, KKAI8D, KKC001, KKC0C1, KKC1C1, KKCCC1, KKD2HH, KKK595, KKK9A5, KKKK95, KKKKKH, KKKMCH, KKM505, KKMEE5, KKMKCH, KM0005, L222E7, L33AAD, L38I8N, LCCC11, LDFBCB, LEL2E7, LELE27, LELL27, LGMMM1, LLE2E7, LM2ME7, M000M5, M006MB, M00E27, M00MM1, M02227, M06M61, M06MM1, M0E227, M0EE27, M0KME5, M0M5GN, M0MM61, M0MMCB, M0MNNN, M0NNM1, M38LLN, M5K505, M77707, M7E227, M7E727, M8CHHH, MBMMCB, MBMMM1, MEEE77, MHH027, MHH505, MHHC6H, MHHH6H, MHHK05, MKK001, MM2ME7, MM7707, MM7E77, MMBMK1, MMM2E7, MMMC0B, MMMK61, N0003D, N0008D, N0030N, N030NN, N0C0AD, N0CKAD, N0DKDD, N0N3GN, N0NN3N, N333AD, N777A7, N77A77, NAACKD, NAAKDD, NACAKD, NACKAD, NC0AKD, NC0KAD, NCA0KD, NCKAKD, NDNNLN, NNNLAD, NNNNLD, 1BBBBBB, 1BBBBG1, 1M6MMMB, 1MMBBBB, 1MMMMK1, 2000227, 2000EE7, 20EEEE7, 2C0FFFH, 2E2EEE7, 2KKKHCH, 2MEE227, 2MEEE27, 333333D, 3333355, 3335555, 333FFF5, 333IIID, 388NNNN, 38INNNN, 3INNNNN, 4000IMN, 4000JJJ, 400IIIN, 444444J, 44JJJJJ, 488888N, 4IIJIIJ, 4JJJ33J, 50002M1, 5001G21, 5006621, 500LGM1, 555083D, 55555I5, 5616G21, 59MMMM1, 5K999A5, 61CCCC1, 66666K1, 6K0000H, 6K0080H, 70000A7, 70077A7, 70700A7, 7070A77, 77700A7, 77770A7, 7777227, 7777E27, 77L2227, 7LE22E7, 888888B, 888888N, 8888BBN, 8888IIN, 888B88B, 888I8IN, 88IINNN, 88NIINN, 88NNIIN, 8INNNNN, 90444IJ, 904I44J, 9666661, 9666FK1, 9666K61, 9966FK1, A00KK0D, A0K000D, AAAAA35, AAKKI8D, BB8888B, BBB0BLB, BBBB1BB, BBBBBB1, BBBBBGB, BBBBBLB, BBBLMBB, C0007KH, C000F11, C00FFFH, C00HH0H, C00K00H, C0C0HHH, C0CCHHH, C0CHH0H, C0CHHCH, C0FFFFH, C0H0H0H, C0KKC0H, CC0HH0H, CCCCC11, CCCCCC1, CCHHHHH, CDKKKKH, CEL7777, CGGG0G7, CGGGGG7, CH00HHH, CHGGGG7, CHHHH0H, CHHHHCH, CHHHHHH, CK0000H, CKDKKKH, D00DDKD, DD0DDD7, DDBBBLB, DDD2EE7, DDDBBLB, DDDDD27, DDDDDBB, DDDDDC7, DDDDDKD, DDDDDMB, DDDDEE7, DDDDKKD, DDDDLDB, DDDFBBB, DDDLFCB, DDDMEE7, DDM2227, DHHEEE7, DK000KD, DK00D0D, DK0D00D, DNN000N, E000CL7, E000EG7, E000GE7, E00C0G7, E00CE07, E00EE27, E0C00G7, E0C0EG7, E0CE007, E0EC0G7, E0EE207, E0G0007, E20EE27, E22EEE7, E2EE227, E2EEE27, E772227, E77LL27, E7L2227, E9IIIIJ, EAKKKA5, EC000G7, ECG00G7, EE00L27, EE0E0G7, EE20EE7, EEE0EG7, EEE22E7, EEEE727, EEEEE27, EEEEG07, EEEEGE7, EEEKKK5, EELLL27, EI0IIIJ, EKKKAA5, ELLLE27, F00FA35, F0333F5, F0F0FE5, F333335, FAAFF35, FCF0FCH, FEEEE35, FF03335, FF0FA35, FF0FE35, FF0FMCH, FFF0A35, FFF0F35, FFFAF35, FFFF5I5, FFFFM2H, FFFI3I5, FFFIII5, FFH5555, FH55555, FL1MMM1, G0000G7, G0000L7, GGGG007, GLE2227, GLLLLE7, GLLLLL7, H000007, H0000C7, H000HCH, H000HM7, H000M27, H000ME7, H00G227, H00HHM7, H02M227, H0C0HHH, H0CH00H, H0E0007, H0FFF35, H0FFFF5, H0H0ME7, H0HFII5, H0HHHCH, H0M0227, H555555, H5F5FF5, HC000G7, HC00H0H, HCCHHCH, HCHHHCH, HCHHHHH, HEEEE27, HFF5FF5, HFF5FI5, HFKKK05, HG00007, HH00E27, HH0G227, HHH2MM7, HHH55F5, HHH9FF5, HHHFFK5, HHHFK55, HHHH7EJ, HHHHCM7, HHHHHAJ, HHHHHF5, HHHHHHJ, HKK5505, I000055, I00A0ID, I0I4IIJ, I0IIIIJ, I88NIIN, III0055, III0I55, III444J, IINNLIN, J000IJJ, K0000DH, K0000KD, K00033D, K000A5D, K000K5D, K00555D, K009995, K00K00D, K00K8ID, K00KI8D, K00KIAD, K01GCC1, K05033D, K0999F5, K2KKKCH, K53333D, K956661, K999991, KCCC1C1, KFFFE55, KFFKKE5, KFKFKE5, KK009A5, KK00C11, KK01GC1, KK99001, KKIII05, KKK09F5, KKKE9E5, KKKEAK5, KKKKI05, KKKKKE5, KMMEEE5, L1BBBG1, LBMMMCB, LBMMMMB, LDEEE07, LEE22E7, LEE2E27, LEEE2E7, LLLLE27, M0000CB, M000C6B, M02EEE7, M0K0005, M0M0005, M2CHHHH, M2HHHHH, M6MMMM1, MC0000B, MCHHHHH, ME7E777, MEE7777, MEEE2E7, MG06661, MHHHCCH, MHHHH27, MHHHHH7, MHM0027, MM6666B, MM77777, MMC000B, MMM7727, MMNM777, N000NLN, N00333D, N003AAD, N0A00DD, N0NN33D, N0NNLLN, N30000N, N777777, NDNNNNN, NN0N0GN, NN0N30N, NNN300N, NNN333D, NNN3LLN, NNNDDDD, NNNNN3N, NNNNNND, 33333F35, 33FFFF35, 3555FFF5, 3FFFFF55, 3NNNNNLN, 40000I0J, 40I0IIIJ, 444440IJ, 4J0000IJ, 500006G1, 5D00DDDD, 5L1MMMM1, 5MMMMMG1, 5NNDDDDD, 5NNNNDDD, 5NNNNN8D, 6000080H, 777777A7, 77777A77, 7944444J, 800000IN, 996666K1, 999999I5, 9999FEA5, A00003ID, AAAAFF35, BBBGMMMB, C0000011, C000007H, C0CC0H0H, C666666B, CCCH0HHH, CCHH0HCH, CE777777, CEEEEE07, CHH0H00H, D00000GN, D000D0LD, D000IIGN, D0DDDDD7, DDD0E2E7, DDDDDDDB, DDDDDME7, DEEEELE7, DEEELEE7, DEELEEE7, DELEE0E7, E00000C7, E00000G7, E0000CG7, E000C0E7, E000G007, E00CG007, E00E0CG7, E0C00007, E0CGGGG7, E0GGGGG7, E20000E7, EAAKAAA5, EAKKAAA5, EE00E727, EE020007, EEEE2027, ELEE2227, F00003F5, F0000A35, F0003335, F0FFFA35, F1999991, F1999MM1, FAAAAF35, FBBBBBG1, FEAAAAA5, FF000A35, FF00FF35, FF0KEEE5, FFAAAF35, FFF555I5, FFFF33I5, FFFFF035, FFFFF3F5, FFFFFKI5, FFFFFMHH, FKFKEEE5, FKKFEEE5, FMMMMMCB, FMMMMMM1, G2000007, GGGGGMM7, GJJJJJ0J, GJJJJJ3J, H0000E27, H0000G27, H000C0G7, H000CEG7, H000CHH7, H000E0E7, H000EE27, H00CHHG7, H00EEE27, H00M0EE7, H05FF5F5, H0E00EE7, H55FF5F5, HCHH0H0H, HE000EE7, HFFIIII5, HGGG2227, HH00CEG7, HH00H0CH, HH0EEEE7, HH0FFFI5, HHEEEEE7, HHH000CH, HHH00EG7, HHHC00G7, HHHFFFF5, HHHHHKK5, HHHK5F55, HK5555F5, I4IIIIIJ, IA0000ID, II0005I5, III000I5, III055I5, III5NNNN, IIIII9IJ, IIIIIII5, IIINNNGN, JAJJJJJJ, JJAJJJJJ, K000005D, K00009A5, K0000M55, K000M555, K008IIID, K00D0K0D, K00III8D, K00K550D, K00LCC11, K0999951, K0D0000H, K0K00595, K0K9AAF5, K0KK0095, K0KK9FF5, K3333IID, KFKFEEE5, KFKKEEE5, KK00000H, KK0000M5, KK099991, KK55583D, KKKEEEA5, KKKKKKI5, LEEEE227, LLLEEE27, LLLL2E07, M000006B, M000M6CB, M0MMMMM1, M222EEE7, M777E777, M7E77777, ME222EE7, ME2EEEE7, MEE222E7, MM0NNNNN, MME77727, MMM6MMM1, N00003GN, N0000ADD, N000N0GN, N000NNND, N033333D, N0NN0NGN, NDDDDKDD, NN000N3N, NN00N03N, NN03000N, NNN003GN, NNNNDNLN, NNNNNADD, 199999MM1, 200FFFFFH, 222MEEEE7, 2FFFFFFCH, 30000000N, 30N00000N, 400000J3J, 500000M01, 5000166G1, 5000666G1, 50DDDDDDD, 8NN33333D, 999999991, C000000FH, C00000K0H, C000H00HH, C77777707, CH00H000H, CHH0000HH, D00000DKD, D00000DLD, D0000200H, D0000KK0D, D000KK00D, D00D0DDLD, D0D00DDLD, D0LEEEEE7, DDBBBBBBB, DDD000KDD, DDDDDDDE7, DK00000DD, DNNNNNNNN, E00000E27, E00007L27, E0000E727, E0E000C07, E20000027, EAAAAKAA5, EAKAAAAK5, EE0000C07, EEE000E27, EEEEEEGL7, F00FFFF35, F0FFFFF35, FF0000035, FF0FFFF35, FF5555FI5, FFFFFFA35, FFFFFFF35, FFFFFFFI5, FKKKKEEE5, FMMMMMMMB, GGGGG2227, GGGGGG207, GJJJJJJJJ, GLMMMMMMB, H000022M7, H000222M7, H000EEEE7, H0EEEEEE7, H0H0000CH, H0IIIIII5, HCH00000H, HE0EEEEE7, HFFFFFI35, HFFFFKKK5, HHHHHHG27, HHHHHHH55, HHHHHHHH7, HHHHHHM55, HHHKK5555, HHIIIII05, HIIIIII05, HKK5555I5, I000000AD, I000000ID, I000A000D, I00A0000D, IIIII0555, IIIIIII9J, K000000AD, K00000595, K000009F5, K0000550D, K099999A5, K0C00000H, K0I00000D, KK0000595, KK0000HCH, KKK000095, KKKFKFFE5, KKKIIIII5, M77777777, MEEEE2227, MMMMMMMM1, N0000000D, N0000003N, N000003NN, N00000N3N, N00000NGN, N00N000GN, N00NNNN8D, N0NNN00GN, N0NNNN3AD, N0NNNNNGN, N999999M1, NN0NNNNGN, NNN000NGN, NNNNNDD8D, NNNNNN0GN, 16MMMMMMMB, 1MMMMMMBCB, 3333333335, 33333333I5, 400000000N, 40IIIIIIJJ, 4IIIIIIIJJ, 4IIIIIIJIJ, 50000000M1, 70F9999991, 777E777727, 9999995MM1, ADD000000D, C00000088B, C000000CF1, C00000F0HH, CH00000H0H, D00KD0000D, D0D0DDDDLD, D0E2EEEEE7, D2EEEEEEE7, DBBBBBBBBB, DD000000KD, DD0000DDLD, DLE0EEEEE7, EEE0000727, EEEAAAAAA5, EEEEEE00G7, EEEEEEE0G7, F000000F35, F00FFKEEE5, F00KFFEEE5, F0M666666B, FCFFFFFFFH, FFFFFFF2HH, FFFKKKEEE5, GGGGGGG227, H00000C06H, H0000HHH6H, H555FFFFF5, H55FFFFF55, H5FFFFFF55, HF5FFFFFF5, HHHH0H0HCH, HHHHH0HHCH, HHHHHH0HCH, HHHHHHHHM5, HHHIIIIII5, IIDNNNNNLN, IIIIIJJIIJ, IIINNNNNLN, IINNNNNNGN, INNNNNNNLN, J0000000IJ, K0000II8ID, K099999995, K0I0000AID, K0K0009FF5, K9999999F5, KK00000095, KKFFFKEEE5, LLLLLLLME7, LLLMEEEEE7, LMEEEEEEE7, M000000005, MHHHHHHHH5, MK00000005, MMMMMMMBCB, NN000000GN, NN0000NNGN, NN99999991, 2HHHHHHHHHH, 38NNNNNNNNN, 3MNNNNNNNNN, 40IIIIIIIIJ, 4AJJJJJJJJJ, 4J000000J0J, 4JJJJJJJJJJ, 506666666G1, 5DDDDDDDDLD, 999999999F5, 99999999EA5, 99999999FE5, A0000000035, C0000000007, C00000000G7, C00000000KH, CEEEEEEEEL7, D0000000FMH, D000DDDDDLD, D0KD000000D, DDDD00000KD, DEEE0EEEEE7, DEL0EEEEEE7, DELEEEEEE07, E0000E20007, E7777777727, EE000000207, EEE20000007, FFFFFFFFMCH, FM66666666B, GGGGGGGG2M7, HFFFFFFFF55, HHHHHHHHH6H, HHHHHHHHHCH, HHHHHK55555, I9IIIIIIIIJ, IIIIIIII44J, IIIIIIIJJIJ, IINNNNNNNNN, JDDDDDDDDDD, JJIIIIIIIIJ, K00000I8IID, LLLLLLLLL27, 9999999EEAA5, AI000000000D, C77700000007, CH0HH000000H, D00D000000LD, DEEEEEEE0EE7, DN000000000N, EAKAAAAAAAA5, EKAAAAAAAAK5, F6666666666B, H000HHHHHH6H, H55FFFFFFFF5, HFFFFFFFFKK5, K00000000I8D, K999999999A5, 3555555555FF5, 5000000000001, 6G66666666661, 99999999999A5, C00000000000H, CFFFFFFFFFFCH, CHHH00000000H, D00000000K0KD, D0000000K00KD, D0D00000000LD, DEEEEEEEEEL07, E000E20000007, E00E200000007, EEE0000000027, GGGGGGGGGGGM7, GGGGGGGGGGM07, H00000000CHHH, H00HC0000000H, HFFFFFFFFFFK5, I0A000000000D, J000000000J9J, K000000000095, K000000000M2H, M0000000000M1, M0EEEEEEEEEE7, MHHHHHHHHHHHH, MMNNNNNNNNNNN, MNNNNNNNNNNNN, N000000DDDDDD, N000DDDDDDDDD, NNDDDDDDDDDDD, 22EEEEEEEEEEE7, 35FFFFFFFFFFF5, 400000000000JJ, 800000000000GN, DDDDDDDDDDD077, DDDDDDDDDDDDD7, E0000000000L27, EAAAAAAAAAAKA5, EEG00000000007, H0000000000C6H, I5500000000005, II0000000000I5, M0666666666661, M6MMMMMMMMMMMB, 4JJ00000000000J, 506666666666661, BGMMMMMMMMMMMCB, CFFFFFFFFFFFFFH, D0000000000KD0D, D0HEEEEEEEEEEE7, F0BBBBBBBBBBBBB, HGGGGGGGGGGGGG7, K0000000000000D, K00000000000MCH, M0M6MMMMMMMMMMB, 5DDDDDDDDDDDDDDD, C00000000000008B, D00000000000000H, DEEEEEEEEEEEE0L7, DEEEEEEEEEEEEEL7, EEE2EEEEEEEEEEE7, GM66666666666661, H5FFFFFFFFFFFFF5, IIIIIIIIIIIIIJJJ, BGMMMMMMMMMMMMMMB, DLEEEEEEEEEEEEEE7, H0000000000000CHH, H000000000C0000HH, I000000000000000D, IIIIIIIIIIIIIIIJJ, INNNNNNNNNNNNNNNN, J000000000000009J, M666666666666666B, N0000000000000LLN, N00DDDDDDDDDDDDDD, 355555555555555555, 60000000000000008H, 6M6666666666666661, C000000000000000F1, N0DDDDDDDDDDDDDDDD, 666666666666666666B, 800000000000000000N, AD000000000000000DD, DEEEEEEEEEEEEEEEEE7, I500000000000000005, 20000000000000000027, 4000000000000000003J, 400000000000000000IJ, 99999999999999999995, DD00DDDDDDDDDDDDDDLD, E2EEEEEEEEEEEEEEEEE7, N00000000000000000LN, 500000000066666666661, EE0000000000000000727, GGGGGGGGGGGGGGGGGGG07, H0000000000000000006H, 40000000000000IIIIIIIJ, AD0000000000000000000D, K0000000000000000000M5, CL777777777777777777777, D000000000000000000000N, D0000000000000000000IIN, HHHHHHHHHHHHHHHHHHHHHK5, NDDDDDDDDDDDDDDDDDDDDDD, 1MMMMMMMMMMMMMMMMMMMMMBB, D00DDDDDDDDDDDDDDDDDDDLD, FFFFFFFFFFFFFFFFFFFFFFFH, 4J0000000000000000000000J, 566666666666666666666666G1, EKKAAAAAAAAAAAAAAAAAAAAAA5, 6666666666666666666666666G1, AJJJJJJJJJJJJJJJJJJJJJJJJJJJ, H00000000000000000000000008H, N0000000000000000000000000GN, DD0000000000000000000000000LD, IIIIIIIIIIIIIIIIIIIIIIIIIIIIJ, G0666666666666666666666666666661, GGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGG7, K000000000000000000000000000000000H, EAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA5, LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLM7, M2EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE7, C000000000000000000000000000000000000000001, MMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMCB, E00000000000000000000000000000000000000000000727, 777777777777777777777777777777777777777777777777727, EG000000000000000000000000000000000000000000000000000007, D000000000000000000000000000000000000000000000000000000000LD, 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==Unsolved families== Families for which not even a probable prime is known nor can be ruled out as only contain composites (only count the numbers > base (''b'')). {|class=wikitable |base (''b'')||unsolved family (base-''b'' form)||unsolved family (algebraic ((''a''×''b''^''n''+''c'')/''d'') form)||current search limit of length||factorization of numbers in this family |- |13||9{5}||(113×13^''n''−5)/12||88000||[http://factordb.com/index.php?query=%28113*13%5En-5%29%2F12&use=n&n=1&VP=on&VC=on&EV=on&OD=on&PR=on&FF=on&PRP=on&CF=on&U=on&C=on&perpage=200&format=1&sent=Show] |- |13||A{3}A||(41×13^''n''+1+27)/4||82000||[http://factordb.com/index.php?query=%2841*13%5E%28n%2B1%29%2B27%29%2F4&use=n&n=0&VP=on&VC=on&EV=on&OD=on&PR=on&FF=on&PRP=on&CF=on&U=on&C=on&perpage=200&format=1&sent=Show] |- |16||{3}AF||(16^''n''+2+619)/5||76000||[http://factordb.com/index.php?query=%2816%5E%28n%2B2%29%2B619%29%2F5&use=n&n=0&VP=on&VC=on&EV=on&OD=on&PR=on&FF=on&PRP=on&CF=on&U=on&C=on&perpage=200&format=1&sent=Show] |} (If these three families contain primes (and they are excepted to contain primes), then the smallest prime in families 9{5} and A{3}A in base ''b'' = 13 will be index 3196 and 3197 quasi-minimal prime in base ''b'' = 13, and the smallest prime in families {3}AF in base ''b'' = 16 will be index 2347 quasi-minimal prime in base ''b'' = 16) === Base 17 === * 15{0}D * 1{7} * 1F{0}7 * 4{7}A * 51{0}D * 70F{0}D * 8{B}9 * 9{5}9 * 95{F} * A{D}F * B{0}B3 * B{0}DB * {B}2BE * {B}2E * {B}E9 * {B}EE * D0G{D} * E9{B} * F1{9} * FD0{D} * G{7}F ==Primality certificates for the proven primes > 10²⁹⁹== See also: [[w:Primality certificate|Primality certificate]] and [[w:Elliptic curve primality|Elliptic curve primality]] {|class=wikitable |base (''b'')||index of this quasi-minimal prime in base ''b''||quasi-minimal prime (base-''b'' form)||quasi-minimal prime (algebraic ((''a''×''b''^''n''+''c'')/''d'') form)||factordb entry of this prime||primality certificate of this prime |- |9||149||76₃₂₉2||(31×9³³⁰−19)/4||[http://factordb.com/index.php?id=1100000002359003642]||[http://factordb.com/cert.php?id=1100000002359003642] |- |9||150||27₆₈₆07||(23×9⁶⁸⁸−511)/8||[http://factordb.com/index.php?id=1100000002495467486]||[http://factordb.com/cert.php?id=1100000002495467486] |- |9||151||30₁₁₅₈11||3×9¹¹⁶⁰+10||[http://factordb.com/index.php?id=1100000002376318423]||[http://factordb.com/cert.php?id=1100000002376318423] |- |11||1065||A₇₁₃58||11⁷¹⁵−58||[http://factordb.com/index.php?id=1100000003576826487]||[http://factordb.com/cert.php?id=1100000003576826487] |- |11||1066||7₇₅₉44||(7×11⁷⁶¹−367)/10||[http://factordb.com/index.php?id=1100000002505568840]||[http://factordb.com/cert.php?id=1100000002505568840] |- |11||1067||557₁₀₁₁||(607×11¹⁰¹¹−7)/10||[http://factordb.com/index.php?id=1100000002361376522]||[http://factordb.com/cert.php?id=1100000002361376522] |- |13||3165||50₂₇₀44||5×13²⁷²+56||[http://factordb.com/index.php?id=1100000002632397005]||[http://factordb.com/cert.php?id=1100000002632397005] |- |13||3166||9₂₇₁095||(3×13²⁷⁴−6103)/4||[http://factordb.com/index.php?id=1100000003590431654]||[http://factordb.com/cert.php?id=1100000003590431654] |- |13||3167||10₂₈₆7771||13²⁹⁰+16654||[http://factordb.com/index.php?id=1100000003590431633]||[http://factordb.com/cert.php?id=1100000003590431633] |- |13||3168||9₃₀₈1||(3×13³⁰⁹−35)/4||[http://factordb.com/index.php?id=1100000000840126705]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], factor ''N''−1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=13&Exp=308&c0=-&EN= 13³⁰⁸−1] |- |13||3169||B₃₄₁C4||(11×13³⁴³+61)/12||[http://factordb.com/index.php?id=1100000003590431618]||[http://factordb.com/cert.php?id=1100000003590431618] |- |13||3170||8B₃₄₃||(107×13³⁴³−11)/12||[http://factordb.com/index.php?id=1100000002321018736]||[http://factordb.com/cert.php?id=1100000002321018736] |- |13||3171||710₃₇₁111||92×13³⁷⁴+183||[http://factordb.com/index.php?id=1100000003590431609]||[http://factordb.com/cert.php?id=1100000003590431609] |- |13||3172||75₃₇₅7||(89×13³⁷⁶+19)/12||[http://factordb.com/index.php?id=1100000003590431596]||[http://factordb.com/cert.php?id=1100000003590431596] |- |13||3173||9B0₃₉₁9||128×13³⁹²+9||[http://factordb.com/index.php?id=1100000002632396790]||[http://factordb.com/cert.php?id=1100000002632396790] |- |13||3174||7B0B₃₉₇||(15923×13³⁹⁷−11)/12||[http://factordb.com/index.php?id=1100000003590431574]||[http://factordb.com/cert.php?id=1100000003590431574] |- |13||3175||10₄₁₄93||13⁴¹⁶+120||[http://factordb.com/index.php?id=1100000002523249240]||[http://factordb.com/cert.php?id=1100000002523249240] |- |13||3176||81010₄₁₅1||17746×13⁴¹⁶+1||[http://factordb.com/index.php?id=1100000003590431555]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], ''N''−1 is trivially 100% factored |- |13||3177||8110₄₃₅1||1366×13⁴³⁶+1||[http://factordb.com/index.php?id=1100000002373259109]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], ''N''−1 is trivially 100% factored |- |13||3178||B7₄₈₆||(139×13⁴⁸⁶−7)/12||[http://factordb.com/index.php?id=1100000002321015892]||[http://factordb.com/cert.php?id=1100000002321015892] |- |13||3179||B₅₆₃C||(11×13⁵⁶⁴+1)/12||[http://factordb.com/index.php?id=1100000000000217927]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], factor ''N''−1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=13&Exp=564&c0=-&EN= 13⁵⁶⁴−1] |- |13||3180||1B₅₇₆||(23×13⁵⁷⁶−11)/12||[http://factordb.com/index.php?id=1100000002321021456]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], factor ''N''−1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=13&Exp=576&c0=-&EN= 13⁵⁷⁶−1] |- |13||3181||80₆₉₃87||8×13⁶⁹⁵+111||[http://factordb.com/index.php?id=1100000002615636527]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], ''N''−1 has a large prime factor, factordb entry of this prime factor is [http://factordb.com/index.php?id=1100000002615636532], and primality certificate of this prime factor is [http://factordb.com/cert.php?id=1100000002615636532] |- |13||3182||CC5₇₁₃||(2021×13⁷¹³−5)/12||[http://factordb.com/index.php?id=1100000002615627353]||[http://factordb.com/cert.php?id=1100000002615627353] |- |13||3183||B₈₃₄74||(11×13⁸³⁶−719)/12||[http://factordb.com/index.php?id=1100000003590430871]||[http://factordb.com/cert.php?id=1100000003590430871] |- |13||3184||9₉₆₈B||(3×13⁹⁶⁹+5)/4||[http://factordb.com/index.php?id=1100000000258566244]||[http://factordb.com/cert.php?id=1100000000258566244] |- |13||3185||10₁₂₉₅181||13¹²⁹⁸+274||[http://factordb.com/index.php?id=1100000002615445013]||[http://factordb.com/cert.php?id=1100000002615445013] |- |13||3186||9₁₃₆₂5||(3×13¹³⁶³−19)/4||[http://factordb.com/index.php?id=1100000002321017776]||[http://factordb.com/cert.php?id=1100000002321017776] |- |13||3187||7₁₅₀₄1||(7×13¹⁵⁰⁵−79)/12||[http://factordb.com/index.php?id=1100000002320890755]||[http://factordb.com/cert.php?id=1100000002320890755] |- |13||3188||930₁₅₅₁1||120×13¹⁵⁵²+1||[http://factordb.com/index.php?id=1100000000765961452]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], ''N''−1 is trivially 100% factored |- |13||3189||720₂₂₉₇2||93×13²²⁹⁸+2||[http://factordb.com/index.php?id=1100000002632396910]||[http://factordb.com/cert.php?id=1100000002632396910] |- |13||3190||1770₂₇₀₃17||267×13²⁷⁰⁵+20||[http://factordb.com/index.php?id=1100000003590430825]||[http://factordb.com/cert.php?id=1100000003590430825] |- |13||3191||390₆₂₆₆1||48×13⁶²⁶⁷+1||[http://factordb.com/index.php?id=1100000000765961441]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], ''N''−1 is trivially 100% factored |- |13||3192||B0₆₅₄₀BBA||11×13⁶⁵⁴³+2012||[http://factordb.com/index.php?id=1100000002616382906]||[http://factordb.com/cert.php?id=1100000002616382906] |- |13||3193||C₁₀₆₃₁92||13¹⁰⁶³³−50||[http://factordb.com/index.php?id=1100000003590493750]||[http://factordb.com/cert.php?id=1100000003590493750] |- |14||649||34D₇₀₈||47×14⁷⁰⁸−1||[http://factordb.com/index.php?id=1100000001540144903]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 is trivially 100% factored |- |14||650||4D₁₉₆₉₈||5×14¹⁹⁶⁹⁸−1||[http://factordb.com/index.php?id=1100000000884560233]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 is trivially 100% factored |- |16||2328||880₂₄₆7||136×16²⁴⁷+7||[http://factordb.com/index.php?id=1100000002468140199]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 has a large prime factor, and this prime factor is < 10²⁹⁹ |- |16||2329||D4₂₆₃D||(199×16²⁶⁴+131)/15||[http://factordb.com/index.php?id=1100000002468170238]||[http://factordb.com/cert.php?id=1100000002468170238] |- |16||2330||E0₂₆₁4DD||14×16²⁶⁴+1245||[http://factordb.com/index.php?id=1100000003588388352]||[http://factordb.com/cert.php?id=1100000003588388352] |- |16||2331||8C0₂₉₀ED||140×16²⁹²+237||[http://factordb.com/index.php?id=1100000003588388307]||[http://factordb.com/cert.php?id=1100000003588388307] |- |16||2332||DA₃₀₅5||(41×16³⁰⁶−17)/3||[http://factordb.com/index.php?id=1100000003588388284]||[http://factordb.com/cert.php?id=1100000003588388284] |- |16||2333||CE80₄₂₂D||3304×16⁴²³+13||[http://factordb.com/index.php?id=1100000003588388257]||[http://factordb.com/cert.php?id=1100000003588388257] |- |16||2334||5F₅₄₄6F||6×16⁵⁴⁶−145||[http://factordb.com/index.php?id=1100000002604723967]||[http://factordb.com/cert.php?id=1100000002604723967] |- |16||2335||88F₅₄₅||137×16⁵⁴⁵−1||[http://factordb.com/index.php?id=1100000000413679658]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 is trivially 100% factored |- |16||2336||BE0₇₉₂BB||190×16⁷⁹⁴+187||[http://factordb.com/index.php?id=1100000003588387938]||[http://factordb.com/cert.php?id=1100000003588387938] |- |16||2337||D9₁₀₅₂||(68×16¹⁰⁵²−3)/5||[http://factordb.com/index.php?id=1100000002321036020]||[http://factordb.com/cert.php?id=1100000002321036020] |- |16||2338||FAF₁₀₆₂45||251×16¹⁰⁶⁴−187||[http://factordb.com/index.php?id=1100000003588387610]||[http://factordb.com/cert.php?id=1100000003588387610] |- |16||2339||F8₁₅₁₇F||(233×16¹⁵¹⁸+97)/15||[http://factordb.com/index.php?id=1100000000633744824]||[http://factordb.com/cert.php?id=1100000000633744824] |- |16||2340||20₁₇₁₃321||2×16¹⁷¹⁶+801||[http://factordb.com/index.php?id=1100000003588386735]||[http://factordb.com/cert.php?id=1100000003588386735] |- |16||2341||300F₁₉₆₀AF||769×16¹⁹⁶²−81||[http://factordb.com/index.php?id=1100000003588368750]||[http://factordb.com/cert.php?id=1100000003588368750] |- |16||2342||90₃₅₄₂91||9×16³⁵⁴⁴+145||[http://factordb.com/index.php?id=1100000000633424191]||[http://factordb.com/cert.php?id=1100000000633424191] |- |16||2343||5BC₃₇₀₀D||(459×16³⁷⁰¹+1)/5||[http://factordb.com/index.php?id=1100000000993764322]||[http://factordb.com/cert.php?id=1100000000993764322] |- |16||2344||D0B₁₇₈₀₄||(3131×16¹⁷⁸⁰⁴−11)/15||[http://factordb.com/index.php?id=1100000003589278511]||[http://factordb.com/cert.php?id=1100000003589278511] |- |18||547||80₂₉₈B||8×18²⁹⁹+11||[http://factordb.com/index.php?id=1100000002355574745]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 has sum-of-two-cubes algebraic factorization, 6×18⁹⁹+1 is an algebraic factor of ''N''+1, factordb entry of 6×18⁹⁹+1 is [http://factordb.com/index.php?id=1100000000900149167] |- |18||548||H₇₆₆FH||18⁷⁶⁸−37||[http://factordb.com/index.php?id=1100000003590430490]||[http://factordb.com/cert.php?id=1100000003590430490] |- |18||549||C0₆₂₆₈C5||12×18⁶²⁷⁰+221||[http://factordb.com/index.php?id=1100000003590442437]||[http://factordb.com/cert.php?id=1100000003590442437] |- |20||3301||H₂₄₇A0H||(17×20²⁵⁰−59677)/19||[http://factordb.com/index.php?id=1100000003590502619]||[http://factordb.com/cert.php?id=1100000003590502619] |- |20||3302||7₂₄₉A7||(7×20²⁵¹+1133)/19||[http://factordb.com/index.php?id=1100000003590502602]||[http://factordb.com/cert.php?id=1100000003590502602] |- |20||3303||J7₂₇₀||(368×20²⁷⁰−7)/19||[http://factordb.com/index.php?id=1100000002325395462]||[http://factordb.com/cert.php?id=1100000002325395462] |- |20||3304||J₃₃₀CCC7||20³³⁴−58953||[http://factordb.com/index.php?id=1100000003590502572]||[http://factordb.com/cert.php?id=1100000003590502572] |- |20||3305||40₃₈₇404B||4×20³⁹¹+32091||[http://factordb.com/index.php?id=1100000003590502563]||[http://factordb.com/cert.php?id=1100000003590502563] |- |20||3306||EC0₄₂₉7||292×20⁴³⁰+7||[http://factordb.com/index.php?id=1100000002633348702]||[http://factordb.com/cert.php?id=1100000002633348702] |- |20||3307||G₄₄₇99||(16×20⁴⁴⁹−2809)/19||[http://factordb.com/index.php?id=1100000000840126753]||[http://factordb.com/cert.php?id=1100000000840126753] |- |20||3308||3A₅₂₇3||(67×20⁵²⁸−143)/19||[http://factordb.com/index.php?id=1100000003590502531]||[http://factordb.com/cert.php?id=1100000003590502531] |- |20||3309||E₅₆₆C7||(14×20⁵⁶⁸−907)/19||[http://factordb.com/index.php?id=1100000003590502516]||[http://factordb.com/cert.php?id=1100000003590502516] |- |20||3310||JCJ₆₂₉||393×20⁶²⁹−1||[http://factordb.com/index.php?id=1100000001559454258]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 is trivially 100% factored |- |20||3311||J₆₅₅05J||20⁶⁵⁸−7881||[http://factordb.com/index.php?id=1100000003590502490]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 has a large prime factor, factordb entry of this prime factor is [http://factordb.com/index.php?id=1100000003591067052], and primality certificate of this prime factor is [http://factordb.com/cert.php?id=1100000003591067052] |- |20||3312||50₁₁₆₃AJ||5×20¹¹⁶⁵+219||[http://factordb.com/index.php?id=1100000003590502412]||[http://factordb.com/cert.php?id=1100000003590502412] |- |20||3313||CD₂₄₄₉||(241×20²⁴⁴⁹−13)/19||[http://factordb.com/index.php?id=1100000002325393915]||[http://factordb.com/cert.php?id=1100000002325393915] |- |20||3314||G0₆₂₆₉D||16×20⁶²⁷⁰+13||[http://factordb.com/index.php?id=1100000003590539457]||[http://factordb.com/cert.php?id=1100000003590539457] |- |22||7984||I7G0₂₅₄H||8882×22²⁵⁵+17||[http://factordb.com/index.php?id=1100000003591372788]||[http://factordb.com/cert.php?id=1100000003591372788] |- |22||7985||D0₂₅₅5EEF||13×22²⁵⁹+60339||[http://factordb.com/index.php?id=1100000003591371932]||[http://factordb.com/cert.php?id=1100000003591371932] |- |22||7986||IK₃₂₂F||(398×22³²³−125)/21||[http://factordb.com/index.php?id=1100000000840384145]||[http://factordb.com/cert.php?id=1100000000840384145] |- |22||7987||C0₃₄₀G9||12×22³⁴²+361||[http://factordb.com/index.php?id=1100000000840384159]||[http://factordb.com/cert.php?id=1100000000840384159] |- |22||7988||77E₃₄₈K7||(485×22³⁵⁰+373)/3||[http://factordb.com/index.php?id=1100000003591369779]||[http://factordb.com/cert.php?id=1100000003591369779] |- |22||7989||J₃₇₉KJ||(19×22³⁸¹+443)/21||[http://factordb.com/index.php?id=1100000003591369027]||[http://factordb.com/cert.php?id=1100000003591369027] |- |22||7990||J₃₈₈EJ||(19×22³⁹⁰−2329)/21||[http://factordb.com/index.php?id=1100000003591367729]||[http://factordb.com/cert.php?id=1100000003591367729] |- |22||7991||DJ₄₀₀||(292×22⁴⁰⁰−19)/21||[http://factordb.com/index.php?id=1100000002325880110]||[http://factordb.com/cert.php?id=1100000002325880110] |- |22||7992||E₄₀₄K7||(2×22⁴⁰⁶+373)/3||[http://factordb.com/index.php?id=1100000003591366298]||[http://factordb.com/cert.php?id=1100000003591366298] |- |22||7993||66F₄₅₃B3||(971×22⁴⁵⁵−705)/7||[http://factordb.com/index.php?id=1100000003591365809]||[http://factordb.com/cert.php?id=1100000003591365809] |- |22||7994||L0₄₅₄B63||21×22⁴⁵⁷+5459||[http://factordb.com/index.php?id=1100000003591365331]||[http://factordb.com/cert.php?id=1100000003591365331] |- |22||7995||L₄₈₃G3||22⁴⁸⁵−129||[http://factordb.com/index.php?id=1100000003591364730]||[http://factordb.com/cert.php?id=1100000003591364730] |- |22||7996||E60₄₉₆L||314×22⁴⁹⁷+21||[http://factordb.com/index.php?id=1100000000632703239]||[http://factordb.com/cert.php?id=1100000000632703239] |- |22||7997||I₆₂₆AF||(6×22⁶²⁸−1259)/7||[http://factordb.com/index.php?id=1100000000632724334]||[http://factordb.com/cert.php?id=1100000000632724334] |- |22||7998||K0₇₆₀EC1||20×22⁷⁶³+7041||[http://factordb.com/index.php?id=1100000000632724415]||[http://factordb.com/cert.php?id=1100000000632724415] |- |22||7999||J0₇₆₇IGGJ||19×22⁷⁷¹+199779||[http://factordb.com/index.php?id=1100000003591362567]||[http://factordb.com/cert.php?id=1100000003591362567] |- |22||8000||7₉₅₉K7||(22⁹⁶¹+857)/3||[http://factordb.com/index.php?id=1100000003591361817]||[http://factordb.com/cert.php?id=1100000003591361817] |- |22||8001||L₂₃₈₅KE7||22²³⁸⁸−653||[http://factordb.com/index.php?id=1100000003591360774]||[http://factordb.com/cert.php?id=1100000003591360774] |- |22||8002||7₃₈₁₅2L||(22³⁸¹⁷−289)/3||[http://factordb.com/index.php?id=1100000003591359839]||[http://factordb.com/cert.php?id=1100000003591359839] |- |24||3400||I0₂₄₁I5||18×24²⁴³+437||[http://factordb.com/index.php?id=1100000002633360037]||[http://factordb.com/cert.php?id=1100000002633360037] |- |24||3401||D0₂₅₉KKD||13×24²⁶²+12013||[http://factordb.com/index.php?id=1100000003593270725]||[http://factordb.com/cert.php?id=1100000003593270725] |- |24||3402||C7₂₉₈||(283×24²⁹⁸−7)/23||[http://factordb.com/index.php?id=1100000002326181235]||[http://factordb.com/cert.php?id=1100000002326181235] |- |24||3403||20₃₁₃7||2×24³¹⁴+7||[http://factordb.com/index.php?id=1100000002355610241]||[http://factordb.com/cert.php?id=1100000002355610241] |- |24||3404||BC0₃₃₁B||276×24³³²+11||[http://factordb.com/index.php?id=1100000002633359842]||[http://factordb.com/cert.php?id=1100000002633359842] |- |24||3405||N₂₆₄₄LLN||24²⁶⁴⁷−1201||[http://factordb.com/index.php?id=1100000003593270089]||[http://factordb.com/cert.php?id=1100000003593270089] |- |24||3406||D₂₆₉₈LD||(13×24²⁷⁰⁰+4403)/23||[http://factordb.com/index.php?id=1100000003593269876]||[http://factordb.com/cert.php?id=1100000003593269876] |- |24||3407||A0₂₉₅₁8ID||10×24²⁹⁵⁴+5053||[http://factordb.com/index.php?id=1100000003593269654]||[http://factordb.com/cert.php?id=1100000003593269654] |- |24||3408||88N₅₉₅₁||201×24⁵⁹⁵¹−1||[http://factordb.com/index.php?id=1100000003593275880]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 is trivially 100% factored |- |24||3409||N00N₈₁₂₉LN||13249×24⁸¹³¹−49||[http://factordb.com/index.php?id=1100000003593391606]||[http://factordb.com/cert.php?id=1100000003593391606] |- |30||2613||AN₂₀₆||(313×30²⁰⁶−23)/29||[http://factordb.com/index.php?id=1100000002327651073]||[http://factordb.com/cert.php?id=1100000002327651073] |- |30||2614||M₂₄₁QB||(22×30²⁴³+3139)/29||[http://factordb.com/index.php?id=1100000003593408295]||[http://factordb.com/cert.php?id=1100000003593408295] |- |30||2615||M0₅₄₇SS7||22×30⁵⁵⁰+26047||[http://factordb.com/index.php?id=1100000003593407988]||[http://factordb.com/cert.php?id=1100000003593407988] |- |30||2616||C0₁₀₂₂1||12×30¹⁰²³+1||[http://factordb.com/index.php?id=1100000000785448736]||proven prime by [https://primes.utm.edu/prove/prove3_1.html ''N''−1 primality test], ''N''−1 is trivially 100% factored |- |30||2617||5₄₈₈₂J||(5×30⁴⁸⁸³+401)/29||[http://factordb.com/index.php?id=1100000002327649423]||[http://factordb.com/cert.php?id=1100000002327649423] |- |30||2619||OT₃₄₂₀₅||25×30³⁴²⁰⁵−1||[http://factordb.com/index.php?id=1100000000800812865]||proven prime by [https://primes.utm.edu/prove/prove3_2.html ''N''+1 primality test], ''N''+1 is trivially 100% factored |} ==Unproven PRPs== {|class=wikitable |base (''b'')||index of this quasi-minimal prime in base ''b'' (assuming the primality of all PRP in base ''b'')||unproven PRP (base-''b'' form)||unproven PRP (algebraic ((''a''×''b''^''n''+''c'')/''d'') form)||factordb entry of this PRP |- |11||1068||57₆₂₆₆₈||(57×11⁶²⁶⁶⁸−7)/10||[http://factordb.com/index.php?id=1100000003573679860] |- |13||3194||C5₂₃₇₅₅C||(149×13²³⁷⁵⁶+79)/12||[http://factordb.com/index.php?id=1100000003590647776] |- |13||3195||80₃₂₀₁₇111||8×13³²⁰²⁰+183||[http://factordb.com/index.php?id=1100000000490878060] |- |16||2345||DB₃₂₂₃₄||(206×16³²²³⁴−11)/15||[http://factordb.com/index.php?id=1100000002383583629] |- |16||2346||4₇₂₇₈₅DD||(4×16⁷²⁷⁸⁷+2291)/15||[http://factordb.com/index.php?id=1100000003615909841] |- |22||8003||BK₂₂₀₀₁5||(251×22²²⁰⁰²−335)/21||[http://factordb.com/index.php?id=1100000003594696838] |- |30||2618||I0₂₄₆₀₈D||18×30²⁴⁶⁰⁹+13||[http://factordb.com/index.php?id=1100000003593967511] |} All these PRPs pass the [[w:Miller–Rabin primality test|Miller–Rabin primality test]] to bases 2, 3, 5, 7, 11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47, 53, 59 and 61, and pass the [[w:Lucas pseudoprime#Strong Lucas pseudoprimes|strong Lucas primality test]] with parameters (''P'', ''Q'') defined by Selfridge's Method ''A'', and [[w:Trial division|trial factored]] to 10¹⁶. (Thus, they pass the [[w:Baillie–PSW primality test|Baillie–PSW primality test]]) ==Proof== ===Base 2=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1) * Case (1,1): ** 11 is prime, and thus the only minimal prime in this family. ===Base 3=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1), (1,2), (2,1), (2,2) * Case (1,1): ** Since 12, 21, 111 are primes, we only need to consider the family 1{0}1 (since any digits 1, 2 between them will produce smaller primes) *** All numbers of the form 1{0}1 are divisible by 2, thus cannot be prime. * Case (1,2): ** 12 is prime, and thus the only minimal prime in this family. * Case (2,1): ** 21 is prime, and thus the only minimal prime in this family. * Case (2,2): ** Since 21, 12 are primes, we only need to consider the family 2{0,2}2 (since any digits 1 between them will produce smaller primes) *** All numbers of the form 2{0,2}2 are divisible by 2, thus cannot be prime. ===Base 4=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1), (1,3), (2,1), (2,3), (3,1), (3,3) * Case (1,1): ** 11 is prime, and thus the only minimal prime in this family. * Case (1,3): ** 13 is prime, and thus the only minimal prime in this family. * Case (2,1): ** Since 23, 11, 31, 221 are primes, we only need to consider the family 2{0}1 (since any digits 1, 2, 3 between them will produce smaller primes) *** All numbers of the form 2{0}1 are divisible by 3, thus cannot be prime. * Case (2,3): ** 23 is prime, and thus the only minimal prime in this family. * Case (3,1): ** 31 is prime, and thus the only minimal prime in this family. * Case (3,3): ** Since 31, 13, 23 are primes, we only need to consider the family 3{0,3}3 (since any digits 1, 2 between them will produce smaller primes) *** All numbers of the form 3{0,3}3 are divisible by 3, thus cannot be prime. ===Base 5=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1), (1,2), (1,3), (1,4), (2,1), (2,2), (2,3), (2,4), (3,1), (3,2), (3,3), (3,4), (4,1), (4,2), (4,3), (4,4) * Case (1,1): ** Since 12, 21, 111, 131 are primes, we only need to consider the family 1{0,4}1 (since any digits 1, 2, 3 between them will produce smaller primes) *** All numbers of the form 1{0,4}1 are divisible by 2, thus cannot be prime. * Case (1,2): ** 12 is prime, and thus the only minimal prime in this family. * Case (1,3): ** Since 12, 23, 43, 133 are primes, we only need to consider the family 1{0,1}3 (since any digits 2, 3, 4 between them will produce smaller primes) *** Since 111 is prime, we only need to consider the families 1{0}3 and 1{0}1{0}3 (since any digit combo 11 between (1,3) will produce smaller primes) **** All numbers of the form 1{0}3 are divisible by 2, thus cannot be prime. **** For the 1{0}1{0}3 family, since 10103 is prime, we only need to consider the families 1{0}13 and 11{0}3 (since any digit combo 010 between (1,3) will produce smaller primes) ***** The smallest prime of the form 1{0}13 is 100000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000013, which can be written as 1(0^93)13 and equal the prime 5^95+8 ([http://factordb.com/index.php?id=1100000000034686071 factordb]) ***** All numbers of the form 11{0}3 are divisible by 3, thus cannot be prime. * Case (1,4): ** Since 12, 34, 104 are primes, we only need to consider the family 1{1,4}4 (since any digits 0, 2, 3 between them will produce smaller primes) *** Since 111, 414 are primes, we only need to consider the families 1{4}4 and 11{4}4 (since any digit combo 11 or 41 between them will produce smaller primes) **** The smallest prime of the form 1{4}4 is 14444. **** All numbers of the form 11{4}4 are divisible by 2, thus cannot be prime. * Case (2,1): ** 21 is prime, and thus the only minimal prime in this family. * Case (2,2): ** Since 21, 23, 12, 32 are primes, we only need to consider the family 2{0,2,4}2 (since any digits 1, 3 between them will produce smaller primes) *** All numbers of the form 2{0,2,4}2 are divisible by 2, thus cannot be prime. * Case (2,3): ** 23 is prime, and thus the only minimal prime in this family. * Case (2,4): ** Since 21, 23, 34 are primes, we only need to consider the family 2{0,2,4}4 (since any digits 1, 3 between them will produce smaller primes) *** All numbers of the form 2{0,2,4}4 are divisible by 2, thus cannot be prime. * Case (3,1): ** Since 32, 34, 21 are primes, we only need to consider the family 3{0,1,3}1 (since any digits 2, 4 between them will produce smaller primes) *** Since 313, 111, 131, 3101 are primes, we only need to consider the families 3{0,3}1 and 3{0,3}11 (since any digit combo 10, 11, 13 between (3,1) will produce smaller primes) **** For the 3{0,3}1 family, we can separate this family to four families: ***** For the 30{0,3}01 family, we have the prime 30301, and the remain case is the family 30{0}01. ****** All numbers of the form 30{0}01 are divisible by 2, thus cannot be prime. ***** For the 30{0,3}31 family, note that there must be an even number of 3's between (30,31), or the result number will be divisible by 2 and cannot be prime. ****** Since 33331 is prime, any digit combo 33 between (30,31) will produce smaller primes. ******* Thus, the only possible prime is the smallest prime in the family 30{0}31, and this prime is 300031. ***** For the 33{0,3}01 family, note that there must be an even number of 3's between (33,01), or the result number will be divisible by 2 and cannot be prime. ****** Since 33331 is prime, any digit combo 33 between (33,01) will produce smaller primes. ******* Thus, the only possible prime is the smallest prime in the family 33{0}01, and this prime is 33001. ***** For the 33{0,3}31 family, we have the prime 33331, and the remain case is the family 33{0}31. ****** All numbers of the form 33{0}31 are divisible by 2, thus cannot be prime. **** All numbers of the form 3{0,3}11 are divisible by 3, thus cannot be prime. * Case (3,2): ** 32 is prime, and thus the only minimal prime in this family. * Case (3,3): ** Since 32, 34, 23, 43, 313 are primes, we only need to consider the family 3{0,3}3 (since any digits 1, 2, 4 between them will produce smaller primes) *** All numbers of the form 3{0,3}3 are divisible by 3, thus cannot be prime. * Case (3,4): ** 34 is prime, and thus the only minimal prime in this family. * Case (4,1): ** Since 43, 21, 401 are primes, we only need to consider the family 4{1,4}1 (since any digits 0, 2, 3 between them will produce smaller primes) *** Since 414, 111 are primes, we only need to consider the families 4{4}1 and 4{4}11 (since any digit combo 14 or 11 between them will produce smaller primes) **** The smallest prime of the form 4{4}1 is 44441. **** All numbers of the form 4{4}11 are divisible by 2, thus cannot be prime. * Case (4,2): ** Since 43, 12, 32 are primes, we only need to consider the family 4{0,2,4}2 (since any digits 1, 3 between them will produce smaller primes) *** All numbers of the form 4{0,2,4}2 are divisible by 2, thus cannot be prime. * Case (4,3): ** 43 is prime, and thus the only minimal prime in this family. * Case (4,4): ** Since 43, 34, 414 are primes, we only need to consider the family 4{0,2,4}4 (since any digits 1, 3 between them will produce smaller primes) *** All numbers of the form 4{0,2,4}4 are divisible by 2, thus cannot be prime. ===Base 6=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1), (1,5), (2,1), (2,5), (3,1), (3,5), (4,1), (4,5), (5,1), (5,5) * Case (1,1): ** 11 is prime, and thus the only minimal prime in this family. * Case (1,5): ** 15 is prime, and thus the only minimal prime in this family. * Case (2,1): ** 21 is prime, and thus the only minimal prime in this family. * Case (2,5): ** 25 is prime, and thus the only minimal prime in this family. * Case (3,1): ** 31 is prime, and thus the only minimal prime in this family. * Case (3,5): ** 35 is prime, and thus the only minimal prime in this family. * Case (4,1): ** Since 45, 11, 21, 31, 51 are primes, we only need to consider the family 4{0,4}1 (since any digits 1, 2, 3, 5 between them will produce smaller primes) *** Since 4401 and 4441 are primes, we only need to consider the families 4{0}1 and 4{0}41 (since any digits combo 40 and 44 between them will produce smaller primes) **** All numbers of the form 4{0}1 are divisible by 5, thus cannot be prime. **** The smallest prime of the form 4{0}41 is 40041 * Case (4,5): ** 45 is prime, and thus the only minimal prime in this family. * Case (5,1): ** 51 is prime, and thus the only minimal prime in this family. * Case (5,5): ** Since 51, 15, 25, 35, 45 are primes, we only need to consider the family 5{0,5}5 (since any digits 1, 2, 3, 4 between them will produce smaller primes) *** All numbers of the form 5{0,5}5 are divisible by 5, thus cannot be prime. ===Base 7=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1), (1,2), (1,3), (1,4), (1,5), (1,6), (2,1), (2,2), (2,3), (2,4), (2,5), (2,6), (3,1), (3,2), (3,3), (3,4), (3,5), (3,6), (4,1), (4,2), (4,3), (4,4), (4,5), (4,6), (5,1), (5,2), (5,3), (5,4), (5,5), (5,6), (6,1), (6,2), (6,3), (6,4), (6,5), (6,6) * Case (1,1): ** Since 14, 16, 41, 61, 131 are primes, we only need to consider the family 1{0,1,2,5}1 (since any digits 3, 4, 6 between them will produce smaller primes) *** Since the digit sum of primes must be odd (otherwise the number will be divisible by 2, thus cannot be prime), there is an odd total number of 1 and 5 in the {} **** If there are >=3 number of 1 and 5 in the {}: ***** If there is 111 in the {}, then we have the prime 11111 ***** If there is 115 in the {}, then the prime 115 is a subsequence ***** If there is 151 in the {}, then the prime 115 is a subsequence ***** If there is 155 in the {}, then the prime 155 is a subsequence ***** If there is 511 in the {}, then the current number is 15111, which has digit sum = 12, but digit sum divisible by 3 will cause the number divisible by 3 and cannot be prime, and we cannot add more 1 or 5 to this number (to avoid 11111, 155, 515, 551 as subsequence), thus we must add at least one 2 to this number, but then the number has both 2 and 5, and will have either 25 or 52 as subsequence, thus cannot be minimal prime ***** If there is 515 in the {}, then the prime 515 is a subsequence ***** If there is 551 in the {}, then the prime 551 is a subsequence ***** If there is 555 in the {}, then the prime 551 is a subsequence **** Thus there is only one 1 (and no 5) or only one 5 (and no 1) in the {}, i.e. we only need to consider the families 1{0,2}1{0,2}1 and 1{0,2}5{0,2}1 ***** For the 1{0,2}1{0,2}1 family, since 1211 is prime, we only need to consider the family 1{0}1{0,2}1 ****** Since all numbers of the form 1{0}1{0}1 are divisible by 3 and cannot be prime, we only need to consider the family 1{0}1{0}2{0}1 ******* Since 11201 is prime, we only need to consider the family 1{0}1{0}21 ******** The smallest prime of the form 11{0}21 is 1100021 ******** All numbers of the form 101{0}21 are divisible by 5, thus cannot be prime ******** The smallest prime of the form 1001{0}21 is 100121 ********* Since this prime has no 0 between 1{0}1 and 21, we do not need to consider more families ***** For the 1{0,2}5{0,2}1 family, since 25 and 52 are primes, we only need to consider the family 1{0}5{0}1 ****** Since 1051 is prime, we only need to consider the family 15{0}1 ******* The smallest prime of the form 15{0}1 is 150001 * Case (1,2): ** Since 14, 16, 32, 52 are primes, we only need to consider the family 1{0,1,2}2 (since any digits 3, 4, 5, 6 between them will produce smaller primes) *** Since 1112 and 1222 are primes, there is at most one 1 and at most one 2 in {} **** If there are one 1 and one 2 in {}, then the digit sum is 6, and the number will be divisible by 6 and cannot be prime. **** If there is one 1 but no 2 in {}, then the digit sum is 4, and the number will be divisible by 2 and cannot be prime. **** If there is no 1 but one 2 in {}, then the form is 1{0}2{0}2 ***** Since 1022 and 1202 are primes, we only need to consider the number 122 ****** 122 is not prime. **** If there is no 1 and no 2 in {}, then the digit sum is 3, and the number will be divisible by 3 and cannot be prime. * Case (1,3): ** Since 14, 16, 23, 43, 113, 133 are primes, we only need to consider the family 1{0,5}3 (since any digits 1, 2, 3, 4, 6 between them will produce smaller primes) *** Since 155 is prime, we only need to consider the family 1{0}3 and 1{0}5{0}3 **** All numbers of the form 1{0}3 are divisible by 2, thus cannot be prime. **** All numbers of the form 1{0}5{0}3 are divisible by 3, thus cannot be prime. * Case (1,4): ** 14 is prime, and thus the only minimal prime in this family. * Case (1,5): ** Since 14, 16, 25, 65, 115, 155 are primes, we only need to consider the family 1{0,3}5 (since any digits 1, 2, 4, 5, 6 between them will produce smaller primes) *** All numbers of the form 1{0,3}5 are divisible by 3, thus cannot be prime. * Case (1,6): ** 16 is prime, and thus the only minimal prime in this family. * Case (2,1): ** Since 23, 25, 41, 61, 221 are primes, we only need to consider the family 2{0,1}1 (since any digits 2, 3, 4, 5, 6 between them will produce smaller primes) *** Since 2111 is prime, we only need to consider the families 2{0}1 and 2{0}1{0}1 **** All numbers of the form 2{0}1 are divisible by 3, thus cannot be prime. **** All numbers of the form 2{0}1{0}1 are divisible by 2, thus cannot be prime. * Case (2,2): ** Since 23, 25, 32, 52, 212 are primes, we only need to consider the family 2{0,2,4,6}2 (since any digits 1, 3, 5 between them will produce smaller primes) *** All numbers of the form 2{0,2,4,6}2 are divisible by 2, thus cannot be prime. * Case (2,3): ** 23 is prime, and thus the only minimal prime in this family. * Case (2,4): ** Since 23, 25, 14 are primes, we only need to consider the family 2{0,2,4,6}4 (since any digits 1, 3, 5 between them will produce smaller primes) *** All numbers of the form 2{0,2,4,6}4 are divisible by 2, thus cannot be prime. * Case (2,5): ** 25 is prime, and thus the only minimal prime in this family. * Case (2,6): ** Since 23, 25, 16, 56 are primes, we only need to consider the family 2{0,2,4,6}6 (since any digits 1, 3, 5 between them will produce smaller primes) *** All numbers of the form 2{0,2,4,6}6 are divisible by 2, thus cannot be prime. * Case (3,1): ** Since 32, 41, 61 are primes, we only need to consider the family 3{0,1,3,5}1 (since any digits 2, 4, 6 between them will produce smaller primes) *** Since 551 is prime, we only need to consider the family 3{0,1,3}1 and 3{0,1,3}5{0,1,3}1 (since any digits combo 55 between (3,1) will produce smaller primes) **** For the 3{0,1,3}1 family, since 3031 and 131 are primes, we only need to consider the families 3{0,1}1 and 3{3}3{0,1}1 (since any digits combo 03, 13 between (3,1) will produce smaller primes, thus for the digits between (3,1), all 3's must be before all 0's and 1's, and thus we can let the red 3 in 3{3}3{0,1}1 be the rightmost 3 between (3,1), all digits before this 3 must be 3's, and all digits after this 3 must be either 0's or 1's) ***** For the 3{0,1}1 family: ****** If there are >=2 0's and >=1 1's between (3,1), then at least one of 30011, 30101, 31001 will be a subsequence. ****** If there are no 1's between (3,1), then the form will be 3{0}1 ******* All numbers of the form 3{0}1 are divisible by 2, thus cannot be prime. ****** If there are no 0's between (3,1), then the form will be 3{1}1 ******* The smallest prime of the form 3{1}1 is 31111 ****** If there are exactly 1 0's between (3,1), then there must be <3 1's between (3,1), or 31111 will be a subsequence. ******* If there are 2 1's between (3,1), then the digit sum is 6, thus the number is divisible by 6 and cannot be prime. ******* If there are 1 1's between (3,1), then the number can only be either 3101 or 3011 ******** Neither 3101 nor 3011 is prime. ******* If there are no 1's between (3,1), then the number must be 301 ******** 301 is not prime. ***** For the 3{3}3{0,1}1 family: ****** If there are at least one 3 between (3,3{0,1}1) and at least one 1 between (3{3}3,1), then 33311 will be a subsequence. ****** If there are no 3 between (3,3{0,1}1), then the form will be 33{0,1}1 ******* If there are at least 3 1's between (33,1), then 31111 will be a subsequence. ******* If there are exactly 2 1's between (33,1), then the digit sum is 12, thus the number is divisible by 3 and cannot be prime. ******* If there are exactly 1 1's between (33,1), then the digit sum is 11, thus the number is divisible by 2 and cannot be prime. ******* If there are no 1's between (33,1), then the form will be 33{0}1 ******** The smallest prime of the form 33{0}1 is 33001 ****** If there are no 1 between (3{3}3,1), then the form will be 3{3}3{0}1 ******* If there are at least 2 0's between (3{3}3,1), then 33001 will be a subsequence. ******* If there are exactly 1 0's between (3{3}3,1), then the form is 3{3}301 ******** The smallest prime of the form 3{3}301 is 33333301 ******* If there are no 0's between (3{3}3,1), then the form is 3{3}31 ******** The smallest prime of the form 3{3}31 is 33333333333333331 **** For the 3{0,1,3}5{0,1,3}1 family, since 335 is prime, we only need to consider the family 3{0,1}5{0,1,3}1 ***** Numbers containing 3 between (3{0,1}5,1): ****** The form is 3{0,1}5{0,1,3}3{0,1,3}1 ******* Since 3031 and 131 are primes, we only need to consider the family 35{3}3{0,1,3}1 (since any digits combo 03, 13 between (3,1) will produce smaller primes) ******** Since 533 is prime, we only need to consider the family 353{0,1}1 (since any digits combo 33 between (35,1) will produce smaller primes) ********* Since 5011 is prime, we only need to consider the family 353{1}{0}1 (since any digits combo 01 between (353,1) will produce smaller primes) ********** If there are at least 3 1's between (353,{0}1), then 31111 will be a subsequence. ********** If there are exactly 2 1's between (353,{0}1), then the digit sum is 20, thus the number is divisible by 2 and cannot be prime. ********** If there are exactly 1 1's between (353,{0}1), then the form is 3531{0}1 *********** The smallest prime of the form 3531{0}1 is 3531001, but it is not minimal prime since 31001 is prime. ********** If there are no 1's between (353,{0}1), then the digit sum is 15, thus the number is divisible by 6 and cannot be prime. ***** Numbers not containing 3 between (3{0,1}5,1): ****** The form is 3{0,1}5{0,1}1 ******* If there are >=2 0's and >=1 1's between (3,1), then at least one of 30011, 30101, 31001 will be a subsequence. ******* If there are no 1's between (3,1), then the form will be 3{0}5{0}1 ******** All numbers of the form 3{0}5{0}1 are divisible by 3, thus cannot be prime. ******* If there are no 0's between (3,1), then the form will be 3{1}5{1}1 ******** If there are >=3 1's between (3,1), then 31111 will be a subsequence. ******** If there are exactly 2 1's between (3,1), then the number can only be 31151, 31511, 35111 ********* None of 31151, 31511, 35111 are primes. ******** If there are exactly 1 1's between (3,1), then the digit sum is 13, thus the number is divisible by 2 and cannot be prime. ******** If there are no 1's between (3,1), then the number is 351 ********* 351 is not prime. ******* If there are exactly 1 0's between (3,1), then the form will be 3{1}0{1}5{1}1 or 3{1}5{1}0{1}1 ******** No matter 3{1}0{1}5{1}1 or 3{1}5{1}0{1}1, if there are >=3 1's between (3,1), then 31111 will be a subsequence. ******** If there are exactly 2 1's between (3,1), then the number can only be 311051, 310151, 310511, 301151, 301511, 305111, 311501, 315101, 315011, 351101, 351011, 350111 ********* Of these numbers, 311051, 301151, 311501, 351101, 350111 are primes. ********** However, 311051, 301151, 311501 have 115 as subsequence, and 350111 has 5011 as subsequence, thus only 351101 is minimal prime. ******** No matter 3{1}0{1}5{1}1 or 3{1}5{1}0{1}1, if there are exactly 1 1's between (3,1), then the digit sum is 13, thus the number is divisible by 2 and cannot be prime. ******** If there are no 1's between (3,1), then the number is 3051 for 3{1}0{1}5{1}1 or 3501 for 3{1}5{1}0{1}1 ********* Neither 3051 nor 3501 is prime. * Case (3,2): ** 32 is prime, and thus the only minimal prime in this family. * Case (3,3): ** Since 32, 23, 43, 313 are primes, we only need to consider the family 3{0,3,5,6}3 (since any digits 1, 2, 4 between them will produce smaller primes) *** If there are >=2 5's in {}, then 553 will be a subsequence. *** If there are no 5's in {}, then the family will be 3{0,3,6}3 **** All numbers of the form 3{0,3,6}3 are divisible by 3, thus cannot be prime. *** If there are exactly 1 5's in {}, then the family will be 3{0,3,6}5{0,3,6}3 **** Since 335, 65, 3503, 533, 56 are primes, we only need to consider the family 3{0}53 (since any digit 3, 6 between (3,5{0,3,6}3) and any digit 0, 3, 6 between (3{0,3,6}5,3) will produce smaller primes) ***** The smallest prime of the form 3{0}53 is 300053 * Case (3,4): ** Since 32, 14, 304, 344, 364 are primes, we only need to consider the family 3{3,5}4 (since any digits 0, 1, 2, 4, 6 between them will produce smaller primes) *** Since 3334 and 335 are primes, we only need to consider the family 3{5}4 and 3{5}34 (since any digits combo 33, 35 between them will produce smaller primes) **** The smallest prime of the form 3{5}4 is 35555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555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with 9234 5's, which can be written as 3(5^9234)4 and equal the prime (23*7^9235-11)/6 ([http://factordb.com/index.php?id=1100000002766595757 factordb]) ([http://factordb.com/cert.php?id=1100000002766595757 primality certificate]) (not minimal prime, since 35555 and 5554 are primes) **** The smallest prime of the form 3{5}34 is 355555555555555555555555555555555555555555555555555555555555555534 (not minimal prime, since 35555, 553, and 5554 are primes) * Case (3,5): ** Since 32, 25, 65, 335 are primes, we only need to consider the family 3{0,1,4,5}5 (since any digits 2, 3, 6 between them will produce smaller primes) *** If there are at least one 1's and at least one 5's in {}, then either 155 or 515 will be a subsequence. *** If there are at least one 1's and at least one 4's in {}, then either 14 or 41 will be a subsequence. *** If there are at least two 1's in {}, then 115 will be a subsequence. *** If there are exactly one 1's and no 4's or 5's in {}, then the family will be 3{0}1{0}5 **** All numbers of the form 3{0}1{0}5 are divisible by 3, thus cannot be prime. *** If there is no 1's in {}, then the family will be 3{0,4,5}5 **** If there are at least to 4's in {}, then 344 and 445 will be subsequences. **** If there is no 4's in {}, then the family will be 3{0,5}5 ***** Since 3055 and 3505 are primes, we only need to consider the families 3{0}5 and 3{5}5 ****** All numbers of the form 3{0}5 are divisible by 2, thus cannot be prime. ****** The smallest prime of the form 3{5}5 is 35555 **** If there is exactly one 4's in {}, then the family will be 3{0,5}4{0,5}5 ***** Since 304, 3545 are primes, we only need to consider the families 34{0,5}5 (since any digits 0 or 5 between (3,4{0,5}5) will produce small primes) ****** All numbers of the form 34{0,5}5 are divisible by 5, thus cannot be prime. * Case (3,6): ** Since 32, 16, 56, 346 are primes, we only need to consider the family 3{0,3,6}6 (since any digits 1, 2, 4, 5 between them will produce smaller primes) *** All numbers of the form 3{0,3,6}6 are divisible by 3, thus cannot be prime. * Case (4,1): ** 41 is prime, and thus the only minimal prime in this family. * Case (4,2): ** Since 41, 43, 32, 52 are primes, we only need to consider the family 4{0,2,4,6}2 (since any digits 1, 3, 5 between them will produce smaller primes) *** All numbers of the form 4{0,2,4,6}2 are divisible by 2, thus cannot be prime. * Case (4,3): ** 43 is prime, and thus the only minimal prime in this family. * Case (4,4): ** Since 41, 43, 14 are primes, we only need to consider the family 4{0,2,4,5,6}4 (since any digits 1, 3 between them will produce smaller primes) *** If there is no 5's in {}, then the family will be 4{0,2,4,6}4 **** All numbers of the form 4{0,2,4,6}4 are divisible by 2, thus cannot be prime. *** If there is at least one 5's in {}, then there cannot be 2 in {} (since if so, then either 25 or 52 will be a subsequence) and there cannot be 6 in {} (since if so, then either 65 or 56 will be a subsequence), thus the family is 4{0,4,5}5{0,4,5}4 **** Since 445, 4504, 544 are primes, we only need to consider the family 4{0,5}5{5}4 (since any digit 4 between (4,5{0,4,5}4) and any digit 0, 4 between (4{0,4,5}5,4) will produce smaller primes) ***** If there are at least two 0's between (4,5{0,4,5}4), then 40054 will be a subsequence. ***** If there is no 0's between (4,5{0,4,5}4), then the family will be 4{5}5{5}4, which is equivalent to 4{5}4 ****** The smallest prime of the form 4{5}4 is 45555555555555554 (not minimal prime, since 4555 and 5554 are primes) ***** If there is exactly one 0's between (4,5{0,4,5}4), then the family will be 4{5}0{5}5{5}4 ****** Since 4504 is prime, we only need to consider the family 40{5}5{5}4 (since any digit 5 between (4,0{5}5{5}4) will produce small primes), which is equivalent to 40{5}4 ******* The smallest prime of the form 40{5}4 is 405555555555555554 (not minimal prime, since 4555 and 5554 are primes) * Case (4,5): ** Since 41, 43, 25, 65, 445 are primes, we only need to consider the family 4{0,5}5 (since any digits 1, 2, 3, 4, 6 between them will produce smaller primes) *** If there are at least two 5's in {}, then 4555 will be a subsequence. *** If there is exactly one 5's in {}, then the digit sum is 20, and the number will be divisible by 2 and cannot be prime. *** If there is no 5's in {}, then the family will be 4{0}5 **** All numbers of the form 4{0}5 are divisible by 3, thus cannot be prime. * Case (4,6): ** Since 41, 43, 16, 56 are primes, we only need to consider the family 4{0,2,4,6}6 (since any digits 1, 3, 5 between them will produce smaller primes) *** All numbers of the form 4{0,2,4,6}6 are divisible by 2, thus cannot be prime. * Case (5,1): ** Since 52, 56, 41, 61, 551 are primes, we only need to consider the family 5{0,1,3}1 (since any digits 2, 4, 5, 6 between them will produce smaller primes) *** If there are at least two 3's in {}, then 533 will be a subsequence. *** If there is no 3's in {}, then the family will be 5{0,1}1 **** Since 5011 is prime, we only need to consider the family 5{1}{0}1 ***** Since 11111 is prime, we only need to consider the families 5{0}1, 51{0}1, 511{0}1, 5111{0}1 (since any digits combo 1111 between (5,1) will produce small primes) ****** All numbers of the form 5{0}1 are divisible by 6, thus cannot be prime. ****** The smallest prime of the form 51{0}1 is 5100000001 ****** All numbers of the form 511{0}1 are divisible by 2, thus cannot be prime. ****** All numbers of the form 5111{0}1 are divisible by 3, thus cannot be prime. *** If there is exactly one 3's in {}, then the family will be 5{0,1}3{0,1}1 **** If there is at least one 1's between (5,3{0,1}1), then 131 will be a subsequence. ***** Thus we only need to consider the family 5{0}3{0,1}1 ****** If there are no 1's between (5{0}3,1), then the digit sum is 12, and the number will be divisible by 3 and cannot be prime. ****** If there are exactly one 1's between (5{0}3,1), then the digit sum is 13, and the number will be divisible by 2 and cannot be prime. ****** If there are exactly three 1's between (5{0}3,1), then the digit sum is 15, and the number will be divisible by 6 and cannot be prime. ****** If there are at least four 1's between (5{0}3,1), then 11111 will be a subsequence. ****** If there are exactly two 1's between (5{0}3,1), then the family will be 5{0}3{0}1{0}1{0}1 ******* Since 5011 is prime, we only need to consider the family 5311{0}1 (since any digit 0 between (5,1{0}1) will produce small primes, this includes the leftmost three {} in 5{0}3{0}1{0}1{0}1, and thus only the rightmost {} can contain 0) ******** The smallest prime of the form 5311{0}1 is 531101 * Case (5,2): ** 52 is prime, and thus the only minimal prime in this family. * Case (5,3): ** Since 52, 56, 23, 43, 533, 553 are primes, we only need to consider the family 5{0,1}3 (since any digits 2, 3, 4, 5, 6 between them will produce smaller primes) *** If there are at least two 1's in {}, then 113 will be a subsequence. *** If there is exactly one 1's in {}, then the digit sum is 12, and the number will be divisible by 3 and cannot be prime. *** If there is no 1's in {}, then the digit sum is 11, and the number will be divisible by 2 and cannot be prime. * Case (5,4): ** Since 52, 56, 14, 544 are primes, we only need to consider the family 5{0,3,5}4 (since any digits 1, 2, 4, 6 between them will produce smaller primes) *** If there are no 5's in {}, then the family will be 5{0,3}4 **** All numbers of the form 5{0,3}4 are divisible by 3, thus cannot be prime. *** If there are at least one 5's and at least one 3's in {}, then either 535 or 553 will be a subsequence. *** If there are exactly one 5's and no 3's in {}, then the digit sum is 20, and the number will be divisible by 2 and cannot be prime. *** If there are at least two 5's in {}, then 5554 will be a subsequence. * Case (5,5): ** Since 52, 56, 25, 65, 515, 535 are primes, we only need to consider the family 5{0,4,5}5 (since any digits 1, 2, 3, 6 between them will produce smaller primes) *** If there are no 4's in {}, then the family will be 5{0,5}5 **** All numbers of the form 5{0,5}5 are divisible by 5, thus cannot be prime. *** If there are no 5's in {}, then the family will be 5{0,4}5 **** All numbers of the form 5{0,4}5 are divisible by 2, thus cannot be prime. *** If there are at least one 4's and at least one 5's in {}, then either 5455 or 5545 will be a subsequence. * Case (5,6): ** 56 is prime, and thus the only minimal prime in this family. * Case (6,1): ** 61 is prime, and thus the only minimal prime in this family. * Case (6,2): ** Since 61, 65, 32, 52 are primes, we only need to consider the family 6{0,2,4,6}2 (since any digits 1, 3, 5 between them will produce smaller primes) *** All numbers of the form 6{0,2,4,6}2 are divisible by 2, thus cannot be prime. * Case (6,3): ** Since 61, 65, 23, 43 are primes, we only need to consider the family 6{0,3,6}3 (since any digits 1, 2, 4, 5 between them will produce smaller primes) *** All numbers of the form 6{0,3,6}3 are divisible by 3, thus cannot be prime. * Case (6,4): ** Since 61, 65, 14 are primes, we only need to consider the family 6{0,2,3,4,6}4 (since any digits 1, 5 between them will produce smaller primes) *** If there is no 3's in {}, then the family will be 6{0,2,4,6}4 **** All numbers of the form 6{0,2,4,6}4 are divisible by 2, thus cannot be prime. *** If there are exactly two 3's in {}, then the family will be 6{0,2,4,6}3{0,2,4,6}3{0,2,4,6}4 **** All numbers of the form 6{0,2,4,6}3{0,2,4,6}3{0,2,4,6}4 are divisible by 2, thus cannot be prime. *** If there are at least three 3's in {}, then 3334 will be a subsequence. *** If there is exactly one 3's in {}, then the family will be 6{0,2,4,6}3{0,2,4,6}4 **** If there is 0 between (6,3{0,2,4,6}4), then 6034 will be a subsequence. **** If there is 2 between (6,3{0,2,4,6}4), then 23 will be a subsequence. **** If there is 4 between (6,3{0,2,4,6}4), then 43 will be a subsequence. **** If there is 6 between (6,3{0,2,4,6}4), then 6634 will be a subsequence. **** If there is 0 between (6{0,2,4,6}3,4), then 304 will be a subsequence. **** If there is 2 between (6{0,2,4,6}3,4), then 32 will be a subsequence. **** If there is 4 between (6{0,2,4,6}3,4), then 344 will be a subsequence. **** If there is 6 between (6{0,2,4,6}3,4), then 364 will be a subsequence. **** Thus the number can only be 634 ***** 634 is not prime. * Case (6,5): ** 65 is prime, and thus the only minimal prime in this family. * Case (6,6): ** Since 61, 65, 16, 56 are primes, we only need to consider the family 6{0,2,3,4,6}6 (since any digits 1, 5 between them will produce smaller primes) *** If there is no 3's in {}, then the family will be 6{0,2,4,6}6 **** All numbers of the form 6{0,2,4,6}6 are divisible by 2, thus cannot be prime. *** If there is no 2's and no 4's in {}, then the family will be 6{0,3,6}6 **** All numbers of the form 6{0,3,6}6 are divisible by 3, thus cannot be prime. *** If there is at least one 3's and at least one 2's in {}, then either 32 or 23 will be a subsequence. *** If there is at least one 3's and at least one 4's in {}, then either 346 or 43 will be a subsequence. ===Base 8=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1), (1,3), (1,5), (1,7), (2,1), (2,3), (2,5), (2,7), (3,1), (3,3), (3,5), (3,7), (4,1), (4,3), (4,5), (4,7), (5,1), (5,3), (5,5), (5,7), (6,1), (6,3), (6,5), (6,7), (7,1), (7,3), (7,5), (7,7) * Case (1,1): ** Since 13, 15, 21, 51, 111, 141, 161 are primes, we only need to consider the family 1{0,7}1 (since any digits 1, 2, 3, 4, 5, 6 between them will produce smaller primes) *** Since 107, 177, 701 are primes, we only need to consider the number 171 and the family 1{0}1 (since any digits combo 07, 70, 77 between them will produce smaller primes) **** 171 is not prime. **** All numbers of the form 1{0}1 factored as 10^n+1 = (2^n+1) * (4^n-2^n+1) (n≥1) (and since if n≥1, 2^n+1 ≥ 2^1+1 = 3 > 1, 4^n-2^n+1 ≥ 4^1-2^1+1 = 3 > 1, this factorization is nontrivial), thus cannot be prime. * Case (1,3): ** 13 is prime, and thus the only minimal prime in this family. * Case (1,5): ** 15 is prime, and thus the only minimal prime in this family. * Case (1,7): ** Since 13, 15, 27, 37, 57, 107, 117, 147, 177 are primes, we only need to consider the family 1{6}7 (since any digits 0, 1, 2, 3, 4, 5, 7 between them will produce smaller primes) *** The smallest prime of the form 1{6}7 is 16667 (not minimal prime, since 667 is prime) * Case (2,1): ** 21 is prime, and thus the only minimal prime in this family. * Case (2,3): ** 23 is prime, and thus the only minimal prime in this family. * Case (2,5): ** Since 21, 23, 27, 15, 35, 45, 65, 75, 225, 255 are primes, we only need to consider the family 2{0}5 (since any digits 1, 2, 3, 4, 5, 6, 7 between them will produce smaller primes) *** All numbers of the form 2{0}5 are divisible by 7, thus cannot be prime. * Case (2,7): ** 27 is prime, and thus the only minimal prime in this family. * Case (3,1): ** Since 35, 37, 21, 51, 301, 361 are primes, we only need to consider the family 3{1,3,4}1 (since any digits 0, 2, 5, 6, 7 between them will produce smaller primes) *** Since 13, 343, 111, 131, 141, 431, 3331, 3411 are primes, we only need to consider the families 3{3}11, 33{1,4}1, 3{3,4}4{4}1 (since any digits combo 11, 13, 14, 33, 41, 43 between them will produce smaller primes) **** All numbers of the form 3{3}11 are divisible by 3, thus cannot be prime. **** For the 33{1,4}1 family, since 111 and 141 are primes, we only need to consider the families 33{4}1 and 33{4}11 (since any digits combo 11, 14 between them will produce smaller primes) ***** The smallest prime of the form 33{4}1 is 3344441 ***** All numbers of the form 33{4}11 are divisible by 301, thus cannot be prime. **** For the 3{3,4}4{4}1 family, since 3331 and 3344441 are primes, we only need to consider the families 3{4}1, 3{4}31, 3{4}341, 3{4}3441, 3{4}34441 (since any digits combo 33 or 34444 between (3,1) will produce smaller primes) ***** All numbers of the form 3{4}1 are divisible by 31, thus cannot be prime. ***** Since 4443 is prime, we only need to consider the numbers 3431, 34431, 34341, 344341, 343441, 3443441, 3434441, 34434441 (since any digit combo 444 between (3,3{4}1) will produce smaller primes) ****** None of 3431, 34431, 34341, 344341, 343441, 3443441, 3434441, 34434441 are primes. * Case (3,3): ** Since 35, 37, 13, 23, 53, 73, 343 are primes, we only need to consider the family 3{0,3,6}3 (since any digits 1, 2, 4, 5, 7 between them will produce smaller primes) *** All numbers of the form 3{0,3,6}3 are divisible by 3, thus cannot be prime. * Case (3,5): ** 35 is prime, and thus the only minimal prime in this family. * Case (3,7): ** 37 is prime, and thus the only minimal prime in this family. * Case (4,1): ** Since 45, 21, 51, 401, 431, 471 are primes, we only need to consider the family 4{1,4,6}1 (since any digits 0, 2, 3, 5, 7 between them will produce smaller primes) *** Since 111, 141, 161, 661, 4611 are primes, we only need to consider the families 4{4}11, 4{4,6}4{1,4,6}1, 4{4}6{4}1 (since any digits combo 11, 14, 16, 61, 66 between them will produce smaller primes) **** The smallest prime of the form 4{4}11 is 44444444444444411 (not minimal prime, since 444444441 is prime) **** For the 4{4,6}4{1,4,6}1 family, we can separate this family to 4{4,6}41, 4{4,6}411, 4{4,6}461 ***** For the 4{4,6}41 family, since 661 and 6441 are primes, we only need to consider the families 4{4}41 and 4{4}641 (since any digits combo 64 or 66 between (4,41) will produce smaller primes) ****** The smallest prime of the form 4{4}41 is 444444441 ****** The smallest prime of the form 4{4}641 is 444641 ***** For the 4{4,6}411 family, since 661 and 6441 are primes, we only need to consider the families 4{4}411 and 4{4}6411 (since any digits combo 64 or 66 between (4,411) will produce smaller primes) ****** The smallest prime of the form 4{4}411 is 444444441 ****** The smallest prime of the form 4{4}6411 is 4444444444444446411 (not minimal prime, since 444444441 and 444641 are primes) ***** For the 4{4,6}461 family, since 661 is prime, we only need to consider the family 4{4}461 ****** The smallest prime of the form 4{4}461 is 4444444461 (not minimal prime, since 444444441 is prime) **** For the 4{4}6{4}1 family, since 6441 is prime, we only need to consider the families 4{4}61 and 4{4}641 (since any digits combo 44 between (4{4}6,1) will produce smaller primes) ***** The smallest prime of the form 4{4}61 is 4444444461 (not minimal prime, since 444444441 is prime) ***** The smallest prime of the form 4{4}641 is 444641 * Case (4,3): ** Since 45, 13, 23, 53, 73, 433, 463 are primes, we only need to consider the family 4{0,4}3 (since any digits 1, 2, 3, 5, 6, 7 between them will produce smaller primes) *** Since 4043 and 4443 are primes, we only need to consider the families 4{0}3 and 44{0}3 (since any digits combo 04, 44 between them will produce smaller primes) **** All numbers of the form 4{0}3 are divisible by 7, thus cannot be prime. **** All numbers of the form 44{0}3 are divisible by 3, thus cannot be prime. * Case (4,5): ** 45 is prime, and thus the only minimal prime in this family. * Case (4,7): ** Since 45, 27, 37, 57, 407, 417, 467 are primes, we only need to consider the family 4{4,7}7 (since any digits 0, 1, 2, 3, 5, 6 between them will produce smaller primes) *** Since 747 is prime, we only need to consider the families 4{4}7, 4{4}77, 4{7}7, 44{7}7 (since any digits combo 74 between (4,7) will produce smaller primes) **** The smallest prime of the form 4{4}7 is 44444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444447, with 220 4's, which can be written as (4^220)7 and equal the prime (4*8^221+17)/7 ([http://factordb.com/index.php?id=1100000000416605822 factordb]) **** The smallest prime of the form 4{4}77 is 4444477 **** The smallest prime of the form 4{7}7 is 47777 **** The smallest prime of the form 44{7}7 is 4477777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777, with 851 7's, which can be written as 44(7^851) and equal the prime 37*8^851-1 ([http://factordb.com/index.php?id=1100000000413677646 factordb]) (not minimal prime, since 47777 is prime) * Case (5,1): ** 51 is prime, and thus the only minimal prime in this family. * Case (5,3): ** 53 is prime, and thus the only minimal prime in this family. * Case (5,5): ** Since 51, 53, 57, 15, 35, 45, 65, 75 are primes, we only need to consider the family 5{0,2,5}5 (since any digits 1, 3, 4, 6, 7 between them will produce smaller primes) *** Since 225, 255, 5205 are primes, we only need to consider the families 5{0,5}5 and 5{0,5}25 (since any digits combo 20, 22, 25 between them will produce smaller primes) **** All numbers of the form 5{0,5}5 are divisible by 5, thus cannot be prime. **** For the 5{0,5}25 family, since 500025 and 505525 are primes, we only need to consider the number 500525 the families 5{5}25, 5{5}025, 5{5}0025, 5{5}0525, 5{5}00525, 5{5}05025 (since any digits combo 000, 055 between (5,25) will produce smaller primes) ***** 500525 is not prime. ***** The smallest prime of the form 5{5}25 is 555555555555525 ***** The smallest prime of the form 5{5}025 is 55555025 ***** The smallest prime of the form 5{5}0025 is 5555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555550025, with 184 5's, which can be written as (5^183)0025 and equal the prime (5*8^187-20333)/7 ([http://factordb.com/index.php?id=1100000002350205912 factordb]) (not minimal prime, since 55555025 and 555555555555525 are primes) ***** The smallest prime of the form 5{5}0525 is 5550525 ***** The smallest prime of the form 5{5}00525 is 5500525 ***** The smallest prime of the form 5{5}05025 is 5555555555555555555555505025 (not minimal prime, since 5550525, 55555025, and 555555555555525 are primes) * Case (5,7): ** 57 is prime, and thus the only minimal prime in this family. * Case (6,1): ** Since 65, 21, 51, 631, 661 are primes, we only need to consider the family 6{0,1,4,7}1 (since any digits 2, 3, 5, 6 between them will produce smaller primes) *** Numbers containing 4: (note that the number cannot contain two or more 4's, or 6441 will be a subsequence) **** The form is 6{0,1,7}4{0,1,7}1 ***** Since 141, 401, 471 are primes, we only need to consider the family 6{0,7}4{1}1 ****** Since 111 is prime, we only need to consider the families 6{0,7}41 and 6{0,7}411 ******* For the 6{0,7}41 family, since 60741 is prime, we only need to consider the family 6{7}{0}41 ******** Since 6777 is prime, we only need to consider the families 6{0}41, 67{0}41, 677{0}41 ********* All numbers of the form 6{0}41 are divisible by 3, thus cannot be prime. ********* All numbers of the form 67{0}41 are divisible by 13, thus cannot be prime. ********* All numbers of the form 677{0}41 are divisible by 3, thus cannot be prime. ******* For the 6{0,7}411 family, since 60411 is prime, we only need to consider the family 6{7}411 ******** The smallest prime of the form 6{7}411 is 67777411 (not minimal prime, since 6777 is prime) *** Numbers not containing 4: **** The form is 6{0,1,7}1 ***** Since 111 is prime, we only need to consider the families 6{0,7}1 and 6{0,7}1{0,7}1 ****** All numbers of the form 6{0,7}1 are divisible by 7, thus cannot be prime. ****** For the 6{0,7}1{0,7}1 family, since 711 and 6101 are primes, we only need to consider the family 6{0}1{7}1 ******* Since 60171 is prime, we only need to consider the families 6{0}11 and 61{7}1 ******** All numbers of the form 6{0}11 are divisible by 3, thus cannot be prime. ******** The smallest prime of the form 61{7}1 is 617771 (not minimal prime, since 6777 is prime) * Case (6,3): ** Since 65, 13, 23, 53, 73, 643 are primes, we only need to consider the family 6{0,3,6}3 (since any digits 1, 2, 4, 5, 7 between them will produce smaller primes) *** All numbers of the form 6{0,3,6}3 are divisible by 3, thus cannot be prime. * Case (6,5): ** 65 is prime, and thus the only minimal prime in this family. * Case (6,7): ** Since 65, 27, 37, 57, 667 are primes, we only need to consider the family 6{0,1,4,7}7 (since any digits 2, 3, 5, 6 between them will produce smaller primes) *** Since 107, 117, 147, 177, 407, 417, 717, 747, 6007, 6477, 6707, 6777 are primes, there cannot be digits combo 00, 10, 11, 14, 17, 40, 41, 47, 70, 71, 74, 77 between them **** If there is 1 between them, then there cannot be 1, 4, 7 before it and cannot be 0, 1, 4, 7 after it, thus the form will be 6{0}17 ***** All numbers of the form 6{0}17 are divisible by 3, thus cannot be prime. **** If there is 7 between them, then there cannot be 1, 4, 7 before it and cannot be 0, 1, 4, 7 after it, thus the form will be 6{0}77 ***** All numbers of the form 6{0}77 are divisible by 3, thus cannot be prime. **** If there is neither 1 nor 7 between them, then the form is 6{0,4}7 ***** Since 6007, 407 at primes, we only need to consider the families 6{4}7 and 60{4}7 (since any digits combo 00, 40 between them will produce smaller primes) ****** All numbers of the form 6{4}7 are divisible by 3, 5, or 15, thus cannot be prime. ****** All numbers of the form 60{4}7 are divisible by 21, thus cannot be prime. * Case (7,1): ** Since 73, 75, 21, 51, 701, 711 are primes, we only need to consider the family 7{4,6,7}1 (since any digits 0, 1, 2, 3, 5 between them will produce smaller primes) *** Since 747, 767, 471, 661, 7461, 7641 are primes, we only need to consider the families 7{4,7}4{4}1, 7{7}61, 7{7}7{4,6,7}1 (since any digits combo 46, 47, 64, 66, 67 between them will produce smaller primes) **** For the 7{4,7}4{4}1 family, since 747, 471 are primes, we only need to consider the family 7{7}{4}1 (since any digits combo 47 between (7,4{4}1) will produce smaller primes) ***** The smallest prime of the form 7{7}1 is 7777777777771 ***** The smallest prime of the form 7{7}41 is 777777777777777777777777777777777777777777777777777777777777777777777777777777741, with 79 7's, which can be written as (7^79)41 and equal the prime 8^81-31 ([http://factordb.com/index.php?id=1100000000294462449 factordb]) (not minimal prime, since 7777777777771 is prime) ***** The smallest prime of the form 7{7}441 is 777777777777777777777777777777777777777777777777777777777777777777777777777777777777441, with 84 7's, which can be written as (7^84)441 and equal the prime 8^87-223 ([http://factordb.com/index.php?id=1100000000294462776 factordb]) (not minimal prime, since 7777777777771 is prime) ***** The smallest prime of the form 7{7}4441 is 777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777774441, with 233 7's, which can be written as (7^233)4441 and equal the prime 8^237-1759 ([http://factordb.com/index.php?id=1100000002352073382 factordb]) (not minimal prime, since 7777777777771 is prime) ***** The smallest prime of the form 7{7}44441 is 7777777777777777777777777777777777777777777777777777777744441, with 56 7's, which can be written as (7^56)44441 and equal the prime 8^61-14047 ([http://factordb.com/index.php?id=1100000002350250002 factordb]) (not minimal prime, since 7777777777771 is prime) ***** All numbers of the form 7{7}444441 are divisible by 7, thus cannot be prime. ***** The smallest prime of the form 7{7}4444441 is 77774444441 ****** Since this prime has just 4 7's, we only need to consider the families with <=3 7's ******* The smallest prime of the form 7{4}1 is 744444441 ******* All numbers of the form 77{4}1 are divisible by 5, thus cannot be prime. ******* The smallest prime of the form 777{4}1 is 777444444444441 (not minimal prime, since 444444441 and 744444441 are primes) * Case (7,3): ** 73 is prime, and thus the only minimal prime in this family. * Case (7,5): ** 75 is prime, and thus the only minimal prime in this family. * Case (7,7): ** Since 73, 75, 27, 37, 57, 717, 747, 767 are primes, we only need to consider the family 7{0,7}7 (since any digits 1, 2, 3, 4, 5, 6 between them will produce smaller primes) *** All numbers of the form 7{0,7}7 are divisible by 7, thus cannot be prime. ===Base 10=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1), (1,3), (1,7), (1,9), (2,1), (2,3), (2,7), (2,9), (3,1), (3,3), (3,7), (3,9), (4,1), (4,3), (4,7), (4,9), (5,1), (5,3), (5,7), (5,9), (6,1), (6,3), (6,7), (6,9), (7,1), (7,3), (7,7), (7,9), (8,1), (8,3), (8,7), (8,9), (9,1), (9,3), (9,7), (9,9) * Case (1,1): ** 11 is prime, and thus the only minimal prime in this family. * Case (1,3): ** 13 is prime, and thus the only minimal prime in this family. * Case (1,7): ** 17 is prime, and thus the only minimal prime in this family. * Case (1,9): ** 19 is prime, and thus the only minimal prime in this family. * Case (2,1): ** Since 23, 29, 11, 31, 41, 61, 71, 251, 281 are primes, we only need to consider the family 2{0,2}1 (since any digits 1, 3, 4, 5, 6, 7, 8, 9 between them will produce smaller primes) *** Since 2221 and 20201 are primes, we only need to consider the families 2{0}1, 2{0}21, 22{0}1 (since any digits combo 22 or 020 between them will produce smaller primes) **** All numbers of the form 2{0}1 are divisible by 3, thus cannot be prime. **** The smallest prime of the form 2{0}21 is 20021 **** The smallest prime of the form 22{0}1 is 22000001 * Case (2,3): ** 23 is prime, and thus the only minimal prime in this family. * Case (2,7): ** Since 23, 29, 17, 37, 47, 67, 97, 227, 257, 277 are primes, we only need to consider the family 2{0,8}7 (since any digits 1, 2, 3, 4, 5, 6, 7, 9 between them will produce smaller primes) *** Since 887 and 2087 are primes, we only need to consider the families 2{0}7 and 28{0}7 (since any digit combo 08 or 88 between them will produce smaller primes) **** All numbers of the form 2{0}7 are divisible by 3, thus cannot be prime. **** All numbers of the form 28{0}7 are divisible by 7, thus cannot be prime. * Case (2,9): ** 29 is prime, and thus the only minimal prime in this family. * Case (3,1): ** 31 is prime, and thus the only minimal prime in this family. * Case (3,3): ** Since 31, 37, 13, 23, 43, 53, 73, 83 are primes, we only need to consider the family 3{0,3,6,9}3 (since any digits 1, 2, 4, 5, 7, 8 between them will produce smaller primes) *** All numbers of the form 3{0,3,6,9}3 are divisible by 3, thus cannot be prime. * Case (3,7): ** 37 is prime, and thus the only minimal prime in this family. * Case (3,9): ** Since 31, 37, 19, 29, 59, 79, 89, 349 are primes, we only need to consider the family 3{0,3,6,9}9 (since any digits 1, 2, 4, 5, 7, 8 between them will produce smaller primes) *** All numbers of the form 3{0,3,6,9}9 are divisible by 3, thus cannot be prime. * Case (4,1): ** 41 is prime, and thus the only minimal prime in this family. * Case (4,3): ** 43 is prime, and thus the only minimal prime in this family. * Case (4,7): ** 47 is prime, and thus the only minimal prime in this family. * Case (4,9): ** Since 41, 43, 47, 19, 29, 59, 79, 89, 409, 449, 499 are primes, we only need to consider the family 4{6}9 (since any digits 0, 1, 2, 3, 4, 5, 7, 8, 9 between them will produce smaller primes) *** All numbers of the form 4{6}9 are divisible by 7, thus cannot be prime. * Case (5,1): ** Since 53, 59, 11, 31, 41, 61, 71, 521 are primes, we only need to consider the family 5{0,5,8}1 (since any digits 1, 2, 3, 4, 6, 7, 9 between them will produce smaller primes) *** Since 881 is prime, we only need to consider the families 5{0,5}1 and 5{0,5}8{0,5}1 (since any digit combo 88 between them will produce smaller primes) **** For the 5{0,5}1 family, since 5051 and 5501 are primes, we only need to consider the families 5{0}1 and 5{5}1 (since any digit combo 05 or 50 between them will produce smaller primes) ***** All numbers of the form 5{0}1 are divisible by 3, thus cannot be prime. ***** The smallest prime of the form 5{5}1 is 555555555551 **** For the 5{0,5}8{0,5}1 family, since 5081, 5581, 5801, 5851 are primes, we only need to consider the number 581 ***** 581 is not prime. * Case (5,3): ** 53 is prime, and thus the only minimal prime in this family. * Case (5,7): ** Since 53, 59, 17, 37, 47, 67, 97, 557, 577, 587 are primes, we only need to consider the family 5{0,2}7 (since any digits 1, 3, 4, 5, 6, 7, 8, 9 between them will produce smaller primes) *** Since 227 and 50207 are primes, we only need to consider the families 5{0}7, 5{0}27, 52{0}7 (since any digits combo 22 or 020 between them will produce smaller primes) **** All numbers of the form 5{0}7 are divisible by 3, thus cannot be prime. **** The smallest prime of the form 5{0}27 is 5000000000000000000000000000027 **** The smallest prime of the form 52{0}7 is 5200007 * Case (5,9): ** 59 is prime, and thus the only minimal prime in this family. * Case (6,1): ** 61 is prime, and thus the only minimal prime in this family. * Case (6,3): ** Since 61, 67, 13, 23, 43, 53, 73, 83 are primes, we only need to consider the family 6{0,3,6,9}3 (since any digits 1, 2, 4, 5, 7, 8 between them will produce smaller primes) *** All numbers of the form 6{0,3,6,9}3 are divisible by 3, thus cannot be prime. * Case (6,7): ** 67 is prime, and thus the only minimal prime in this family. * Case (6,9): ** Since 61, 67, 19, 29, 59, 79, 89 are primes, we only need to consider the family 6{0,3,4,6,9}9 (since any digits 1, 2, 5, 7, 8 between them will produce smaller primes) *** Since 449 is prime, we only need to consider the families 6{0,3,6,9}9 and 6{0,3,6,9}4{0,3,6,9}9 (since any digit combo 44 between them will produce smaller primes) **** All numbers of the form 6{0,3,6,9}9 are divisible by 3, thus cannot be prime. **** For the 6{0,3,6,9}4{0,3,6,9}9 family, since 409, 43, 6469, 499 are primes, we only need to consider the family 6{0,3,6,9}49 ***** Since 349, 6949 are primes, we only need to consider the family 6{0,6}49 ****** Since 60649 is prime, we only need to consider the family 6{6}{0}49 (since any digits combo 06 between {6,49} will produce smaller primes) ******* The smallest prime of the form 6{6}49 is 666649 ******** Since this prime has just 4 6's, we only need to consider the families with <=3 6's ********* The smallest prime of the form 6{0}49 is 60000049 ********* The smallest prime of the form 66{0}49 is 66000049 ********* The smallest prime of the form 666{0}49 is 66600049 * Case (7,1): ** 71 is prime, and thus the only minimal prime in this family. * Case (7,3): ** 73 is prime, and thus the only minimal prime in this family. * Case (7,7): ** Since 71, 73, 79, 17, 37, 47, 67, 97, 727, 757, 787 are primes, we only need to consider the family 7{0,7}7 (since any digits 1, 2, 3, 4, 5, 6, 8, 9 between them will produce smaller primes) *** All numbers of the form 7{0,7}7 are divisible by 7, thus cannot be prime. * Case (7,9): ** 79 is prime, and thus the only minimal prime in this family. * Case (8,1): ** Since 83, 89, 11, 31, 41, 61, 71, 821, 881 are primes, we only need to consider the family 8{0,5}1 (since any digits 1, 2, 3, 4, 6, 7, 8, 9 between them will produce smaller primes) *** Since 8501 is prime, we only need to consider the family 8{0}{5}1 (since any digits combo 50 between them will produce smaller primes) **** Since 80051 is prime, we only need to consider the families 8{0}1, 8{5}1, 80{5}1 (since any digits combo 005 between them will produce smaller primes) ***** All numbers of the form 8{0}1 are divisible by 3, thus cannot be prime. ***** The smallest prime of the form 8{5}1 is 8555555555555555555551 (not minimal prime, since 555555555551 is prime) ***** The smallest prime of the form 80{5}1 is 80555551 * Case (8,3): ** 83 is prime, and thus the only minimal prime in this family. * Case (8,7): ** Since 83, 89, 17, 37, 47, 67, 97, 827, 857, 877, 887 are primes, we only need to consider the family 8{0}7 (since any digits 1, 2, 3, 4, 5, 6, 7, 8, 9 between them will produce smaller primes) *** All numbers of the form 8{0}7 are divisible by 3, thus cannot be prime. * Case (8,9): ** 89 is prime, and thus the only minimal prime in this family. * Case (9,1): ** Since 97, 11, 31, 41, 61, 71, 991 are primes, we only need to consider the family 9{0,2,5,8}1 (since any digits 1, 3, 4, 6, 7, 9 between them will produce smaller primes) *** Since 251, 281, 521, 821, 881, 9001, 9221, 9551, 9851 are primes, we only need to consider the families 9{2,5,8}0{2,5,8}1, 9{0}2{0}1, 9{0}5{0,8}1, 9{0,5}8{0}1 (since any digits combo 00, 22, 25, 28, 52, 55, 82, 85, 88 between them will produce smaller primes) **** For the 9{2,5,8}0{2,5,8}1 family, since any digits combo 22, 25, 28, 52, 55, 82, 85, 88 between (9,1) will produce smaller primes, we only need to consider the numbers 901, 9021, 9051, 9081, 9201, 9501, 9801, 90581, 95081, 95801 ***** 95801 is the only prime among 901, 9021, 9051, 9081, 9201, 9501, 9801, 90581, 95081, 95801, but it is not minimal prime since 5801 is prime. **** For the 9{0}2{0}1 family, since 9001 is prime, we only need to consider the numbers 921, 9201, 9021 ***** None of 921, 9201, 9021 are primes. **** For the 9{0}5{0,8}1 family, since 9001 and 881 are primes, we only need to consider the numbers 951, 9051, 9501, 9581, 90581, 95081, 95801 ***** 95801 is the only prime among 951, 9051, 9501, 9581, 90581, 95081, 95801, but it is not minimal prime since 5801 is prime. **** For the 9{0,5}8{0}1 family, since 9001 and 5581 are primes, we only need to consider the numbers 981, 9081, 9581, 9801, 90581, 95081, 95801 ***** 95801 is the only prime among 981, 9081, 9581, 9801, 90581, 95081, 95801, but it is not minimal prime since 5801 is prime. * Case (9,3): ** Since 97, 13, 23, 43, 53, 73, 83 are primes, we only need to consider the family 9{0,3,6,9}3 (since any digits 1, 2, 4, 5, 7, 8 between them will produce smaller primes) *** All numbers of the form 9{0,3,6,9}3 are divisible by 3, thus cannot be prime. * Case (9,7): ** 97 is prime, and thus the only minimal prime in this family. * Case (9,9): ** Since 97, 19, 29, 59, 79, 89 are primes, we only need to consider the family 9{0,3,4,6,9}9 (since any digits 1, 2, 5, 7, 8 between them will produce smaller primes) *** Since 449 is prime, we only need to consider the families 9{0,3,6,9}9 and 9{0,3,6,9}4{0,3,6,9}9 (since any digit combo 44 between them will produce smaller primes) **** All numbers of the form 9{0,3,6,9}9 are divisible by 3, thus cannot be prime. **** For the 9{0,3,6,9}4{0,3,6,9}9 family, since 9049, 349, 9649, 9949 are primes, we only need to consider the family 94{0,3,6,9}9 ***** Since 409, 43, 499 are primes, we only need to consider the family 94{6}9 (since any digits 0, 3, 9 between (94,9) will produce smaller primes) ****** The smallest prime of the form 94{6}9 is 946669 ===Base 12=== The possible (first digit,last digit) combo for a quasi-minimal prime with ≥3 digits are: (1,1), (1,5), (1,7), (1,B), (2,1), (2,5), (2,7), (2,B), (3,1), (3,5), (3,7), (3,B), (4,1), (4,5), (4,7), (4,B), (5,1), (5,5), (5,7), (5,B), (6,1), (6,5), (6,7), (6,B), (7,1), (7,5), (7,7), (7,B), (8,1), (8,5), (8,7), (8,B), (9,1), (9,5), (9,7), (9,B), (A,1), (A,5), (A,7), (A,B), (B,1), (B,5), (B,7), (B,B) * Case (1,1): ** 11 is prime, and thus the only minimal prime in this family. * Case (1,5): ** 15 is prime, and thus the only minimal prime in this family. * Case (1,7): ** 17 is prime, and thus the only minimal prime in this family. * Case (1,B): ** 1B is prime, and thus the only minimal prime in this family. * Case (2,1): ** Since 25, 27, 11, 31, 51, 61, 81, 91, 221, 241, 2A1, 2B1 are primes, we only need to consider the family 2{0}1 (since any digits 1, 2, 3, 4, 5, 6, 7, 8, 9, A, B between them will produce smaller primes) *** The smallest prime of the form 2{0}1 is 2001 * Case (2,5): ** 25 is prime, and thus the only minimal prime in this family. * Case (2,7): ** 27 is prime, and thus the only minimal prime in this family. * Case (2,B): ** Since 25, 27, 1B, 3B, 4B, 5B, 6B, 8B, AB, 2BB are primes, we only need to consider the family 2{0,2,9}B (since any digits 1, 3, 4, 5, 6, 7, 8, A, B between them will produce smaller primes) *** Since 90B, 200B, 202B, 222B, 229B, 292B, 299B are primes, we only need to consider the numbers 20B, 22B, 29B, 209B, 220B (since any digits combo 00, 02, 22, 29, 90, 92, 99 between them will produce smaller primes) **** None of 20B, 22B, 29B, 209B, 220B are primes. * Case (3,1): ** 31 is prime, and thus the only minimal prime in this family. * Case (3,5): ** 35 is prime, and thus the only minimal prime in this family. * Case (3,7): ** 37 is prime, and thus the only minimal prime in this family. * Case (3,B): ** 3B is prime, and thus the only minimal prime in this family. * Case (4,1): ** Since 45, 4B, 11, 31, 51, 61, 81, 91, 401, 421, 471 are primes, we only need to consider the family 4{4,A}1 (since any digit 0, 1, 2, 3, 5, 6, 7, 8, 9, B between them will produce smaller primes) *** Since A41 and 4441 are primes, we only need to consider the families 4{A}1 and 44{A}1 (since any digit combo 44, A4 between them will produce smaller primes) **** All numbers of the form 4{A}1 are divisible by 5, thus cannot be prime. **** The smallest prime of the form 44{A}1 is 44AAA1 * Case (4,5): ** 45 is prime, and thus the only minimal prime in this family. * Case (4,7): ** Since 45, 4B, 17, 27, 37, 57, 67, 87, A7, B7, 447, 497 are primes, we only need to consider the family 4{0,7}7 (since any digit 1, 2, 3, 4, 5, 6, 8, 9, A, B between them will produce smaller primes) *** Since 4707 and 4777 are primes, we only need to consider the families 4{0}7 and 4{0}77 (since any digit combo 70, 77 between them will produce smaller primes) **** All numbers of the form 4{0}7 are divisible by B, thus cannot be prime. **** The smallest prime of the form 4{0}77 is 400000000000000000000000000000000000000077 * Case (4,B): ** 4B is prime, and thus the only minimal prime in this family. * Case (5,1): ** 51 is prime, and thus the only minimal prime in this family. * Case (5,5): ** Since 51, 57, 5B, 15, 25, 35, 45, 75, 85, 95, B5, 565 are primes, we only need to consider the family 5{0,5,A}5 (since any digits 1, 2, 3, 4, 6, 7, 8, 9, B between them will produce smaller primes) *** All numbers of the form 5{0,5,A}5 are divisible by 5, thus cannot be prime. * Case (5,7): ** 57 is prime, and thus the only minimal prime in this family. * Case (5,B): ** 5B is prime, and thus the only minimal prime in this family. * Case (6,1): ** 61 is prime, and thus the only minimal prime in this family. * Case (6,5): ** Since 61, 67, 6B, 15, 25, 35, 45, 75, 85, 95, B5, 655, 665 are primes, we only need to consider the family 6{0,A}5 (since any digits 1, 2, 3, 4, 5, 6, 7, 8, 9, B between them will produce smaller primes) *** Since 6A05 and 6AA5 are primes, we only need to consider the families 6{0}5 and 6{0}A5 (since any digit combo A0, AA between them will produce smaller primes) **** All numbers of the form 6{0}5 are divisible by B, thus cannot be prime. **** The smallest prime of the form 6{0}A5 is 600A5 * Case (6,7): ** 67 is prime, and thus the only minimal prime in this family. * Case (6,B): ** 6B is prime, and thus the only minimal prime in this family. * Case (7,1): ** Since 75, 11, 31, 51, 61, 81, 91, 701, 721, 771, 7A1 are primes, we only need to consider the family 7{4,B}1 (since any digits 0, 1, 2, 3, 5, 6, 7, 8, 9, A between them will produce smaller primes) *** Since 7BB, 7441 and 7B41 are primes, we only need to consider the numbers 741, 7B1, 74B1 **** None of 741, 7B1, 74B1 are primes. * Case (7,5): ** 75 is prime, and thus the only minimal prime in this family. * Case (7,7): ** Since 75, 17, 27, 37, 57, 67, 87, A7, B7, 747, 797 are primes, we only need to consider the family 7{0,7}7 (since any digits 1, 2, 3, 4, 5, 6, 8, 9, A, B between them will produce smaller primes) *** All numbers of the form 7{0,7}7 are divisible by 7, thus cannot be prime. * Case (7,B): ** Since 75, 1B, 3B, 4B, 5B, 6B, 8B, AB, 70B, 77B, 7BB are primes, we only need to consider the family 7{2,9}B (since any digits 0, 1, 3, 4, 5, 6, 7, 8, A, B between them will produce smaller primes) *** Since 222B, 729B is prime, we only need to consider the families 7{9}B, 7{9}2B, 7{9}22B (since any digits combo 222, 29 between them will produce smaller primes) **** The smallest prime of the form 7{9}B is 7999B **** The smallest prime of the form 7{9}2B is 79992B (not minimal prime, since 992B and 7999B are primes) **** The smallest prime of the form 7{9}22B is 79922B (not minimal prime, since 992B is prime) * Case (8,1): ** 81 is prime, and thus the only minimal prime in this family. * Case (8,5): ** 85 is prime, and thus the only minimal prime in this family. * Case (8,7): ** 87 is prime, and thus the only minimal prime in this family. * Case (8,B): ** 8B is prime, and thus the only minimal prime in this family. * Case (9,1): ** 91 is prime, and thus the only minimal prime in this family. * Case (9,5): ** 95 is prime, and thus the only minimal prime in this family. * Case (9,7): ** Since 91, 95, 17, 27, 37, 57, 67, 87, A7, B7, 907 are primes, we only need to consider the family 9{4,7,9}7 (since any digit 0, 1, 2, 3, 5, 6, 8, A, B between them will produce smaller primes) *** Since 447, 497, 747, 797, 9777, 9947, 9997 are primes, we only need to consider the numbers 947, 977, 997, 9477, 9977 (since any digits combo 44, 49, 74, 77, 79, 94, 99 between them will produce smaller primes) **** None of 947, 977, 997, 9477, 9977 are primes. * Case (9,B): ** Since 91, 95, 1B, 3B, 4B, 5B, 6B, 8B, AB, 90B, 9BB are primes, we only need to consider the family 9{2,7,9}B (since any digit 0, 1, 3, 4, 5, 6, 8, A, B between them will produce smaller primes) *** Since 27, 77B, 929B, 992B, 997B are primes, we only need to consider the families 9{2,7}2{2}B, 97{2,9}B, 9{7,9}9{9}B (since any digits combo 27, 29, 77, 92, 97 between them will produce smaller primes) **** For the 9{2,7}2{2}B family, since 27 and 77B are primes, we only need to consider the families 9{2}2{2}B and 97{2}2{2}B (since any digits combo 27, 77 between (9,2{2}B) will produce smaller primes) ***** The smallest prime of the form 9{2}2{2}B is 9222B (not minimal prime, since 222B is prime) ***** The smallest prime of the form 97{2}2{2}B is 9722222222222B (not minimal prime, since 222B is prime) **** For the 97{2,9}B family, since 729B and 929B are primes, we only need to consider the family 97{9}{2}B (since any digits combo 29 between (97,B) will produce smaller primes) ***** Since 222B is prime, we only need to consider the families 97{9}B, 97{9}2B, 97{9}22B (since any digit combo 222 between (97,B) will produce smaller primes) ****** All numbers of the form 97{9}B are divisible by 11, thus cannot be prime. ****** The smallest prime of the form 97{9}2B is 979999992B (not minimal prime, since 9999B is prime) ****** All numbers of the form 97{9}22B are divisible by 11, thus cannot be prime. **** For the 9{7,9}9{9}B family, since 77B and 9999B are primes, we only need to consider the numbers 99B, 999B, 979B, 9799B, 9979B ***** None of 99B, 999B, 979B, 9799B, 9979B are primes. * Case (A,1): ** Since A7, AB, 11, 31, 51, 61, 81, 91, A41 are primes, we only need to consider the family A{0,2,A}1 (since any digits 1, 3, 4, 5, 6, 7, 8, 9, B between them will produce smaller primes) *** Since 221, 2A1, A0A1, A201 are primes, we only need to consider the families A{A}{0}1 and A{A}{0}21 (since any digits combo 0A, 20, 22, 2A between them will produce smaller primes) **** For the A{A}{0}1 family: ***** All numbers of the form A{0}1 are divisible by B, thus cannot be prime. ***** The smallest prime of the form AA{0}1 is AA000001 ***** The smallest prime of the form AAA{0}1 is AAA0001 ***** The smallest prime of the form AAAA{0}1 is AAAA1 ****** Since this prime has no 0's, we do not need to consider the families {A}1, {A}01, {A}001, etc. **** All numbers of the form A{A}{0}21 are divisible by 5, thus cannot be prime. * Case (A,5): ** Since A7, AB, 15, 25, 35, 45, 75, 85, 95, B5 are primes, we only need to consider the family A{0,5,6,A}5 (since any digits 1, 2, 3, 4, 7, 8, 9, B between them will produce smaller primes) *** Since 565, 655, 665, A605, A6A5, AA65 are primes, we only need to consider the families A{0,5,A}5 and A{0}65 (since any digits combo 56, 60, 65, 66, 6A, A6 between them will produce smaller primes) **** All numbers of the form A{0,5,A}5 are divisible by 5, thus cannot be prime. **** The smallest prime of the form A{0}65 is A00065 * Case (A,7): ** A7 is prime, and thus the only minimal prime in this family. * Case (A,B): ** AB is prime, and thus the only minimal prime in this family. * Case (B,1): ** Since B5, B7, 11, 31, 51, 61, 81, 91, B21 are primes, we only need to consider the family B{0,4,A,B}1 (since any digits 1, 2, 3, 5, 6, 7, 8, 9 between them will produce smaller primes) *** Since 4B, AB, 401, A41, B001, B0B1, BB01, BB41 are primes, we only need to consider the families B{A}0{4,A}1, B{0,4}4{4,A}1, B{0,4,A,B}A{0,A}1, B{B}B{A,B}1 (since any digits combo 00, 0B, 40, 4B, A4, AB, B0, B4 between them will produce smaller primes) **** For the B{A}0{4,A}1 family, since A41 is prime, we only need consider the families B0{4}{A}1 and B{A}0{A}1 ***** For the B0{4}{A}1 family, since B04A1 is prime, we only need to consider the families B0{4}1 and B0{A}1 ****** The smallest prime of the form B0{4}1 is B04441 (not minimal prime, since 4441 is prime) ****** The smallest prime of the form B0{A}1 is B0AAAAA1 (not minimal prime, since AAAA1 is prime) ***** For the B{A}0{A}1 family, since A0A1 is prime, we only need to consider the families B{A}01 and B0{A}1 ****** The smallest prime of the form B{A}01 is BAA01 ****** The smallest prime of the form B0{A}1 is B0AAAAA1 (not minimal prime, since AAAA1 is prime) **** For the B{0,4}4{4,A}1 family, since 4441 is prime, we only need to consider the families B{0}4{4,A}1 and B{0,4}4{A}1 ***** For the B{0}4{4,A}1 family, since B001 is prime, we only need to consider the families B4{4,A}1 and B04{4,A}1 ****** For the B4{4,A}1 family, since A41 is prime, we only need to consider the family B4{4}{A}1 ******* Since 4441 and BAAA1 are primes, we only need to consider the numbers B41, B441, B4A1, B44A1, B4AA1, B44AA1 ******** None of B41, B441, B4A1, B44A1, B4AA1, B44AA1 are primes. ****** For the B04{4,A}1 family, since B04A1 is prime, we only need to consider the family B04{4}1 ******* The smallest prime of the form B04{4}1 is B04441 (not minimal prime, since 4441 is prime) ***** For the B{0,4}4{A}1 family, since 401, 4441, B001 are primes, we only need to consider the families B4{A}1, B04{A}1, B44{A}1, B044{A}1 (since any digits combo 00, 40, 44 between (B,4{A}1) will produce smaller primes) ****** The smallest prime of the form B4{A}1 is B4AAA1 (not minimal prime, since BAAA1 is prime) ****** The smallest prime of the form B04{A}1 is B04A1 ****** The smallest prime of the form B44{A}1 is B44AAAAAAA1 (not minimal prime, since BAAA1 is prime) ****** The smallest prime of the form B044{A}1 is B044A1 (not minimal prime, since B04A1 is prime) **** For the B{0,4,A,B}A{0,A}1 family, since all numbers in this family with 0 between (B,1) are in the B{A}0{4,A}1 family, and all numbers in this family with 4 between (B,1) are in the B{0,4}4{4,A}1 family, we only need to consider the family B{A,B}A{A}1 ***** Since BAAA1 is prime, we only need to consider the families B{A,B}A1 and B{A,B}AA1 ****** For the B{A,B}A1 family, since AB and BAAA1 are primes, we only need to consider the families B{B}A1 and B{B}AA1 ******* All numbers of the form B{B}A1 are divisible by B, thus cannot be prime. ******* The smallest prime of the form B{B}AA1 is BBBAA1 ****** For the B{A,B}AA1 family, since BAAA1 is prime, we only need to consider the families B{B}AA1 ******* The smallest prime of the form B{B}AA1 is BBBAA1 **** For the B{B}B{A,B}1 family, since AB and BAAA1 are primes, we only need to consider the families B{B}B1, B{B}BA1, B{B}BAA1 (since any digits combo AB or AAA between (B{B}B,1) will produce smaller primes) ***** The smallest prime of the form B{B}B1 is BBBB1 ***** All numbers of the form B{B}BA1 are divisible by B, thus cannot be prime. ***** The smallest prime of the form B{B}BAA1 is BBBAA1 * Case (B,5): ** B5 is prime, and thus the only minimal prime in this family. * Case (B,7): ** B7 is prime, and thus the only minimal prime in this family. * Case (B,B): ** Since B5, B7, 1B, 3B, 4B, 5B, 6B, 8B, AB, B2B are primes, we only need to consider the family B{0,9,B}B (since any digits 1, 2, 3, 4, 5, 6, 7, 8, A between them will produce smaller primes) *** Since 90B and 9BB are primes, we only need to consider the families B{0,B}{9}B **** Since 9999B is prime, we only need to consider the families B{0,B}B, B{0,B}9B, B{0,B}99B, B{0,B}999B ***** All numbers of the form B{0,B}B are divisible by B, thus cannot be prime. ***** For the B{0,B}9B family: ****** Since B0B9B and BB09B are primes, we only need to consider the families B{0}9B and B{B}9B (since any digits combo 0B, B0 between (B,9B) will produce smaller primes) ******* The smallest prime of the form B{0}9B is B0000000000000000000000000009B ******* All numbers of the from B{B}9B is either divisible by 11 (if totally number of B's is even) or factored as 10^(2*n)-21 = (10^n-5) * (10^n+5) (if totally number of B's is odd number 2*n-1 (n≥1)) (and since if n≥1, 10^n-5 ≥ 10^1-5 = 7 > 1, 10^n+5 ≥ 10^1+5 = 15 > 1, this factorization is nontrivial), thus cannot be prime. ***** For the B{0,B}99B family: ****** Since B0B9B and BB09B are primes, we only need to consider the families B{0}99B and B{B}99B (since any digits combo 0B, B0 between (B,99B) will produce smaller primes) ******* The smallest prime of the form B{0}99B is B00099B ******* The smallest prime of the form B{B}99B is BBBBBB99B ***** For the B{0,B}999B family: ****** Since B0B9B and BB09B are primes, we only need to consider the families B{0}999B and B{B}999B (since any digits combo 0B, B0 between (B,999B) will produce smaller primes) ******* The smallest prime of the form B{0}999B is B0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000999B, with 1765 0's, which can be written as B(0^1765)999B and equal the prime 11*12^1769+16967 ([http://factordb.com/index.php?id=1100000002378273165 factordb]) ([http://factordb.com/cert.php?id=1100000002378273165 primality certificate]) (not minimal prime, since B00099B and B0000000000000000000000000009B are primes) ******* The smallest prime of the form B{B}999B is BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB999B, with 245 B's, which can be written as (B^244)999B and equal the prime 12^248-3769 ([http://factordb.com/index.php?id=1100000002378270237 factordb]) (not minimal prime, since BBBBBB99B is prime) == Examples of families which can be ruled out as contain no primes > ''b'' == It is not known if this problem is solvable: Problem: Given strings ''x'', ''y'', ''z'', and a base ''b'', does there exist a prime number whose base-''b'' expansion is of the form ''x''{''y''}''z''? It will be necessary for our algorithm to determine if families of the form ''x''{''y''}''z'' contain a prime > ''b'' or not. We use two different heuristic strategies to show that such families contain no primes > ''b''. In the first strategy, we mimic the well-known technique of “covering congruences”, by finding some finite set ''S'' of primes ''p'' such that every number in a given family is divisible by some element of ''S''. In the second strategy, we attempt to find an algebraic factorization, such as difference-of-squares factorization, difference-of-cubes factorization, and Aurifeuillian factorization for numbers of the form ''x''⁴+4''y''⁴. Examples of first strategy: (we can show that the corresponding numbers are > all elements in ''S'', if ''n'' makes corresponding numbers > ''b'' (i.e. ''n''≥1 for 5{1} in base 9 and 2{5} in base 11 and {4}D in base 16 and {8}F in base 16, ''n''≥0 for other examples), thus these factorizations are nontrivial) * In base 10, all numbers of the form 4{6}9 are divisible by 7 * In base 6, all numbers of the form 4{0}1 are divisible by 5 * In base 15, all numbers of the form 9{6}8 are divisible by 11 * In base 9, all numbers of the form 5{1} are divisible by some element of {2, 5} * In base 11, all numbers of the form 2{5} are divisible by some element of {2, 3} * In base 14, all numbers of the form B{0}1 are divisible by some element of {3, 5} * In base 8, all numbers of the form 6{4}7 are divisible by some element of {3, 5, 13} * In base 13, all numbers of the form 3{0}95 are divisible by some element of {5, 7, 17} * In base 16, all numbers of the form {4}D are divisible by some element of {3, 7, 13} * In base 16, all numbers of the form {8}F are divisible by some element of {3, 7, 13} Examples of second strategy: (we can show that both factors are > 1, if ''n'' makes corresponding numbers > ''b'' (i.e. ''n''≥2 for {1} in base 9, ''n''≥0 for 1{0}1 in base 8 and B{4}1 in base 16, ''n''≥1 for other examples), thus these factorizations are nontrivial) * In base 9, all numbers of the form {1} factored as difference of squares * In base 8, all numbers of the form 1{0}1 factored as sum of cubes * In base 9, all numbers of the form 3{8} factored as difference of squares * In base 16, all numbers of the form 8{F} factored as difference of squares * In base 16, all numbers of the form {F}7 factored as difference of squares * In base 9, all numbers of the form 3{1} factored as difference of squares * In base 16, all numbers of the form {4}1 factored as difference of squares * In base 16, all numbers of the form 1{5} factored as difference of squares * In base 16, all numbers of the from {C}D factored as ''x''⁴+4''y''⁴ * In base 16, all numbers of the form B{4}1 factored as difference of squares Examples of combine of the two strategies: (we can show that for the part of the first strategy, the corresponding numbers are > all elements in S, and for the part of the second strategy, both factors are > 1, if n makes corresponding numbers > b, thus these factorizations are nontrivial) * In base 14, numbers of the form 8{D} are divisible by 5 if ''n'' is odd and factored as difference of squares if ''n'' is even * In base 12, numbers of the form {B}9B are divisible by 13 if ''n'' is odd and factored as difference of squares if ''n'' is even * In base 14, numbers of the form {D}5 are divisible by 5 if ''n'' is even and factored as difference of squares if ''n'' is odd * In base 17, numbers of the form 1{9} are divisible by 2 if ''n'' is odd and factored as difference of squares if ''n'' is even * In base 19, numbers of the form 1{6} are divisible by 5 if ''n'' is odd and factored as difference of squares if ''n'' is even == Bases 2≤''b''≤1024 such that these families can be ruled out as contain no primes > ''b'' == (using A−Z to represent digit values 10 to 35, z−a to represent digit values ''b''−1 to ''b''−26 (e.g. "z" means 1 in base 2, 2 in base 3, 3 in base 4, ..., 8 in base 9, 9 in base 10, A in base 11, B in base 12, ..., Y in base 35, Z in base 36, ...), only consider bases which these families are interpretable, e.g. digit "7" is only interpretable for bases ≥8, and digit "u" (means ''b''−6) is only interpretable for bases ≥7) === 1{0}1 === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' = ''m''^''r'' with odd ''r''>1: Sum-of-''r''th-powers factorization === 1{0}2 === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' == 1 mod 3: Finite covering set {3} === 1{0}3 === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 0 mod 3: Finite covering set {3} === 1{0}4 === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' == 1 mod 5: Finite covering set {5} * ''b'' == 14 mod 15: Finite covering set {3, 5} * ''b'' = ''m''⁴: Aurifeuillian factorization of ''x''⁴+4''y''⁴ === 1{0}5 === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 1 mod 3: Finite covering set {3} * ''b'' == 0 mod 5: Finite covering set {5} === 1{0}6 === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' == 0 mod 3: Finite covering set {3} * ''b'' == 1 mod 7: Finite covering set {7} === 1{0}7 === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 0 mod 7: Finite covering set {7} === 1{0}z === (none) === 1{0}11 (not quasi-minimal prime if there is smaller prime of the form 1{0}1) === * ''b'' == 1 mod 3: Finite covering set {3} === 10{z} (not quasi-minimal prime if there is smaller prime of the form 1{z}) === (none) === 11{0}1 (not quasi-minimal prime if there is smaller prime of the form 1{0}1) === * ''b'' == 1 mod 3: Finite covering set {3} === {1}0z (not quasi-minimal prime if there is smaller prime of the form {1} or {1}z) === * ''b'' such that ''b'' and 2''b''−1 are both squares: Difference-of-squares factorization (such bases are 25, 841) === {1} === * ''b'' = ''m''^''r'' with ''r''>1: Difference-of-''r''th-powers factorization (some bases still have primes, since for the corresponding length this factorization is trivial, but they only have this prime, they are 4 (length 2), 8 (length 3), 16 (length 2), 27 (length 3), 36 (length 2), 100 (length 2), 128 (length 7), 196 (length 2), 256 (length 2), 400 (length 2), 512 (length 3), 576 (length 2), 676 (length 2)) === {1}2 (not quasi-minimal prime if there is smaller prime of the form {1}) === * ''b'' == 0 mod 2: Finite covering set {2} === 1{2} === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' such that ''b'' and 2(''b''+1) are both squares: Difference-of-squares factorization (such bases are 49) === 1{3} === * ''b'' == 0 mod 3: Finite covering set {3} * ''b'' such that ''b'' and 3(''b''+2) are both squares: Difference-of-squares factorization (such bases are 25, 361) * ''b'' == 1 mod 2 such that 3(''b''+2) is square: Combine of finite covering set {2} (when length is even) and difference-of-squares factorization (when length is odd) (such bases are 25, 73, 145, 241, 361, 505, 673, 865) === 1{4} === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' such that ''b'' and 4(''b''+3) are both squares: Difference-of-squares factorization === 1{z} === (none) === 2{0}1 === * ''b'' == 1 mod 3: Finite covering set {3} === 2{0}3 === * ''b'' == 0 mod 3: Finite covering set {3} * ''b'' == 1 mod 5: Finite covering set {5} === 2{1} (not quasi-minimal prime if there is smaller prime of the form {1}) === * ''b'' such that ''b'' and 2''b''−1 are both squares: Difference-of-squares factorization (such bases are 25, 841) === {2}1 === * ''b'' such that ''b'' and 2(''b''+1) are both squares: Difference-of-squares factorization (such bases are 49) === 2{z} === * ''b'' == 1 mod 2: Finite covering set {2} === 3{0}1 === * ''b'' == 1 mod 2: Finite covering set {2} === 3{0}2 === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' == 1 mod 5: Finite covering set {5} === 3{0}4 === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' == 1 mod 7: Finite covering set {7} === {3}1 === * ''b'' such that ''b'' and 3(2''b''+1) are both squares: Difference-of-squares factorization (such bases are 121) === 3{z} === * ''b'' == 1 mod 3: Finite covering set {3} * ''b'' == 14 mod 15: Finite covering set {3, 5} * ''b'' = ''m''²: Difference-of-squares factorization * ''b'' == 4 mod 5: Combine of finite covering set {5} (when length is even) and difference-of-squares factorization (when length is odd) === 4{0}1 === * ''b'' == 1 mod 5: Finite covering set {5} * ''b'' == 14 mod 15: Finite covering set {3, 5} * ''b'' = ''m''⁴: Aurifeuillian factorization of ''x''⁴+4''y''⁴ === 4{0}3 === * ''b'' == 0 mod 3: Finite covering set {3} * ''b'' == 1 mod 7: Finite covering set {7} === {4}1 === * ''b'' such that ''b'' and 4(3''b''+1) are both squares: Difference-of-squares factorization (such bases are 16, 225) === 4{z} === * ''b'' == 1 mod 2: Finite covering set {2} === 5{0}1 === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 1 mod 3: Finite covering set {3} === 5{z} === * ''b'' == 1 mod 5: Finite covering set {5} * ''b'' == 34 mod 35: Finite covering set {5, 7} * ''b'' = 6''m''² with ''m'' == 2 or 3 mod 5: Combine of finite covering set {5} (when length is odd) and difference-of-squares factorization (when length is even) (such bases are 24, 54, 294, 384, 864, 1014) === 6{0}1 === * ''b'' == 1 mod 7: Finite covering set {7} * ''b'' == 34 mod 35: Finite covering set {5, 7} === 6{z} === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 1 mod 3: Finite covering set {3} === 7{0}1 === * ''b'' == 1 mod 2: Finite covering set {2} === 7{z} === * ''b'' == 1 mod 7: Finite covering set {7} * ''b'' == 20 mod 21: Finite covering set {3, 7} * ''b'' == 83, 307 mod 455: Finite covering set {5, 7, 13} (such bases are 83, 307, 538, 762, 993) * ''b'' = ''m''³: Difference-of-cubes factorization === 8{0}1 === * ''b'' == 1 mod 3: Finite covering set {3} * ''b'' == 20 mod 21: Finite covering set {3, 7} * ''b'' == 47, 83 mod 195: Finite covering set {3, 5, 13} (such bases are 47, 83, 242, 278, 437, 473, 632, 668, 827, 863, 1022) * ''b'' = 467: Finite covering set {3, 5, 7, 19, 37} * ''b'' = 722: Finite covering set {3, 5, 13, 73, 109} * ''b'' = ''m''³: Sum-of-cubes factorization * ''b'' = 128: Cannot have primes since 7''n''+3 cannot be power of 2 === 8{z} === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' = ''m''²: Difference-of-squares factorization * ''b'' == 4 mod 5: Combine of finite covering set {5} (when length is even) and difference-of-squares factorization (when length is odd) === 9{0}1 === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 1 mod 5: Finite covering set {5} === 9{z} === * ''b'' == 1 mod 3: Finite covering set {3} * ''b'' == 32 mod 33: Finite covering set {3, 11} === A{0}1 === * ''b'' == 1 mod 11: Finite covering set {11} * ''b'' == 32 mod 33: Finite covering set {3, 11} === A{z} === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 1 mod 5: Finite covering set {5} * ''b'' == 14 mod 15: Finite covering set {3, 5} === B{0}1 === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 1 mod 3: Finite covering set {3} * ''b'' == 14 mod 15: Finite covering set {3, 5} === B{z} === * ''b'' == 1 mod 11: Finite covering set {11} * ''b'' == 142 mod 143: Finite covering set {11, 13} * ''b'' = 307: Finite covering set {5, 11, 29} * ''b'' = 901: Finite covering set {7, 11, 13, 19} === C{0}1 === * ''b'' == 1 mod 13: Finite covering set {13} * ''b'' == 142 mod 143: Finite covering set {11, 13} * ''b'' = 296, 901: Finite covering set {7, 11, 13, 19} * ''b'' = 562, 828, 900: Finite covering set {7, 13, 19} * ''b'' = 563: Finite covering set {5, 7, 13, 19, 29} * ''b'' = 597: Finite covering set {5, 13, 29} === {#}$ (for bases ''b'' == 1 mod 3, # = (''b''−1)/3, $ = (''b''+2)/3) === (none) === {#}$ (for odd bases ''b'', # = (''b''−1)/2, $ = (''b''+1)/2) === * ''b'' = ''m''^''r'' with odd ''r''>1: Sum-of-''r''th-power factorization === #{z} (for even bases b, # = b/2−1) === (none) === y{z} === (none) === {y}z === (none) === z{0}1 === (none) === {z0}z1 (almost cannot be quasi-minimal prime, since this is not simple family) === * ''b'' = ''m''^''r'' with odd ''r''>1: Sum-of-''r''th-power factorization (some bases still have primes, since for the corresponding length this factorization is trivial, but they only have this prime, they are 128 (length 7), 216 (length 3), 343 (length 3), 729 (length 3)) * ''b'' = 4''m''⁴: Aurifeuillian factorization of ''x''⁴+4''y''⁴ (base 4 still have primes, since for the corresponding length this factorization is trivial, but it only have this prime, at length 2) === {z}yz (not quasi-minimal prime if there is smaller prime of the form {z}y) === (none) === {z}1 === (none) === {z}t === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 1 mod 3: Finite covering set {3} * ''b'' == 0 mod 7: Finite covering set {7} === {z}u === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' == 0 mod 3: Finite covering set {3} * ''b'' == 1 mod 5: Finite covering set {5} * ''b'' == 34 mod 35: Finite covering set {5, 7} === {z}v === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 0 mod 5: Finite covering set {5} === {z}w === * ''b'' == 0 mod 2: Finite covering set {2} * ''b'' == 1 mod 3: Finite covering set {3} * ''b'' == 14 mod 15: Finite covering set {3, 5} * ''b'' = ''m''²: Difference-of-squares factorization * ''b'' == 4 mod 5: Combine of finite covering set {5} (when length is even) and difference-of-squares factorization (when length is odd) === {z}x === * ''b'' == 1 mod 2: Finite covering set {2} * ''b'' == 0 mod 3: Finite covering set {3} === {z}y === * ''b'' == 0 mod 2: Finite covering set {2} == Large known (probable) primes (length ≥10000) in these families (for bases 2≤''b''≤1024) == Format: base (length) (using A−Z to represent digit values 10 to 35, z−a to represent digit values ''b''−1 to ''b''−26 (e.g. "z" means 1 in base 2, 2 in base 3, 3 in base 4, ..., 8 in base 9, 9 in base 10, A in base 11, B in base 12, ..., Y in base 35, Z in base 36, ...), only consider bases which these families are interpretable, e.g. digit "7" is only interpretable for bases ≥8, and digit "u" (means ''b''−6) is only interpretable for bases ≥7) === 1{0}1 === (none) === 1{0}2 === (none) === 1{0}3 === (none) === 1{0}4 === 53 (13403) 113 (10647) === 1{0}z === 113 (20089) 123 (64371) === 1{0}11 (not quasi-minimal prime if there is smaller prime of the form 1{0}1) === (none) === 10{z} (not quasi-minimal prime if there is smaller prime of the form 1{z}) === 208 (26682) 607 (11032) 828 (19659) === 11{0}1 (not quasi-minimal prime if there is smaller prime of the form 1{0}1) === 201 (31276) 222 (52727) 227 (36323) 327 (135983) 425 (11231) 710 (24112) 717 (37508) 719 (13420) === {1} === 152 (270217) 184 (16703) 200 (17807) 311 (36497) 326 (26713) 331 (25033) 371 (15527) 485 (99523) 629 (32233) 649 (43987) 670 (18617) 684 (22573) 691 (62903) 693 (41189) 731 (15427) 752 (32833) 872 (10093) 932 (20431) === {1}2 (not quasi-minimal prime if there is smaller prime of the form {1}) === (none) === 1{z} === 107 (21911) 170 (166429) 278 (43909) 303 (40175) 383 (20957) 515 (58467) 522 (62289) 578 (129469) 590 (15527) 647 (21577) 662 (16591) 698 (127559) 704 (62035) 845 (39407) 938 (40423) 969 (24097) 989 (26869) === 2{0}1 === 101 (192276) 206 (46206) 218 (333926) 236 (161230) 257 (12184) 305 (16808) 467 (126776) 578 (44166) 626 (174204) 695 (94626) 752 (26164) 788 (72918) 869 (49150) 887 (27772) 899 (15732) 932 (13644) === 2{z} === 432 (16003) === 3{0}1 === (none) === 3{z} === 72 (1119850) 212 (34414) 218 (23050) 270 (89662) 303 (198358) 312 (51566) 422 (21738) 480 (93610) 513 (38032) 527 (46074) 566 (23874) 650 (498102) 686 (16584) 758 (15574) 783 (12508) 800 (33838) 921 (98668) 947 (10056) === 4{0}1 === 107 (32587) 227 (13347) 257 (160423) 355 (10990) 410 (144079) 440 (56087) 452 (14155) 482 (30691) 542 (15983) 579 (67776) 608 (20707) 635 (11723) 650 (96223) 679 (69450) 737 (269303) 740 (58043) 789 (149140) 797 (468703) 920 (103687) 934 (101404) 962 (84235) === 4{z} === 14 (19699) 68 (13575) 254 (15451) 800 (20509) === 5{0}1 === 326 (400786) 350 (20392) 554 (10630) 662 (13390) 926 (40036) === 5{z} === 258 (212135) 272 (148427) 299 (64898) 307 (26263) 354 (25566) 433 (283919) 635 (36163) 678 (40859) 692 (45447) 719 (20552) 768 (70214) 857 (23083) 867 (61411) 972 (36703) === 6{0}1 === 108 (16318) 129 (16797) 409 (369833) 522 (52604) 587 (24120) 643 (164916) 762 (11152) 789 (27297) 986 (21634) === 6{z} === 68 (25396) 332 (15222) 338 (42868) 362 (146342) 488 (33164) 566 (164828) 980 (50878) 986 (12506) 1016 (23336) === 7{0}1 === 398 (17473) 1004 (54849) === 7{z} === 97 (192336) 170 (15423) 194 (38361) 202 (155772) 282 (21413) 283 (164769) 332 (13205) 412 (29792) 560 (19905) 639 (10668) 655 (53009) 811 (31784) 814 (17366) 866 (108591) 908 (61797) 962 (31841) 992 (10605) 997 (15815) === 8{0}1 === 23 (119216) 53 (227184) 158 (123476) 254 (67716) 320 (52004) 410 (279992) 425 (94662) 513 (19076) 518 (11768) 596 (148446) 641 (87702) 684 (23387) 695 (39626) 785 (900326) 788 (11408) 893 (86772) 908 (243440) 920 (107822) 962 (47222) 998 (81240) 1013 (43872) === 8{z} === 138 (35686) 412 (12154) 788 (11326) 990 (23032) === 9{0}1 === 248 (39511) 592 (96870) === 9{z} === 431 (43574) 446 (152028) 458 (126262) 599 (11776) 846 (12781) === A{0}1 === 173 (264235) 198 (47665) 311 (314807) 341 (106009) 449 (18507) 492 (42843) 605 (12395) 708 (17563) 710 (31039) 743 (285479) 744 (137056) 786 (68169) 800 (15105) 802 (149320) 879 (25004) 929 (13065) 977 (125873) 986 (48279) 1004 (10645) === A{z} === 368 (10867) 488 (10231) 534 (80328) 662 (13307) 978 (14066) === B{0}1 === 710 (15272) 740 (33520) 878 (227482) === B{z} === 153 (21660) 186 (112718) 439 (18752) 593 (16064) 602 (36518) 707 (10573) 717 (67707) === C{0}1 === 68 (656922) 219 (29231) 230 (94751) 312 (21163) 334 (83334) 353 (20262) 359 (61295) 457 (10024) 481 (45941) 501 (20140) 593 (42779) 600 (11242) 604 (17371) 641 (26422) 700 (91953) 887 (13961) 919 (45359) 923 (64365) 992 (10300) === {#}$ (for bases ''b'' == 1 mod 3, # = (''b''−1)/3, $ = (''b''+2)/3) === (none) === {#}$ (for odd bases ''b'', # = (''b''−1)/2, $ = (''b''+1)/2) === (none) === #{z} (for even bases b, # = b/2−1) === (none) === y{z} === 38 (136212) 83 (21496) 113 (286644) 188 (13508) 401 (103670) 417 (21003) 458 (46900) 494 (21580) 518 (129372) 527 (65822) 602 (17644) 608 (36228) 638 (74528) 663 (47557) 723 (24536) 758 (50564) 833 (12220) 904 (13430) 938 (50008) 950 (16248) === z{0}1 === 202 (46774) 251 (102979) 272 (16681) 297 (14314) 298 (60671) 326 (64757) 347 (69661) 363 (142877) 452 (71941) 543 (10042) 564 (38065) 634 (84823) 788 (13541) 869 (12289) 890 (37377) 953 (60995) 1004 (29685) === {z0}z1 (almost cannot be quasi-minimal prime, since this is not simple family) === 53 (21942) 124 (16426) 175 (31626) 188 (22036) 316 (48538) 365 (25578) 373 (24006) 434 (10090) 530 (11086) 545 (12346) 560 (15072) 596 (12762) 701 (12576) 706 (10656) 821 (13536) 833 (17116) 966 (14820) 983 (11272) === {z}yz (not quasi-minimal prime if there is smaller prime of the form {z}y) === (none) === {z}1 === (none) === {z}y === 317 (13896) == Bases 2≤''b''≤1024 which have these families as unsolved families == Unsolved families are families which are neither primes (>''b'') found nor can be ruled out as contain no primes > ''b'' (using A−Z to represent digit values 10 to 35, z−a to represent digit values ''b''−1 to ''b''−26 (e.g. "z" means 1 in base 2, 2 in base 3, 3 in base 4, ..., 8 in base 9, 9 in base 10, A in base 11, B in base 12, ..., Y in base 35, Z in base 36, ...), only consider bases which these families are interpretable, e.g. digit "7" is only interpretable for bases ≥8, and digit "u" (means ''b''−6) is only interpretable for bases ≥7) 1{0}1: 38, 50, 62, 68, 86, 92, 98, 104, 122, 144, 168, 182, 186, 200, 202, 212, 214, 218, 244, 246, 252, 258, 286, 294, 298, 302, 304, 308, 322, 324, 338, 344, 354, 356, 362, 368, 380, 390, 394, 398, 402, 404, 410, 416, 422, 424, 446, 450, 454, 458, 468, 480, 482, 484, 500, 514, 518, 524, 528, 530, 534, 538, 552, 558, 564, 572, 574, 578, 580, 590, 602, 604, 608, 620, 622, 626, 632, 638, 648, 650, 662, 666, 668, 670, 678, 684, 692, 694, 698, 706, 712, 720, 722, 724, 734, 744, 746, 752, 754, 762, 766, 770, 792, 794, 802, 806, 812, 814, 818, 836, 840, 842, 844, 848, 854, 868, 870, 872, 878, 888, 896, 902, 904, 908, 922, 924, 926, 932, 938, 942, 944, 948, 954, 958, 964, 968, 974, 978, 980, 988, 994, 998, 1002, 1006, 1014, 1016 (length limit: ≥8388608) 1{0}2: 167, 257, 323, 353, 383, 527, 557, 563, 623, 635, 647, 677, 713, 719, 803, 815, 947, 971, 1013 (length limit: 2000) 1{0}3: 646, 718, 998 (length limit: 2000) 1{0}4: 139, 227, 263, 315, 335, 365, 485, 515, 647, 653, 683, 773, 789, 797, 815, 857, 875, 893, 939, 995, 1007 (length limit: 2000) 1{0}5 1{0}6 1{0}7 1{0}8 1{0}9 1{0}A 1{0}B 1{0}C 1{0}D 1{0}E 1{0}F 1{0}G 1{0}z: 173, 179, 257, 277, 302, 333, 362, 392, 422, 452, 467, 488, 512, 527, 545, 570, 575, 614, 622, 650, 677, 680, 704, 707, 734, 740, 827, 830, 851, 872, 886, 887, 902, 904, 908, 929, 932, 942, 947, 949, 962, 973, 1022 (length limit: 2000) 1{0}11 (not quasi-minimal prime if there is smaller prime of the form 1{0}1): 198, 213, 318, 327, 353, 375, 513, 591, 647, 732, 734, 738, 759, 948, 951, 957, 1013, 1014 (length limit: 2000) 10{z} (not quasi-minimal prime if there is smaller prime of the form 1{z}): 575 (length limit: 247000) 11{0}1 (not quasi-minimal prime if there is smaller prime of the form 1{0}1): 813, 863, 962, 1017 (length limit: ≥100000) {1}0z (not quasi-minimal prime if there is smaller prime of the form {1} or {1}z): 137, 161, 167, 217, 229, 232, 253, 261, 317, 325, 337, 347, 355, 375, 403, 411, 421, 427, 457, 479, 483, 505, 507, 537, 547, 577, 597, 599, 601, 613, 627, 631, 632, 641, 643, 649, 657, 679, 688, 697, 707, 711, 729, 733, 737, 742, 762, 773, 787, 793, 797, 817, 819, 841, 843, 853, 859, 861, 874, 877, 895, 899, 907, 913, 916, 917, 927, 957, 959, 997, 1003, 1009, 1015, 1017 (length limit: 2000) {1}: 185, 269, 281, 380, 384, 385, 394, 452, 465, 511, 574, 601, 631, 632, 636, 711, 713, 759, 771, 795, 861, 866, 881, 938, 948, 951, 956, 963, 1005, 1015 (length limit: ≥100000) 11{z} (not quasi-minimal prime if there is smaller prime of the form 1{z}) {1}2 (not quasi-minimal prime if there is smaller prime of the form {1}): 31, 61, 91, 93, 143, 247, 253, 293, 313, 329, 371, 383, 391, 393, 403, 415, 435, 443, 451, 491, 493, 513, 523, 527, 537, 541, 553, 565, 581, 587, 601, 613, 615, 623, 627, 635, 663, 729, 735, 757, 763, 775, 783, 823, 843, 865, 873, 877, 883, 897, 931, 941, 943, 955, 983, 1013, 1015, 1021, 1023 (length limit: 2000) {1}z 1{2}: 265, 355, 379, 391, 481, 649, 661, 709, 745, 811, 877, 977 (length limit: 2000) 1{3}: 107, 133, 179, 281, 305, 365, 473, 485, 487, 491, 535, 541, 601, 617, 665, 737, 775, 787, 802, 827, 905, 911, 928, 953, 955, 995 1{4}: 83, 143, 185, 239, 269, 293, 299, 305, 319, 325, 373, 383, 395, 431, 471, 503, 551, 577, 581, 593, 605, 617, 631, 659, 743, 761, 773, 781, 803, 821, 857, 869, 897, 911, 917, 923, 935, 983, 1019 (length limit: 2000) 1{z}: 581, 992, 1019 (length limit: ≥100000) 2{0}1: 365, 383, 461, 512, 542, 647, 773, 801, 836, 878, 908, 914, 917, 947, 1004 (length limit: ≥100000) 2{0}3: 79, 149, 179, 254, 359, 394, 424, 434, 449, 488, 499, 532, 554, 578, 664, 683, 694, 749, 794, 839, 908, 944, 982 (length limit: 2000) 2{1} (not quasi-minimal prime if there is smaller prime of the form {1}): 109, 117, 137, 147, 157, 175, 177, 201, 227, 235, 256, 269, 271, 297, 310, 331, 335, 397, 417, 427, 430, 437, 442, 451, 465, 467, 481, 502, 517, 547, 557, 567, 572, 577, 591, 597, 607, 627, 649, 654, 655, 667, 679, 687, 691, 697, 715, 727, 739, 759, 766, 782, 787, 796, 797, 808, 817, 821, 829, 841, 852, 877, 881, 899, 903, 907, 937, 947, 955, 1007, 1011, 1021 (length limit: 2000) {2}1: 106, 238, 262, 295, 364, 382, 391, 397, 421, 458, 463, 478, 517, 523, 556, 601, 647, 687, 754, 790, 793, 832, 872, 898, 962, 1002, 1021 (length limit: 2000) 2{z}: 588, 972 (length limit: ≥100000) 3{0}1: 718, 912 (length limit: ≥100000) 3{0}2: 223, 283, 359, 489, 515, 529, 579, 619, 669, 879, 915, 997 (length limit: 2000) 3{0}4: 167, 391, 447, 487, 529, 653, 657, 797, 853, 913, 937 (length limit: 2000) {3}1: 79, 101, 189, 215, 217, 235, 243, 253, 255, 265, 313, 338, 341, 378, 379, 401, 402, 413, 489, 498, 499, 508, 525, 535, 589, 591, 599, 611, 621, 635, 667, 668, 681, 691, 711, 717, 719, 721, 737, 785, 804, 805, 813, 831, 835, 837, 849, 873, 911, 915, 929, 933, 941, 948, 959, 999, 1013, 1019 (length limit: 2000) 3{z}: 275, 438, 647, 653, 812, 927, 968 (length limit: ≥100000) 4{0}1: 32, 53, 155, 174, 204, 212, 230, 332, 334, 335, 395, 467, 512, 593, 767, 803, 848, 875, 1024 (length limit: ≥100000) 4{0}3: 83, 88, 97, 167, 188, 268, 289, 293, 412, 419, 425, 433, 503, 517, 529, 548, 613, 620, 622, 650, 668, 692, 706, 727, 763, 818, 902, 913, 937, 947, 958 (length limit: 2000) {4}1: 46, 77, 103, 107, 119, 152, 198, 203, 211, 217, 229, 257, 263, 291, 296, 305, 332, 371, 374, 407, 413, 416, 440, 445, 446, 464, 467, 500, 542, 545, 548, 557, 566, 586, 587, 605, 611, 614, 632, 638, 641, 653, 659, 698, 701, 731, 733, 736, 755, 786, 812, 820, 821, 827, 830, 887, 896, 899, 901, 922, 923, 935, 941, 953, 977, 983, 991, 1004 (length limit: 2000) 4{z}: 338, 998 (length limit: ≥100000) 5{0}1: 308, 512, 824 (length limit: ≥100000) 5{z}: 234, 412, 549, 553, 573, 619, 750, 878, 894, 954 (length limit: ≥100000) 6{0}1: 212, 509, 579, 625, 774, 794, 993, 999 (length limit: ≥100000) 6{z}: 308, 392, 398, 518, 548, 638, 662, 878 (length limit: ≥100000) 7{0}1: (none) 7{z}: 321, 328, 374, 432, 665, 697, 710, 721, 727, 728, 752, 800, 815, 836, 867, 957, 958, 972 (length limit: ≥100000) 8{0}1: 86, 140, 182, 263, 353, 368, 389, 395, 422, 426, 428, 434, 443, 488, 497, 558, 572, 575, 593, 606, 698, 710, 746, 758, 770, 773, 824, 828, 866, 911, 930, 953, 957, 983, 993, 1014 (length limit: ≥100000) 8{z}: 378, 438, 536, 566, 570, 592, 636, 688, 718, 830, 852, 926, 1010 (length limit: ≥100000) 9{0}1: 724, 884 (length limit: ≥100000) 9{z}: 80, 233, 530, 551, 611, 899, 912, 980 (length limit: ≥100000) A{0}1: 185, 338, 417, 432, 614, 668, 773, 863, 935, 1000 (length limit: ≥100000) A{z}: 214, 422, 444, 452, 458, 542, 638, 668, 804, 872, 950, 962 (length limit: ≥100000) B{0}1: 560, 770, 968 (length limit: ≥100000) B{z}: 263, 615, 912, 978 (length limit: ≥100000) C{0}1: 163, 207, 354, 362, 368, 480, 620, 692, 697, 736, 753, 792, 978, 998, 1019, 1022 (length limit: ≥100000) C{z} D{0}1 D{z} E{0}1 E{z} F{0}1 F{z} G{0}1 {&#35;}$ (for bases ''b'' == 1 mod 3, # = (''b''−1)/3, $ = (''b''+2)/3): 808, 829, 859, 1006 (length limit: 2000) {&#35;}$ (for odd bases ''b'', # = (''b''−1)/2, $ = (''b''+1)/2): 31, 37, 55, 63, 67, 77, 83, 89, 91, 93, 97, 99, 107, 109, 117, 123, 127, 133, 135, 137, 143, 147, 149, 151, 155, 161, 177, 179, 183, 189, 193, 197, 207, 211, 213, 215, 217, 223, 225, 227, 233, 235, 241, 247, 249, 255, 257, 263, 265, 269, 273, 277, 281, 283, 285, 287, 291, 293, 297, 303, 307, 311, 319, 327, 347, 351, 355, 357, 359, 361, 367, 369, 377, 381, 383, 385, 387, 389, 393, 397, 401, 407, 411, 413, 417, 421, 423, 437, 439, 443, 447, 457, 465, 467, 469, 473, 475, 481, 483, 489, 493, 495, 497, 509, 511, 515, 533, 541, 547, 549, 555, 563, 591, 593, 597, 601, 603, 611, 615, 619, 621, 625, 627, 629, 633, 635, 637, 645, 647, 651, 653, 655, 659, 663, 667, 671, 673, 675, 679, 683, 687, 691, 693, 697, 707, 709, 717, 731, 733, 735, 737, 741, 743, 749, 753, 755, 757, 759, 765, 767, 771, 773, 775, 777, 783, 785, 787, 793, 797, 801, 807, 809, 813, 817, 823, 825, 849, 851, 853, 865, 867, 873, 877, 887, 889, 893, 897, 899, 903, 907, 911, 915, 923, 927, 933, 937, 939, 941, 943, 945, 947, 953, 957, 961, 967, 975, 977, 983, 987, 993, 999, 1003, 1005, 1009, 1017 (length limit: ≥262143) &#35;{z} (for even bases ''b'', # = ''b''/2−1): 108, 278, 296, 338, 386, 494, 626, 920 (length limit: 2000) ${&#35;} (for odd bases ''b'', # = (''b''−1)/2, $ = (''b''+1)/2) x{z} y{z}: 128, 233, 268, 383, 478, 488, 533, 554, 665, 698, 779, 863, 878, 932, 941, 1010 (length limit: ≥200000) z{0}1: 123, 342, 362, 422, 438, 479, 487, 512, 542, 602, 757, 767, 817, 830, 872, 893, 932, 992, 997, 1005, 1007 (length limit: ≥100000) {y}z: 143, 173, 176, 213, 235, 248, 253, 279, 327, 343, 353, 358, 373, 383, 401, 413, 416, 427, 439, 448, 453, 463, 481, 513, 522, 527, 535, 547, 559, 565, 583, 591, 598, 603, 621, 623, 653, 659, 663, 679, 691, 698, 711, 743, 745, 757, 768, 785, 793, 796, 801, 808, 811, 821, 835, 845, 847, 853, 856, 883, 898, 903, 927, 955, 961, 971, 973, 993, 1005, 1013, 1019, 1021 (length limit: 2000) {z0}z1 (almost cannot be quasi-minimal prime, since this is not simple family): 97, 103, 113, 186, 187, 220, 304, 306, 309, 335, 414, 416, 428, 433, 445, 459, 486, 498, 539, 550, 557, 587, 592, 597, 598, 617, 624, 637, 659, 665, 671, 677, 696, 717, 726, 730, 740, 754, 766, 790, 851, 873, 890, 914, 923, 929, 943, 944, 965, 984, 985, 996, 1004, 1005 (length limit: ≥17326) zy{z} (not quasi-minimal prime if there is smaller prime of the form y{z}) {z}yz (not quasi-minimal prime if there is smaller prime of the form {z}y): 215, 353, 517, 743, 852, 899, 913 (length limit: 2000) {z}01 (not quasi-minimal prime if there is smaller prime of the form {z}1) {z}1: 93, 113, 152, 158, 188, 217, 218, 226, 227, 228, 233, 240, 275, 278, 293, 312, 338, 350, 353, 383, 404, 438, 464, 471, 500, 533, 576, 614, 641, 653, 704, 723, 728, 730, 758, 779, 788, 791, 830, 878, 881, 899, 908, 918, 929, 944, 953, 965, 968, 978, 983, 986, 1013 (length limit: 2000) {z}k {z}l {z}m {z}n {z}o {z}p {z}q {z}r {z}s {z}t {z}u {z}v {z}w: 207, 221, 293, 375, 387, 533, 633, 647, 653, 687, 701, 747, 761, 785, 863, 897, 905, 965, 1017 (length limit: 2000) {z}x: (none) {z}y: 305, 353, 397, 485, 487, 535, 539, 597, 641, 679, 731, 739, 755 (length limit: 2000) == List of lengths for quasi-minimal primes in some simple families == [https://docs.google.com/spreadsheets/d/e/2PACX-1vTKkSNKGVQkUINlp1B3cXe90FWPwiegdA07EE7-U7sqXntKAEQrynoI1sbFvvKriieda3LfkqRwmKME/pubhtml list of lengths for quasi-minimal primes in some simple families for bases 2≤''b''≤1024] NB: this family is not interpretable in this base (e.g. family 7{0}1 and 7{z} in bases <=7, family {z}x in bases <=3) (including the case which this family has either leading zeros (leading zeros do not count) or ending zeros (numbers ending in zero cannot be prime > base) in this base) RC: this family can be proven to only contain composite numbers (only count numbers > base) unknown: this family has no primes or PRPs found, nor can this family be proven to only contain composite numbers (only count numbers > base) Background color: red for title (bases or families), green for length > 10000, orange for 2500 < length ≤ 10000, white for length ≤ 2500, cyan for "RC", pink for "NB", yellow for "unknown". Search limit for lengths: ≥8388608 for 1{0}1, ≥200000 for y{z}, ≥100000 for ''d''{0}1 (''d'' = one of digits in {2, 3, 4, 5, 6, 7, 8, 9, A, B, C}) and ''d''{z} (''d'' = one of digits in {1, 2, 3, 4, 5, 6, 7, 8, 9, A, B}) and z{0}1 and {1}, ≥5000 for 1{0}2, {z}y, 1{0}z, {z}1, {y}z, ≥2500 for other families. == References == * [https://mersenneforum.org/showthread.php?t=24972 mersenneforum thread of this problem] * [https://docs.google.com/document/d/e/2PACX-1vQct6Hx-IkJd5-iIuDuOKkKdw2teGmmHW-P75MPaxqBXB37u0odFBml5rx0PoLa0odTyuW67N_vn96J/pub Minimal elements for the base ''b'' representations of the primes which are > ''b'' for bases ''b''≤16] * [https://primes.utm.edu/glossary/xpage/MinimalPrime.html article “minimal prime” in The Prime Glossary] * [https://en.wikipedia.org/wiki/Minimal_prime_(recreational_mathematics article “minimal prime” in Wikipedia] * [https://www.primepuzzles.net/puzzles/puzz_178.htm the puzzle of minimal primes (when the restriction of prime>base is not required) in The Prime Puzzles & Problems Connection] * [https://www.primepuzzles.net/problems/prob_083.htm the problem of minimal primes in The Prime Puzzles & Problems Connection] * [https://github.com/xayahrainie4793/non-single-digit-primes my data for these M(Lb) sets for 2 ≤ b ≤ 16] * [http://www.cs.uwaterloo.ca/~shallit/Papers/minimal5.pdf Shallit’s proof of base 10 minimal primes, when the restriction of prime>base is not required] * [https://scholar.colorado.edu/downloads/hh63sw661 proofs of minimal primes in bases b≤10, when the restriction of prime>base is not required] * [https://cs.uwaterloo.ca/~cbright/reports/mepn.pdf the article for this minimal prime problem in bases b≤30, when the restriction of prime>base is not required] * [https://cs.uwaterloo.ca/~cbright/talks/minimal-slides.pdf the article for this minimal prime problem in bases b≤30, when the restriction of prime>base is not required] * [https://doi.org/10.1080/10586458.2015.1064048 the article for this minimal prime problem in bases b≤30, when the restriction of prime>base is not required] * [https://github.com/curtisbright/mepn-data data for these M(Lb) sets and unsolved families for 2 ≤ b ≤ 30, when the restriction of prime>base is not required, search limits of lengths: 1000000 for b=17, 707000 for b=19, 506000 for b=21, 292000 for b=25, 486000 for b=26, 543000 for b=28, 233000 for b=29] * [https://github.com/RaymondDevillers/primes data for these M(Lb) sets and unsolved families for 2 ≤ b ≤ 50, when the restriction of prime>base is not required, search limits of lengths: 10000 for all b] * [http://www.bitman.name/math/article/730 article for minimal primes, when the restriction of prime>base is not required] * [http://www.bitman.name/math/table/497 data for minimal primes in bases 2 ≤ b ≤ 16, when the restriction of prime>base is not required] * [http://www.prothsearch.com/sierp.html the Sierpinski problem] * [http://www.prothsearch.com/rieselprob.html the Riesel problem] * [https://oeis.org/A076336/a076336c.html the dual Sierpinski problem] * [http://www.noprimeleftbehind.net/crus/Sierp-conjectures.htm generalized Sierpinski conjectures in bases b≤1030, some primes found in these conjectures are minimal primes in base b, especially, all primes for k&lt;b (if exist for a (k,b) combo) are always minimal primes in the base b) (also some examples for simple families contain no primes &gt; b] * [http://www.noprimeleftbehind.net/crus/Riesel-conjectures.htm generalized Riesel conjectures in bases b≤1030, some primes found in these conjectures are minimal primes in base b, especially, all primes for k&lt;b (if exist for a (k,b) combo) are always minimal primes in the base b) (also some examples for simple families contain no primes &gt; b] * [http://www.noprimeleftbehind.net/crus/tab/CRUS_tab.htm list for the status of the generalized Sierpinski conjectures and the generalized Riesel conjectures in bases b≤1030] * [https://www.utm.edu/staff/caldwell/preprints/2to100.pdf article for generalized Sierpinski conjectures in bases b≤100] * [http://www.kurims.kyoto-u.ac.jp/EMIS/journals/INTEGERS/papers/i61/i61.pdf article for the mixed (original+dual) Sierpinski problem] * [http://www.fermatquotient.com/PrimSerien/GenRepu.txt generalized repunit primes (primes of the form (bn−1)/(b−1)) in bases b≤160, the smallest such prime for base b (if exists) is always minimal prime in base b] * [https://web.archive.org/web/20021111141203/http://www.users.globalnet.co.uk/~aads/primes.html generalized repunit primes (primes of the form (bn−1)/(b−1)) in bases b≤1000, the smallest such prime for base b (if exists) is always minimal prime in base b] * [http://jeppesn.dk/generalized-fermat.html generalized Fermat primes (primes of the form b2^n+1) in even bases b≤1000, the smallest such prime for base b (if exists) is always minimal prime in base b] * [http://www.noprimeleftbehind.net/crus/GFN-primes.htm generalized Fermat primes (primes of the form b2^n+1) in even bases b≤1030, the smallest such prime for base b (if exists) is always minimal prime in base b] * [http://www.fermatquotient.com/PrimSerien/GenFermOdd.txt list of generalized half Fermat primes (primes of the form (b2^n+1)/2) sorted by n, the smallest such prime for base b (if exists) is always minimal prime in base b] * [https://harvey563.tripod.com/wills.txt primes of the form (b−1)*bn−1 for bases b≤2049, the smallest such prime for base b (if exists) is always minimal prime in base b] * [https://www.rieselprime.de/ziki/Williams_prime_MM_least the smallest primes of the form (b−1)*bn−1 for bases b≤2049, these primes (if exists) is always minimal prime in base b] * [https://www.rieselprime.de/ziki/Williams_prime_MP_least the smallest primes of the form (b−1)*bn+1 for bases b≤1024, these primes (if exists) is always minimal prime in base b] * [https://www.rieselprime.de/ziki/Riesel_prime_small_bases_least_n the smallest primes of the form k*bn−1 for k≤12 and bases b≤1024, these primes (if exists) is always minimal prime in base b if b>k] * [https://www.rieselprime.de/ziki/Proth_prime_small_bases_least_n the smallest primes of the form k*bn+1 for k≤12 and bases b≤1024, these primes (if exists) is always minimal prime in base b if b>k] * [https://docs.google.com/spreadsheets/d/e/2PACX-1vTKkSNKGVQkUINlp1B3cXe90FWPwiegdA07EE7-U7sqXntKAEQrynoI1sbFvvKriieda3LfkqRwmKME/pubhtml list for the smallest primes in given simple family in bases b≤1024] * [https://www.rose-hulman.edu/~rickert/Compositeseq/ a problem related to this project] * [http://www.worldofnumbers.com/Appending%201s%20to%20n.txt a problem related to this project] * [https://stdkmd.net/nrr/prime/primecount.txt near- and quasi- repdigit (probable) primes sorted by count] * [https://stdkmd.net/nrr/prime/primedifficulty.txt near- and quasi- repdigit (probable) primes sorted by difficulty] * [http://www.prothsearch.com/fermat.html factoring status of Fermat numbers] * [http://www.rieselprime.de/dl/CRUS_pack.zip srsieve, sr1sieve, sr2sieve, pfgw, and llr softwares] * [https://www.bc-team.org/app.php/dlext/?cat=3 srsieve, sr1sieve, sr2sieve, sr5sieve software] * [https://sourceforge.net/projects/openpfgw/ pfgw software] * [http://jpenne.free.fr/index2.html llr software] * [http://www.ellipsa.eu/public/primo/primo.html PRIMO software] * [https://primes.utm.edu/prove/index.html website for primality proving] * [https://primes.utm.edu/curios/page.php?number_id=22380 the largest base 10 minimal prime in Prime Curios!] * [https://oeis.org/A071062 OEIS sequence for base 10 minimal primes, when the restriction of prime>base is not required] * [https://oeis.org/A326609 OEIS sequence for the largest base b minimal prime, when the restriction of prime>base is not required] * [https://primes.utm.edu/primes/lists/all.txt top proven primes] * [http://www.primenumbers.net/prptop/prptop.php top PRPs] * [http://factordb.com online factor database, 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first2= Jeremy M. | year= 1994 | title= The Principles Of Bioinorganic Chemistry | publisher= University Science Books | isbn= 978-0-935-70272-9 | url= https://www.google.com/books/edition/Principles_of_Bioinorganic_Chemistry/zGJtXzPINAUC?hl=en }} {{User:Jtwsaddress42/Bibliography/Litman, Gary W.}} {{User:Jtwsaddress42/Bibliography/Llinas, Rudolf R.}} * {{cite journal | last1= Lookingland | first1= K.J. | last2= Moore | first2= K.E. | year= 1984 | title= Dopamine receptor-mediated regulation of incertohypothalamic dopaminergic neurons in the male rat | journal= Brain Research | volume= 304 | number= 2 | pages= 329-338 | publication-date= June 25, 1984 | pmid= 6331589 | doi= 10.1016/0006-8993(84)90337-8 | url= https://www.sciencedirect.com/science/article/abs/pii/0006899384903378?via%3Dihub }} {{User:Jtwsaddress42/Bibliography/Love, Alan C.}} {{User:Jtwsaddress42/Bibliography/Lovelock, James E.}} * {{cite book | last= Lowe | first= John P. | year= 1978 | title= Quantum Chemistry | edition= Student | publisher= Academic Press, Inc. | publication-date= December 2, 2012 | isbn= 978-0-323-14443-8 | url= https://www.google.com/books/edition/_/_n87jE72I5wC?hl=en&sa=X&ved=2ahUKEwj4o43enqj0AhXiHDQIHYwjB3gQ8fIDegQIAxA-}} * {{cite journal | last1= Lowry | first1= Christopher A. | last2= Rodda | first2= Joanne E. | last3= Lightman | first3= Stafford L. | last4= Ingram | first4= Colin D. | year= 2000 | title= Corticotropin-Releasing Factor Increases <i>in vitro</i> Firing Rates of Serotonergic Neurons in the Rat Dorsal Raphe Nucleus: Evidence for Activation of a Topographically Organized Mesolimbocortical Serotonergic System | journal= The Journal of Neuroscience | volume= 20 | number= 20 | pages= 7728-7736 | publication-date= October 15, 2000 | pmid= 11027235 | pmc= 6772886 | doi= 10.1523/JNEUROSCI.20-20-07728.2000 | url= https://www.jneurosci.org/content/20/20/7728.long }} * {{cite book | last= Lowther | first= Adam (editor) | year= 2020 | title= Guide to Nuclear Deterrence in the Age of Great-Power Competition | publisher= Louisiana Tech Research Institute | publication-date= September 2020 | isbn= 978-0-578-74727-9 | lccn= 2020916905 | url= https://www.researchgate.net/profile/Stephen-Blank-2/publication/344330391_Guide_to_Nuclear_Deterrence_in_the_Age_of_Great-Power_Competition/links/5f68cc29a6fdcc00863395b0/Guide-to-Nuclear-Deterrence-in-the-Age-of-Great-Power-Competition.pdf }} * {{cite journal | last1= Luithle | first1= Joachim E.A. | last2= Pietruszka | first2= Jorg | year= 1997 | title= Synthesis of Enantiomerically Pure Cyclopropanes from Cyclopropylboronic Acids | journal= Liebigs Annalen | volume= 1997 | number= 11 | pages= 2297-2302 | publication-date= October 22, 1997 | doi= 10.1021/jo9910278 | url= https://pubs.acs.org/doi/abs/10.1021/jo9910278 }} * {{cite journal | last1= Lumsden | first1= Andrew | last2= Krumlauf | first2= Robb | year= 1996 | title= Patterning the vertebrate neuraxis | journal= Science | volume= 274 | number= 5290 | pages= 1109-1115 | publication-date= November 15, 1996 | pmid= 8895453 | doi= 10.1126/science.274.5290.1109 | url= https://www.science.org/doi/10.1126/science.274.5290.1109?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed }} * {{cite book | last1= Lumsden | first1= Charles J. | last2= Wilson | first2= Edward O. | year= 1983 | title= Promethean Fire: Reflections on the Origin of the Mind | publisher= Harvard University Press | isbn= 978-0-674-71445-8 | url= https://www.google.com/books/edition/Promethean_Fire/DAyAAAAAMAAJ?hl=en }} {{User:Jtwsaddress42/Bibliography/Lynch, Gary}} * {{cite journal | last1= Lyubarev | first1= Arkadii E. | last2= Kurganov | first2= Boris I. | year= 1997 | title= Origin of Biochemical Organization | journal= Biosystems | volume= 42 | number= 2-3 | pages= 103-110 | pmid= 9184756 | doi= 10.1016/s0303-2647(96)01698-x | url= https://www.sciencedirect.com/science/article/abs/pii/S030326479601698X?via%3Dihub}} {{RoundBoxBottom}} {{User:Jtwsaddress42/Includes/Notes_&_Citations}} {{User:Jtwsaddress42/Navigation/Footer Navbar}} {{User:Jtwsaddress42/Includes/Categories}} a9fttg0qyhibboxrn6frspud1tcft98 2 277881 2408134 2407120 2022-07-20T06:22:11Z Jtwsaddress42 234843 /* Cavalier-Smith, Thomas (1942 - 2021) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Thomas Cavalier-Smith|Cavalier-Smith, Thomas (1942 - 2021)]] === '''Notable Accomplishments''' * Classification of Organisms * Obcell Theory * Neomuran Theory <br /> <hr /> {{User:Jtwsaddress42/Includes/Project Box - Remembering Thomas Cavalier-Smith}} {{User:Jtwsaddress42/Gallery/The_Neomuran_Revolution}} {{User:Jtwsaddress42/Quotes/Cavalier-Smith,_Thomas_2010a(a)}} {{User:Jtwsaddress42/Quotes/Cavalier-Smith, Thomas 2010a(b)}} {{User:Jtwsaddress42/Gallery/Animal Origins}} {{User:Jtwsaddress42/Quotes/Cavalier-Smith, Thomas 2017a}} {{User:Jtwsaddress42/Quotes/Cavalier-Smith, Thomas 2017b}} {{User:Jtwsaddress42/Quotes/Cavalier-Smith, Thomas 2017c}} '''Publications''' {{User:Jtwsaddress42/Bibliography/Cavalier-Smith,_Thomas}} <br /> '''Web Resources''' * [https://royalsociety.org/people/thomas-cavalier-smith-11202/ The Royal Society - Cavalier-Smith, Thomas (1942 - 2021)] {{RoundBoxBottom}} <hr /> imotvlfgy8b946wzw1qoa63kfmcn17z 2 277886 2408105 2407124 2022-07-20T04:07:49Z Jtwsaddress42 234843 /* Darwin, Charles (1809 - 1882) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Charles_Darwin|Darwin, Charles (1809 - 1882)]] === [[File:Charles-darwin-portrait-svg.svg|thumb|Charles Darwin (1809 – 1882)]] '''Notable Accomplishments''' * The Theory of Natural Selection <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Darwin,_Charles}} '''Web Resources''' * [http://darwin-online.org.uk/Freeman_intro.html Darwin Online] * [https://www.darwinproject.ac.uk/ Darwin Correspondence Project] * [https://www.khanacademy.org/science/ap-biology/natural-selection/natural-selection-ap/a/darwin-evolution-natural-selection Khan Academy - Darwin, evolution, & natural selection] <br /><hr /> {{User:Jtwsaddress42/Gallery/The Darwinian Revolution}} {{RoundBoxBottom}} <hr /> to40wio71sbnr87sfv69z4z81qtcdrb 2 277887 2408110 2407127 2022-07-20T04:29:08Z Jtwsaddress42 234843 /* Descartes, René (1596 - 1650) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Rene_Descartes|Descartes, René (1596 - 1650)]] === [[File:Portrait of René Descartes, bust, three-quarter facing left in an oval border, (white background removed).png|thumb|René Descartes (1596 - 1650)]] [[File:Descartes Discours de la Methode.jpg|thumb|Descartes Discours de la Methode]] '''Notable Accomplishments''' * Meditations on First Philosophy * Discourse On The Method <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Descartes,_René}} {{RoundBoxBottom}} <hr /> 7wtghlj84dpn53or5xaw4oz8pbsid1i 2 277944 2408111 2337891 2022-07-20T04:30:37Z Jtwsaddress42 234843 /* Dubrovsky, Bernardo (1938 - 2016) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [https://www.mcgill.ca/psychiatry/channels/news/obituary-dr-bernardo-durbovsky-263526 Dubrovsky, Bernardo (1938 - 2016)] === '''Notable Accomplishments''' * Darwinian Evolutionary Psychiatry <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Dubrovsky,_Bernardo}} {{RoundBoxBottom}} <hr /> 57o4x99i1xsyoo6qfw8o26s4kd5hqs3 2 277945 2408120 2366015 2022-07-20T04:43:02Z Jtwsaddress42 234843 wikitext text/x-wiki * {{cite book | last= Eccles | first= John C. | year= 1973| title= The Understanding Of The Brain | publisher= McGraw-Hill | publication-date= 1977 | isbn= 978-0-070-18865-5 | url= https://www.google.com/books/edition/_/psRqAAAAMAAJ?hl=en&sa=X&ved=2ahUKEwjarM_onJT1AhV4CjQIHToqD-oQ8fIDegQIBhAK }} * {{cite book | last= Eccles | first= John C. | year= 1989 | title= Evolution of the Brain: Creation of the Self | publisher= Routledge | edition= 1st | publication-date= May 16, 1991 | isbn= 978-0-415-03224-7 | url= https://www.routledge.com/Evolution-of-the-Brain-Creation-of-the-Self/Eccles/p/book/9780415032247}} * {{cite book | last1= Eccles | first1= John C. | last2= Popper | first2= Karl | year= 1977 | title= The Self and Its Brain | publisher=Routledge | isbn= 978-0-387-08307-0 | url= https://www.google.com/books/edition/_/IFN9AAAAMAAJ?hl=en&sa=X&ved=2ahUKEwjjn-CZ04b5AhWjFjQIHalPDBMQ8fIDegQIERAN }} ifwtmsoro7r2eqiiehovq3wf909wopq 2408123 2408120 2022-07-20T04:55:08Z Jtwsaddress42 234843 wikitext text/x-wiki * {{cite journal | last= Eccles | first= John C. | year= 1964 | title= The Ionic Mechanism of Postsynaptic Inhibition (Nobel Lecture) | series= Delivered December 11, 1963 | journal= Science | volume= 145 | number= 3637 | pages= 1140-1147 | publication-date= September 11, 1964 |pmid= 14173402 | doi= 10.1126/science.145.3637.1140 | url= https://www.nobelprize.org/uploads/2016/07/eccles-lecture.pdf }} * {{cite book | last= Eccles | first= John C. | year= 1973 | title= The Understanding Of The Brain | publisher= McGraw-Hill | publication-date= 1977 | isbn= 978-0-070-18865-5 | url= https://www.google.com/books/edition/_/psRqAAAAMAAJ?hl=en&sa=X&ved=2ahUKEwjarM_onJT1AhV4CjQIHToqD-oQ8fIDegQIBhAK }} * {{cite book | last= Eccles | first= John C. | year= 1989 | title= Evolution of the Brain: Creation of the Self | publisher= Routledge | edition= 1st | publication-date= May 16, 1991 | isbn= 978-0-415-03224-7 | url= https://www.routledge.com/Evolution-of-the-Brain-Creation-of-the-Self/Eccles/p/book/9780415032247}} * {{cite book | last1= Eccles | first1= John C. | last2= Popper | first2= Karl | year= 1977 | title= The Self and Its Brain | publisher=Routledge | isbn= 978-0-387-08307-0 | url= https://www.google.com/books/edition/_/IFN9AAAAMAAJ?hl=en&sa=X&ved=2ahUKEwjjn-CZ04b5AhWjFjQIHalPDBMQ8fIDegQIERAN }} pxqf91rfas4v3i06j9yc0h7iyzmg8ju 2408124 2408123 2022-07-20T04:55:38Z Jtwsaddress42 234843 wikitext text/x-wiki * {{cite journal | last= Eccles | first= John C. | year= 1963 | title= The Ionic Mechanism of Postsynaptic Inhibition (Nobel Lecture) | series= Delivered December 11, 1963 | journal= Science | volume= 145 | number= 3637 | pages= 1140-1147 | publication-date= September 11, 1964 |pmid= 14173402 | doi= 10.1126/science.145.3637.1140 | url= https://www.nobelprize.org/uploads/2016/07/eccles-lecture.pdf }} * {{cite book | last= Eccles | first= John C. | year= 1973 | title= The Understanding Of The Brain | publisher= McGraw-Hill | publication-date= 1977 | isbn= 978-0-070-18865-5 | url= https://www.google.com/books/edition/_/psRqAAAAMAAJ?hl=en&sa=X&ved=2ahUKEwjarM_onJT1AhV4CjQIHToqD-oQ8fIDegQIBhAK }} * {{cite book | last= Eccles | first= John C. | year= 1989 | title= Evolution of the Brain: Creation of the Self | publisher= Routledge | edition= 1st | publication-date= May 16, 1991 | isbn= 978-0-415-03224-7 | url= https://www.routledge.com/Evolution-of-the-Brain-Creation-of-the-Self/Eccles/p/book/9780415032247}} * {{cite book | last1= Eccles | first1= John C. | last2= Popper | first2= Karl | year= 1977 | title= The Self and Its Brain | publisher=Routledge | isbn= 978-0-387-08307-0 | url= https://www.google.com/books/edition/_/IFN9AAAAMAAJ?hl=en&sa=X&ved=2ahUKEwjjn-CZ04b5AhWjFjQIHalPDBMQ8fIDegQIERAN }} ncqa0tn5ncs97dbrv585ambijgdx036 2 277947 2408122 2407581 2022-07-20T04:44:08Z Jtwsaddress42 234843 /* Eccles, John C. (1903 - 1997) */ wikitext text/x-wiki <br clear= both /> {{RoundBoxTop|theme=3}} === [[w:John_Eccles_(neurophysiologist)|Eccles, John C. (1903 - 1997)]] === [[File:Sir John Eccles Wellcome L0026812.jpg|thumb|Sir John Eccles (1903 - 1997){{efn|Wellcome_L0026812}}]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/1963/eccles/facts/ The Nobel Prize in Physiology or Medicine 1963] - shared with Alan Hodgkin and Andrew Huxley, "for their discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the nerve cell membrane." <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Eccles,_John C.}} {{RoundBoxBottom}} <hr /> ljgpkgwgd6egpe8s0mym1wnf9g19lcg 2 278018 2408093 2407261 2022-07-20T03:18:25Z Jtwsaddress42 234843 /* Urey, Harold Clayton (1893 – 1981) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Harold_Urey|Urey, Harold Clayton (1893 – 1981)]] === [[File:Urey.jpg|thumb|Harold Clayton Urey (1893 – 1981)]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/1934/urey/facts/ The Nobel Prize in Chemistry 1934] - “for his discovery of heavy hydrogen.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Urey, Harold Clayton}} {{RoundBoxBottom}} <hr /> aam8550iyo711q9g2pf1igm1i7950h4 2408133 2408093 2022-07-20T06:03:15Z Jtwsaddress42 234843 /* Urey, Harold Clayton (1893 – 1981) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Harold_Urey|Urey, Harold Clayton (1893 – 1981)]] === [[File:Urey.jpg|thumb|Harold Clayton Urey (1893 – 1981)]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/1934/urey/facts/ The Nobel Prize in Chemistry 1934] - “for his discovery of heavy hydrogen.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Urey, Harold Clayton}} <br /><hr /> {| align= center |'''Harold C. Urey, Ernest O. Lawrence, James B. Conant, Lyman J. Briggs, E. V. Murphree and A. H. Compton.''' [[File:S1 Committee 1942.jpg|640px]] |} {{RoundBoxBottom}} <hr /> siz5hjje61niwah502pqp90y7imvj2o 2 278019 2408068 2407243 2022-07-20T01:58:34Z Jtwsaddress42 234843 /* Onsager, Lars (1903 – 1976) */ wikitext text/x-wiki <br clear= both /> {{RoundBoxTop|theme=3}} === [[w:Lars_Onsager|Onsager, Lars (1903 – 1976)]] === '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/1968/onsager/facts/ The Nobel Prize in Chemistry 1968] - “for the discovery of the reciprocal relations bearing his name, which are fundamental for the thermodynamics of irreversible processes.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Onsager, Lars}} {{RoundBoxBottom}} <hr /> kksi1uu4uob2o87ap1oc46tibxk9xs1 2 278020 2408069 2407245 2022-07-20T02:03:18Z Jtwsaddress42 234843 /* Oparin, Aleksandr Ivanovich (1894 – 1980) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Alexander_Oparin|Oparin, Aleksandr Ivanovich (1894 – 1980)]] === [[File:Oparin.jpg|thumb|Aleksandr Oparin (1894 – 1980)]] '''Notable Accomplishments''' * First serious chemical theory on the Origin of Life * Coacervates <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Oparin, Aleksandr Ivanovich}} {{RoundBoxBottom}} <hr /> 9hg8iq6pg4oq8ayplpuu70hdib3jz85 2 278022 2408070 2407250 2022-07-20T02:16:53Z Jtwsaddress42 234843 /* Popper, Karl R. (1902 – 1994) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Karl_Popper|Popper, Karl R. (1902 – 1994)]] === [[File:Karl Popper2.jpg|thumb|Karl Popper (1902 – 1994)]] '''Notable Accomplishments''' * Criteria for Falsifiability in Scientific Theorizing * The Open Society and Its Enemies * Logic of Scientific Discovery <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Popper, Karl R.}} {{RoundBoxBottom}} <hr /> 9oi1xy0dhczvat8hy0a4rjvfvut8z70 2 278023 2408071 2407253 2022-07-20T02:22:27Z Jtwsaddress42 234843 /* Porges, Stephen W. (1945 – ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Stephen_Porges|Porges, Stephen W. (1945 – )]] === '''Notable Accomplishments''' * Evolutionary Analysis of the Vertebrate Autonomic Nervous System * Polyvagal Theory <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Porges, Stephen W.}} {{RoundBoxBottom}} <hr /> fdqzb0unixp6mu4x4g4sa8vwcpg8avy 2408079 2408071 2022-07-20T02:38:17Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Stephen_Porges|Porges, Stephen W. (1945 – )]] === '''Notable Accomplishments''' * Evolutionary Analysis of the Vertebrate Autonomic Nervous System * Polyvagal Theory <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Porges, Stephen W.}} <br /><hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Dunning, Brian}} {{RoundBoxBottom}} <hr /> 9ljgs22h1fwbqa57nwimoqyx7j8cht3 2 278024 2408083 2407255 2022-07-20T02:52:29Z Jtwsaddress42 234843 /* Raff, Rudolf (1941 – 2019) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Rudolf_Raff|Raff, Rudolf (1941 – 2019)]] === [[File:Rudolf A. Raff, June 2011.jpg|thumb|Rudolf A. Raff (1941 – 2019)]] '''Publications''' {{User:Jtwsaddress42/Bibliography/Raff, Rudolf}} <br /><hr /> Love et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Love, Alan C.}} {{RoundBoxBottom}} <hr /> genglco9cqmcruniuf66qdp3gwn9lwk 2 278025 2408084 2407256 2022-07-20T02:54:03Z Jtwsaddress42 234843 /* Romer, Alfred Sherwood (1894 – 1973) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Alfred_Romer|Romer, Alfred Sherwood (1894 – 1973)]] === [[Image:Spindle diagram.jpg|thumb|'''A Romerogram''' - Spindle diagram of taxonomic diversity over time within the Vertebrate classes Agnatha, Chondrichthyes, Osteichthyes, Amphibia, Reptilia, Aves and Mammalia with two extinct classes, Placodermi and Acanthodii also being shown.{{sfn|Benton|1998}} {{efn|Based on Benton (1998), all classes interpreted traditionally. Bentons notes to his own tree: Number of families is an imperfect measure of diversity. Reptilia in particular should probably have been shown as far more diverse in the Mesozoic.}}]] '''Notable Accomplishments''' * The Vertebrate as a Dual Organism <br /> <hr /> {{User:Jtwsaddress42/Quotes/Romer,_Alfred_Sherwood_1972a}} {{User:Jtwsaddress42/Gallery/The Functional Welding of the CNS to the ENS}} {{User:Jtwsaddress42/Quotes/Romer,_Alfred_Sherwood_1972d}} '''Publications''' {{User:Jtwsaddress42/Bibliography/Romer, Alfred Sherwood}} {{RoundBoxBottom}} <hr /> 3052lbp5nw3mw1ize9bdidwxa676vdl 2408085 2408084 2022-07-20T02:54:54Z Jtwsaddress42 234843 /* Romer, Alfred Sherwood (1894 – 1973) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Alfred_Romer|Romer, Alfred Sherwood (1894 – 1973)]] === [[Image:Spindle diagram.jpg|thumb|'''A Romerogram''' - Spindle diagram of taxonomic diversity over time within the Vertebrate classes Agnatha, Chondrichthyes, Osteichthyes, Amphibia, Reptilia, Aves and Mammalia with two extinct classes, Placodermi and Acanthodii also being shown.{{sfn|Benton|1998}} {{efn|Based on Benton (1998), all classes interpreted traditionally. Bentons notes to his own tree: Number of families is an imperfect measure of diversity. Reptilia in particular should probably have been shown as far more diverse in the Mesozoic.}}]] '''Notable Accomplishments''' * The Somatovisceral Animial - The Vertebrate as a Dual Animal <br /> <hr /> {{User:Jtwsaddress42/Quotes/Romer,_Alfred_Sherwood_1972a}} {{User:Jtwsaddress42/Gallery/The Functional Welding of the CNS to the ENS}} {{User:Jtwsaddress42/Quotes/Romer,_Alfred_Sherwood_1972d}} '''Publications''' {{User:Jtwsaddress42/Bibliography/Romer, Alfred Sherwood}} {{RoundBoxBottom}} <hr /> glc7eow4cemfduktg54hnd7qy30l3cp 2408086 2408085 2022-07-20T02:55:15Z Jtwsaddress42 234843 /* Romer, Alfred Sherwood (1894 – 1973) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Alfred_Romer|Romer, Alfred Sherwood (1894 – 1973)]] === [[Image:Spindle diagram.jpg|thumb|'''A Romerogram''' - Spindle diagram of taxonomic diversity over time within the Vertebrate classes Agnatha, Chondrichthyes, Osteichthyes, Amphibia, Reptilia, Aves and Mammalia with two extinct classes, Placodermi and Acanthodii also being shown.{{sfn|Benton|1998}} {{efn|Based on Benton (1998), all classes interpreted traditionally. Bentons notes to his own tree: Number of families is an imperfect measure of diversity. Reptilia in particular should probably have been shown as far more diverse in the Mesozoic.}}]] '''Notable Accomplishments''' * The Somatovisceral Animal - The Vertebrate as a Dual Animal <br /> <hr /> {{User:Jtwsaddress42/Quotes/Romer,_Alfred_Sherwood_1972a}} {{User:Jtwsaddress42/Gallery/The Functional Welding of the CNS to the ENS}} {{User:Jtwsaddress42/Quotes/Romer,_Alfred_Sherwood_1972d}} '''Publications''' {{User:Jtwsaddress42/Bibliography/Romer, Alfred Sherwood}} {{RoundBoxBottom}} <hr /> ias18rmn7wf2y8zgv86cqxwt4uuvqjx 2 278109 2408129 2338142 2022-07-20T05:43:08Z Jtwsaddress42 234843 /* Scott, William G. */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:User:Wgscott|Scott, William G.]] === [[File:Full length hammerhead ribozyme.png|thumb|Full length hammerhead ribozyme]] '''Notable Accomplishments''' * <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Scott, William G.}} <br /><hr /> '''Web Resources''' * [http://scottlab.ucsc.edu/scottlab/index.html The Scott Lab] {{RoundBoxBottom}} <hr /> pzccolxog6dj0bdjbztent679ixz858 2408130 2408129 2022-07-20T05:45:02Z Jtwsaddress42 234843 /* Scott, William G. */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:User:Wgscott|Scott, William G.]] === [[File:Full length hammerhead ribozyme.png|thumb|Full length hammerhead ribozyme]] '''Notable Accomplishments''' * The Chemistry of RNA & Ribozymes <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Scott, William G.}} <br /><hr /> '''Web Resources''' * [http://scottlab.ucsc.edu/scottlab/index.html The Scott Lab] {{RoundBoxBottom}} <hr /> qd57uuqc5a6xkdppqxpdz1nsmf6e6nj 2408131 2408130 2022-07-20T05:51:49Z Jtwsaddress42 234843 /* Scott, William G. */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:User:Wgscott|Scott, William G.]] === [[File:Full length hammerhead ribozyme.png|thumb|Full length hammerhead ribozyme]] '''Notable Accomplishments''' * UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department, Faculty Professorr, Center for Molecular Biology of RNA * The Chemistry of RNA & Ribozymes <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Scott, William G.}} <br /><hr /> '''Web Resources''' * [http://scottlab.ucsc.edu/scottlab/index.html The Scott Lab] {{RoundBoxBottom}} <hr /> cf8915rjs392fbfn00bj192cfuh8wib 2408132 2408131 2022-07-20T05:54:10Z Jtwsaddress42 234843 /* Scott, William G. */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:User:Wgscott|Scott, William G.]] === [[File:Full length hammerhead ribozyme.png|thumb|Full length hammerhead ribozyme]] '''Notable Accomplishments''' * UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department, Faculty Professorr, Center for Molecular Biology of RNA * [http://scottlab.ucsc.edu/scottlab/index.html The Scott Lab] - The Chemistry of RNA & Ribozymes <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Scott, William G.}} {{RoundBoxBottom}} <hr /> 07bf7vvo8xkb8kbvrgp8zdqefs0sf93 2 278111 2408091 2407259 2022-07-20T03:05:39Z Jtwsaddress42 234843 /* Seaborg, Glenn T. (1912 – 1999) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Glenn_T._Seaborg|Seaborg, Glenn T. (1912 – 1999)]] === [[File:Glenn Seaborg - 1964.jpg|thumb|Glenn Seaborg (1912 – 1999)]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/1951/seaborg/facts/ The Nobel Prize in Chemistry 1951] - shared with Edwin Mattison McMillan “for their discoveries in the chemistry of the transuranium elements.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Seaborg, Glenn T.}} {{RoundBoxBottom}} <hr /> 1lna1modxw8v2p9cxwar5j1atmkdqhy 2408098 2408091 2022-07-20T03:35:10Z Jtwsaddress42 234843 /* Seaborg, Glenn T. (1912 – 1999) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Glenn_T._Seaborg|Seaborg, Glenn T. (1912 – 1999)]] === [[File:Glenn Seaborg - 1964.jpg|thumb|Glenn Seaborg (1912 – 1999)]] [[File:Seaborg in lab - restoration.jpg|thumb|Seaborg in 1950, with the ion exchanger elution column of actinide elements.]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/1951/seaborg/facts/ The Nobel Prize in Chemistry 1951] - shared with Edwin Mattison McMillan “for their discoveries in the chemistry of the transuranium elements.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Seaborg, Glenn T.}} {{RoundBoxBottom}} <hr /> jczxv5et8oa2nqgg3u0umbsvuqrt9c2 1 278241 2408001 2375616 2022-07-19T13:49:32Z Eyoungstrom 1933979 /* Materials for Edit-a-thons */ new section wikitext text/x-wiki =996 FDFxHGAPS Conferences and Grants= The members are Natalie, Brei, and Hide ==''Mtg Notes 9.30.21 - FDF x HGAPS Conferences & Grants''== [https://docs.google.com/document/d/1UW2AuWfDann8i4U1Jzwugh6-sJmExqJwlD_t_wBwGBE/edit# Mingenda] Eric Youngstrom - Ey ==Stuff we need to work faster in the future== # Add project number-#996 [https://docs.google.com/spreadsheets/d/1yM6c0zrt1yHDe55OJZqYZzo-heaa_M93nWweFUsIjZk/edit?usp=sharing on project list] # Add Drive Folder on @HGAPS.org # add Shared drive account to Eric’s main searchable page ===TODO=== # add citations to Zotero objects #[https://docs.google.com/spreadsheets/d/1yM6c0zrt1yHDe55OJZqYZzo-heaa_M93nWweFUsIjZk/edit?usp=sharing MECCA Writing Tracking Link] # 996 team to review APA BEA Award grant due 02/22 Grant team to: #Make a shared drive account (eric/Hannah Kim/Emma Chopin have the ability to do so) #Create a page for the project and move conference and grant documents into it from the HGAPS page ==High level objectives== ===Objective 0:=== Make infrastructure for this group to work together and accomplish the following objectives (slack channel? Google Doc with notes, OKRs? Wikiversity page about the project?, etc. ) 0.1 - Yes Slack channel #996? 0.1.1 []messaged Emma to ask her to change the name 0.2- Yes, Google Drive: #996 https://drive.google.com/drive/u/1/folders/0AEjtrLGjEoH-Uk9PVA 0.3 -- (.8 target) develop OKRs on this page 0.4 -- ===Objective 1:=== Have a “model page” that includes all the examples of good content and great style # Space created (Model Page Folder added) felt more open-ended than one google doc # organize space in silos of content, style, production, etc. ===Objective 2:=== Make FDF 2022 have all of its pages look like the model page ß Design the process now to implement in run-up ===Objective 3:=== Write grants (2K rapid, foundation) to extend this process to other meetings ===Objective 4:=== Write larger conference grant for HGAPS/FDF mashup (FDF plus Satellite) with high-quality videography, investment in training cadre ===Objective 5:=== Showcase “model page” to other teams to have them think about how to extend the model (add YouTube, Infographics, Tweets & Insta, QR codes, etc.) FDF Programs/ Website Link etc. Website: [https://jccapfuturedirectionsforum.com] OSF (2021 Posters): https://osf.io/frkpz/ Workshop Details will be published on 10/15/2021 [[User:Eyoungstrom|Eyoungstrom]] ([[User talk:Eyoungstrom|discuss]] • [[Special:Contributions/Eyoungstrom|contribs]]) 00:23, 3 October 2021 (UTC) == Materials for Edit-a-thons == Here are some resources for the edit-a-thons, including a set of slides that Natale made and is sharing [https://docs.google.com/presentation/d/1ytQs-nP151UP4LYt3ziHJwrEMa3Yg50TedvlTGLopAg/edit?usp=sharing here]. [[User:Eyoungstrom|Eyoungstrom]] ([[User talk:Eyoungstrom|discuss]] • [[Special:Contributions/Eyoungstrom|contribs]]) 13:49, 19 July 2022 (UTC) acuo0s1tccdfhpo2kz53176q74zthwt 1 278582 2407998 2326637 2022-07-19T12:57:24Z Eyoungstrom 1933979 /* "Sandbox" on the Discuss Page */ new section wikitext text/x-wiki == 1004. Squid Game Project Sandbox == This is the Discuss/Talk page where we are dropping links to other tools the team is using, and also putting in comments and suggestions. [[User:Eyoungstrom|Eyoungstrom]] ([[User talk:Eyoungstrom|discuss]] • [[Special:Contributions/Eyoungstrom|contribs]]) 22:52, 6 October 2021 (UTC) ==Links== Our [https://docs.google.com/document/d/1YvvAVgpeeXKHBlojbzE2zyfBjzXWlPP1BCYvl5gOECM/edit?usp=sharing GoogleDoc] scratchpad. == "Sandbox" on the Discuss Page == So that we don't (a) rush to edit material on the main page, nor (b) lose content in people's personal sandboxes, let's use the Discuss page as a place to work on drafts if we have new sections that we want to add to the main page. This will keep the material close and easy to find, and give us a place to move things into code and build links to then copy and paste into the source for the main page. Feel free to add new sections as helpful. (Remember that each section can have a different person editing it at the same time, without creating "conflicted copies"). [[User:Eyoungstrom|Eyoungstrom]] ([[User talk:Eyoungstrom|discuss]] • [[Special:Contributions/Eyoungstrom|contribs]]) 12:57, 19 July 2022 (UTC) 32p4hllu8ruujys3uk63iavebtqpnwc 2408135 2407998 2022-07-20T06:57:49Z Eyoungstrom 1933979 /* Links */ added short wiki link wikitext text/x-wiki == 1004. Squid Game Project Sandbox == This is the Discuss/Talk page where we are dropping links to other tools the team is using, and also putting in comments and suggestions. [[User:Eyoungstrom|Eyoungstrom]] ([[User talk:Eyoungstrom|discuss]] • [[Special:Contributions/Eyoungstrom|contribs]]) 22:52, 6 October 2021 (UTC) ==Links== Our [https://docs.google.com/document/d/1YvvAVgpeeXKHBlojbzE2zyfBjzXWlPP1BCYvl5gOECM/edit?usp=sharing GoogleDoc] scratchpad. The Wiki short URL for this page is https://w.wiki/5Ubt (This may be preferable to a Bit.Ly or similar from a security perspective) You can make others and read more at https://meta.wikimedia.org/wiki/Special:UrlShortener == "Sandbox" on the Discuss Page == So that we don't (a) rush to edit material on the main page, nor (b) lose content in people's personal sandboxes, let's use the Discuss page as a place to work on drafts if we have new sections that we want to add to the main page. This will keep the material close and easy to find, and give us a place to move things into code and build links to then copy and paste into the source for the main page. Feel free to add new sections as helpful. (Remember that each section can have a different person editing it at the same time, without creating "conflicted copies"). [[User:Eyoungstrom|Eyoungstrom]] ([[User talk:Eyoungstrom|discuss]] • [[Special:Contributions/Eyoungstrom|contribs]]) 12:57, 19 July 2022 (UTC) 2nc91qpxu5p13789qho04fezdc6vuvh 2408136 2408135 2022-07-20T07:01:27Z Eyoungstrom 1933979 link to step #3 Google Doc wikitext text/x-wiki == 1004. Squid Game Project Sandbox == This is the Discuss/Talk page where we are dropping links to other tools the team is using, and also putting in comments and suggestions. [[User:Eyoungstrom|Eyoungstrom]] ([[User talk:Eyoungstrom|discuss]] • [[Special:Contributions/Eyoungstrom|contribs]]) 22:52, 6 October 2021 (UTC) ==Links== Our [https://docs.google.com/document/d/1YvvAVgpeeXKHBlojbzE2zyfBjzXWlPP1BCYvl5gOECM/edit?usp=sharing GoogleDoc] scratchpad. The #3. Document organizing English-language resources is a GoogleDoc [https://docs.google.com/document/d/1TyIrD4rd-JAD7o7VfaHeyB9aVw5_VV4Yekn6xMwWAko/edit?usp=sharing Here]. The Wiki short URL for this page is https://w.wiki/5Ubt (This may be preferable to a Bit.Ly or similar from a security perspective) You can make others and read more at https://meta.wikimedia.org/wiki/Special:UrlShortener == "Sandbox" on the Discuss Page == So that we don't (a) rush to edit material on the main page, nor (b) lose content in people's personal sandboxes, let's use the Discuss page as a place to work on drafts if we have new sections that we want to add to the main page. This will keep the material close and easy to find, and give us a place to move things into code and build links to then copy and paste into the source for the main page. Feel free to add new sections as helpful. (Remember that each section can have a different person editing it at the same time, without creating "conflicted copies"). [[User:Eyoungstrom|Eyoungstrom]] ([[User talk:Eyoungstrom|discuss]] • [[Special:Contributions/Eyoungstrom|contribs]]) 12:57, 19 July 2022 (UTC) lfdyzqtvzjbknxhjyta0q1k5axfx7oa 2408138 2408136 2022-07-20T07:39:30Z Eyoungstrom 1933979 /* Links */ added link to GoogleSheet wikitext text/x-wiki == 1004. Squid Game Project Sandbox == This is the Discuss/Talk page where we are dropping links to other tools the team is using, and also putting in comments and suggestions. [[User:Eyoungstrom|Eyoungstrom]] ([[User talk:Eyoungstrom|discuss]] • [[Special:Contributions/Eyoungstrom|contribs]]) 22:52, 6 October 2021 (UTC) ==Links== Our [https://docs.google.com/document/d/1YvvAVgpeeXKHBlojbzE2zyfBjzXWlPP1BCYvl5gOECM/edit?usp=sharing GoogleDoc] scratchpad. The #2. Sheet for organizing links to Wiki pages and online resources is [https://docs.google.com/spreadsheets/d/1pPk7LjVlHMMLqdLxwXYj5q05c7dDfvPEXvTH4_YtrmQ/edit?usp=sharing here] in both English and Hanguel. The #3. Document organizing English-language resources is a GoogleDoc [https://docs.google.com/document/d/1TyIrD4rd-JAD7o7VfaHeyB9aVw5_VV4Yekn6xMwWAko/edit?usp=sharing Here]. The Wiki short URL for this page is https://w.wiki/5Ubt (This may be preferable to a Bit.Ly or similar from a security perspective) You can make others and read more at https://meta.wikimedia.org/wiki/Special:UrlShortener == "Sandbox" on the Discuss Page == So that we don't (a) rush to edit material on the main page, nor (b) lose content in people's personal sandboxes, let's use the Discuss page as a place to work on drafts if we have new sections that we want to add to the main page. This will keep the material close and easy to find, and give us a place to move things into code and build links to then copy and paste into the source for the main page. Feel free to add new sections as helpful. (Remember that each section can have a different person editing it at the same time, without creating "conflicted copies"). [[User:Eyoungstrom|Eyoungstrom]] ([[User talk:Eyoungstrom|discuss]] • [[Special:Contributions/Eyoungstrom|contribs]]) 12:57, 19 July 2022 (UTC) dq2p0yg7lkn4ze1eqvsvhgl13rds48q 2 278672 2408066 2407268 2022-07-20T01:51:08Z Jtwsaddress42 234843 /* Metchnikoff, Élie (1845 - 1916) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Elie_Metchnikoff|Metchnikoff, Élie (1845 - 1916)]] === [[File:Professor Élie Metchnikoff.jpg|thumb|Élie Metchnikoff (1845 - 1916)]] also known as: ''Ilya Ilyich Mechnikov''<br /><br /> '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/1908/mechnikov/facts/ The Nobel Prize in Physiology or Medicine 1908] - shared with Ilya Ilyich Mechnikov and Paul Ehrlich “in recognition of their work on immunity.” <br /> <hr /> {{User:Jtwsaddress42/Gallery/Metchnikoff}} '''Publications'''<br /> {{User:Jtwsaddress42/Bibliography/Metchnikoff, Élie}} <br /><hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Bibel, Jan D.}} {{User:Jtwsaddress42/Bibliography/Cooper, Edwin L.}} {{User:Jtwsaddress42/Bibliography/Tauber, Alfred I.}} {{RoundBoxBottom}} <hr /> segkifvpvv7ss1bdxavn6w7kp95bhl5 2408067 2408066 2022-07-20T01:51:38Z Jtwsaddress42 234843 /* Metchnikoff, Élie (1845 - 1916) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Elie_Metchnikoff|Metchnikoff, Élie (1845 - 1916)]] === [[File:Professor Élie Metchnikoff.jpg|thumb|Élie Metchnikoff (1845 - 1916)]] also known as: ''Ilya Ilyich Mechnikov''<br /><br /> '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/1908/mechnikov/facts/ The Nobel Prize in Physiology or Medicine 1908] - shared with Paul Ehrlich “in recognition of their work on immunity.” <br /> <hr /> {{User:Jtwsaddress42/Gallery/Metchnikoff}} '''Publications'''<br /> {{User:Jtwsaddress42/Bibliography/Metchnikoff, Élie}} <br /><hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Bibel, Jan D.}} {{User:Jtwsaddress42/Bibliography/Cooper, Edwin L.}} {{User:Jtwsaddress42/Bibliography/Tauber, Alfred I.}} {{RoundBoxBottom}} <hr /> p5zekp96gtf5bv3b84jk8isvyy9dmy6 2 278684 2408112 2407128 2022-07-20T04:31:50Z Jtwsaddress42 234843 /* Dobzhansky, Theodosius (1900 - 1975) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Theodosius_Dobzhansky|Dobzhansky, Theodosius (1900 - 1975)]] === {{User:Jtwsaddress42/Quotes/Dobzhansky, Theodosius 1973a}} '''Notable Accomplishments''' * Major Contributor to the Modern Synthesis in Biology <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Dobzhansky, Theodosius}} {{RoundBoxBottom}} <hr /> 6nidqreuvcd08v8pcto4962fond7k6y 2408113 2408112 2022-07-20T04:32:32Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Theodosius_Dobzhansky|Dobzhansky, Theodosius (1900 - 1975)]] === '''Notable Accomplishments''' * Major Contributor to the Modern Synthesis in Biology <br /> <hr /> {{User:Jtwsaddress42/Quotes/Dobzhansky, Theodosius 1973a}} <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Dobzhansky, Theodosius}} {{RoundBoxBottom}} <hr /> oi8ugedm2rhbr7uov6fuyy8ecw9l7p4 2408114 2408113 2022-07-20T04:32:53Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Theodosius_Dobzhansky|Dobzhansky, Theodosius (1900 - 1975)]] === '''Notable Accomplishments''' * Major Contributor to the Modern Synthesis in Biology <br /> {{User:Jtwsaddress42/Quotes/Dobzhansky, Theodosius 1973a}} <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Dobzhansky, Theodosius}} {{RoundBoxBottom}} <hr /> c0dtws8cmna3bauunsrk425prrwb3n3 0 283959 2408022 2406336 2022-07-19T14:51:33Z 210.242.153.201 wikitext text/x-wiki == Definition == For the original Riesel problem, it is finding and proving the smallest k such that k×bⁿ-1 is not prime for all integers n ≥ 1 and GCD(k-1, b-1)=1. === Extended definiton === Finding and proving the smallest k such that (k×bⁿ-1)/GCD(k-1, b-1) is not prime for all integers n ≥ 1. === Notes === All n must be >= 1. k-values that make a full covering set with all or partial algebraic factors are excluded from the conjectures. k-values that are a multiple of base (b) and where (k-1)/gcd(k-1,b-1) is not prime are included in the conjectures but excluded from testing. Such k-values will have the same prime as k / b. == Table == {| class="wikitable" | colspan="1" rowspan="1" |Base | colspan="1" rowspan="1" |Conjectured smallest Riesel k | colspan="1" rowspan="1" |Covering set | colspan="1" rowspan="1" |k's that make a full covering set with all or partial algebraic factors | colspan="1" rowspan="1" |Remaining k to find prime (n testing limit) | colspan="1" rowspan="1" |Top 10 k's with largest first primes: k (n) (sorted by n only) | colspan="1" rowspan="1" |Comments |- | colspan="1" rowspan="1" |2 | colspan="1" rowspan="1" |509203 | colspan="1" rowspan="1" |3, 5, 7, 13, 17, 241 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |23669, 31859, 38473, 46663, 67117, 74699, 81041, 93839, 97139, 107347, 121889, 129007, 143047, 161669, 206231, 215443, 226153, 234343, 245561, 250027, 315929, 319511, 324011, 325123, 327671, 336839, 342847, 344759, 351134, 362609, 363343, 364903, 365159, 368411, 371893, 384539, 386801, 397027, 409753, 444637, 470173, 474491, 477583, 478214, 485557, 494743 (k = 351134 and 478214 at n=8M, other k at n=12.5M) | colspan="1" rowspan="1" |192971 (14773498) 206039 (13104952) 2293 (12918431) 9221 (11392194) 146561 (11280802) 273809 (8932416) 502573 (7181987) 402539 (7173024) 40597 (6808509) 304207 (6643565) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |3 | colspan="1" rowspan="1" |12119 | colspan="1" rowspan="1" |2, 5, 7, 13, 73 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1613, 1831, 1937, 3131, 3589, 5755, 6787, 7477, 7627, 7939, 8713, 8777, 9811, 10651, 11597 (all at n=50K) | colspan="1" rowspan="1" |8059 (47256) 11753 (36665) 6119 (28580) 7511 (26022) 313 (24761) 11251 (24314) 9179 (21404) 997 (20847) 6737 (17455) 7379 (16856) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |361 | colspan="1" rowspan="1" |3, 5, 7, 13 | colspan="1" rowspan="1" |All k = m^2 for all n; factors to: (m*2^n - 1) * (m*2^n + 1) | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000350048535 primality certificate for k=106]) | colspan="1" rowspan="1" |106 (4553) 74 (1276) 219 (206) 191 (113) 312 (51) 247 (42) 223 (33) 274 (22) 234 (18) 91 (17) | colspan="1" rowspan="1" |k = 1, 4, 9, 16, 25, 36, 49, 64, 81, 100, 121, 144, 169, 196, 225, 256, 289, and 324 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (4) 1 (3) 11 (2) 8 (2) 12 (1) 9 (1) 7 (1) 6 (1) 4 (1) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |6 | colspan="1" rowspan="1" |84687 | colspan="1" rowspan="1" |7, 13, 31, 37, 97 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1597, 6236, 9491, 37031, 49771, 50686, 53941, 55061, 57926, 76761, 79801, 83411 (k = 1597 at n=5.6M, other k at n=40K) | colspan="1" rowspan="1" |36772 (1723287) 43994 (569498) 77743 (560745) 51017 (528803) 57023 (483561) 78959 (458114) 59095 (171929) 48950 (143236), 29847 (141526) 9577 (121099) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |7 | colspan="1" rowspan="1" |457 | colspan="1" rowspan="1" |2, 3, 5, 13, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (with probable primes that have not been certified: k = 197) (the k=139 prime is proven prime by N-1, and [http://factordb.com/cert.php?id=1100000000900876693 primality certificate for the large prime factor of N-1]) ([http://factordb.com/cert.php?id=1100000000887911299 primality certificate for k=367], [http://factordb.com/cert.php?id=1100000000887911292 primality certificate for k=313], [http://factordb.com/cert.php?id=1100000000887911277 primality certificate for k=159], [http://factordb.com/cert.php?id=1100000000887911327 primality certificate for k=429], [http://factordb.com/cert.php?id=1100000000887902040 primality certificate for k=391], [http://factordb.com/cert.php?id=1100000000900877143 primality certificate for k=299], [http://factordb.com/cert.php?id=1100000000854476434 primality certificate for k=79) | colspan="1" rowspan="1" |197 (181761) 367 (15118) 313 (5907) 159 (4896) 429 (3815) 419 (1052) 391 (938) 299 (600) 139 (468) 79 (424) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |8 | colspan="1" rowspan="1" |14 | colspan="1" rowspan="1" |3, 5, 13 | colspan="1" rowspan="1" |All k = m^3 for all n; factors to: (m*2^n - 1) * (m^2*4^n + m*2^n + 1) | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |11 (18) 5 (4) 12 (3) 7 (3) 2 (2) 13 (1) 10 (1) 9 (1) 6 (1) 4 (1) | colspan="1" rowspan="1" |k = 1 and 8 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |9 | colspan="1" rowspan="1" |41 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" |All k = m^2 for all n; factors to: (m*3^n - 1) * (m*3^n + 1) | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |11 (11) 24 (8) 14 (8) 38 (3) 18 (3) 39 (2) 34 (2) 32 (2) 29 (2) 27 (2) | colspan="1" rowspan="1" |k = 1, 4, 9, 16, 25, and 36 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |10 | colspan="1" rowspan="1" |334 | colspan="1" rowspan="1" |3, 7, 13, 37 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000291649394 primality certificate for k=121]) | colspan="1" rowspan="1" |121 (483) 109 (136) 98 (90) 230 (60) 289 (35) 89 (33) 32 (28) 233 (18) 324 (17) 100 (17) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |11 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (17) 3 (2) 2 (2) 4 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |12 | colspan="1" rowspan="1" |376 | colspan="1" rowspan="1" |5, 13, 29 | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 5 or 8 mod 13: for even n let k = m^2 and let n = 2*q; factors to: (m*12^q - 1) * (m*12^q + 1) odd n: factor of 13 (Condition 2): All k where k = 3*m^2 and m = = 3 or 10 mod 13: even n: factor of 13 for odd n let k = 3*m^2 and let n=2*q-1; factors to: [m*2^(2q-1)*3^q - 1] * [m*2^(2q-1)*3^q + 1] | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000800797310 primality certificate for k=298]) | colspan="1" rowspan="1" |298 (1676) 157 (285) 46 (194) 304 (40) 259 (40) 94 (36) 292 (30) 147 (28) 301 (27) 349 (25) | colspan="1" rowspan="1" |k = 25, 64, and 324 proven composite by condition 1. k = 27 and 300 proven composite by condition 2. |- | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |29 | colspan="1" rowspan="1" |2, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |25 (15) 28 (14) 20 (10) 1 (5) 22 (3) 17 (3) 16 (3) 27 (2) 21 (2) 12 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |14 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (4) 1 (3) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |15 | colspan="1" rowspan="1" |622403 | colspan="1" rowspan="1" |2, 17, 113, 1489 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |47, 203, 239, 407, 437, 451, 889, 893, 1945, 2049, 2245, 2487, 2507, 2689, 2699, 2863, 3059, 3163, 3179, 3261, 3409, 3697, 3701, 3725, 4173, 4249, 4609, 4771, 4877, 5041, 5243, 5425, 5441, 5503, 5669, 5857, 5913, 5963, 6231, 6447, 6787, 6879, 6999, 7386, 7407, 7459, 7473, 7527, 7615, 7683, 7687, 7859, 8099, 8621, 8671, 8839, 8863, 9025, 9267, 9409, 9655, 9663, 9707, 9817, 9955 (for k <= 10K) (all at n=1.5K) | colspan="1" rowspan="1" |2940 (13254) 8610 (5178) 2069 (1461) 3917 (1427) 1145 (1349) 1583 (1330) 7027 (1316) 8831 (1296) 5305 (1273) 4865 (1265) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |16 | colspan="1" rowspan="1" |100 | colspan="1" rowspan="1" |3, 7, 13 | colspan="1" rowspan="1" |All k = m^2 for all n; factors to: (m*4^n - 1) * (m*4^n + 1) | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |74 (638) 78 (26) 48 (15) 58 (12) 31 (12) 95 (8) 46 (8) 88 (6) 44 (6) 39 (6) | colspan="1" rowspan="1" |k = 1, 4, 9, 16, 25, 36, 49, 64, and 81 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |17 | colspan="1" rowspan="1" |49 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000889581395 primality certificate for k=29], [http://factordb.com/cert.php?id=1100000000033706286 primality certificate for k=13]) | colspan="1" rowspan="1" |44 (6488) 29 (4904) 13 (1123) 36 (243) 10 (117) 26 (110) 5 (60) 11 (46) 46 (25) 35 (24) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |18 | colspan="1" rowspan="1" |246 | colspan="1" rowspan="1" |5, 13, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |151 (418) 78 (172) 50 (110) 79 (63) 237 (44) 184 (44) 75 (44) 215 (36) 203 (32) 93 (32) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |19 | colspan="1" rowspan="1" |9 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*19^q - 1) * (m*19^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (19) 7 (2) 3 (2) 8 (1) 6 (1) 5 (1) 2 (1) | colspan="1" rowspan="1" |k = 4 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |20 | colspan="1" rowspan="1" |8 | colspan="1" rowspan="1" |3, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (10) 1 (3) 6 (2) 5 (2) 7 (1) 4 (1) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |21 | colspan="1" rowspan="1" |45 | colspan="1" rowspan="1" |2, 11 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |29 (98) 34 (17) 43 (10) 32 (4) 5 (4) 6 (3) 1 (3) 44 (2) 37 (2) 31 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |22 | colspan="1" rowspan="1" |2738 | colspan="1" rowspan="1" |5, 23, 97 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |208, 211, 898, 976, 1036, 1885, 1933, 2050, 2161, 2278, 2347, 2434 (all at n=13K) | colspan="1" rowspan="1" |1013 (26067) 185 (11433) 1335 (11155) 2719 (9671) 2083 (8046) 883 (5339) 2529 (3700) 2116 (3371) 2230 (3236) 1119 (2849) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |23 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |3 (6) 2 (6) 4 (5) 1 (5) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |24 | colspan="1" rowspan="1" |32336 | colspan="1" rowspan="1" |5, 7, 13, 73, 577 | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*24^q - 1) * (m*24^q + 1) odd n: factor of 5 (Condition 2): All k where k = 6*m^2 and m = = 1 or 4 mod 5: even n: factor of 5 for odd n let k = 6*m^2 and let n=2*q-1; factors to: [m*2^(3q-1)*3^q - 1] * [m*2^(3q-1)*3^q + 1] | colspan="1" rowspan="1" |389, 461, 1581, 1711, 2094, 2606, 3006, 3754, 4239, 5356, 5784, 5791, 6116, 6579, 6781, 6831, 7321, 7809, 10219, 10399, 10666, 11101, 11516, 12326, 12429, 12674, 13269, 13691, 15019, 15151, 15614, 15641, 16124, 16234, 16616, 17019, 17436, 18054, 18454, 18964, 19116, 20026, 20576, 20611, 20879, 21004, 21464, 21524, 21639, 21809, 23549, 24404, 25046, 25136, 25349, 25389, 25419, 25646, 25731, 26176, 26229, 26661, 27049, 27154, 28001, 28384, 28849, 28859, 29211, 29531, 29569, 29581, 31071, 31466, 31734, 31854, 31994, 31996, 32099 (k = 1 mod 23 at n=12.4K, other k at n=260K) | colspan="1" rowspan="1" |10171 (259815) 11906 (252629) 23059 (252514) 21411 (252303) 28554 (239686) 20804 (233296) 8894 (210624) 2844 (203856) 25379 (175842) 22604 (169372) | colspan="1" rowspan="1" |k = 2^2, 3^2, 7^2, 8^2, 12^2, 13^2, 17^2, 18^2 (etc. pattern repeating every 5m) proven composite by condition 1. k = 6*1^2, 6*4^2, 6*6^2, 6*9^2, 6*11^2, 6*14^2, 6*16^2, 6*19^2 (etc. pattern repeating every 5m) proven composite by condition 2. |- | colspan="1" rowspan="1" |25 | colspan="1" rowspan="1" |105 | colspan="1" rowspan="1" |2, 13 | colspan="1" rowspan="1" |All k = m^2 for all n; factors to: (m*5^n - 1) * (m*5^n + 1) | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |86 (1029) 58 (26) 72 (24) 67 (24) 79 (21) 37 (17) 38 (14) 92 (13) 57 (10) 98 (9) | colspan="1" rowspan="1" |k = 1, 4, 9, 16, 25, 36, 49, 64, 81, and 100 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |26 | colspan="1" rowspan="1" |149 | colspan="1" rowspan="1" |3, 7, 31, 37 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000894500022 primality certificate for k=121]) | colspan="1" rowspan="1" |115 (520277) 32 (9812) 121 (1509) 73 (537) 80 (382) 128 (300) 124 (249) 37 (233) 25 (133) 65 (100) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |27 | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |2, 7 | colspan="1" rowspan="1" |All k = m^3 for all n; factors to: (m*3^n - 1) * (m^2*9^n + m*3^n + 1) | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |9 (23) 11 (10) 12 (2) 7 (2) 6 (2) 3 (2) 10 (1) 5 (1) 4 (1) 2 (1) | colspan="1" rowspan="1" |k = 1 and 8 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |28 | colspan="1" rowspan="1" |3769 | colspan="1" rowspan="1" |5, 29, 157 | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 12 or 17 mod 29: for even n let k = m^2 and let n = 2*q; factors to: (m*28^q - 1) * (m*28^q + 1) odd n: factor of 29 (Condition 2): All k where k = 7*m^2 and m = = 5 or 24 mod 29: even n: factor of 29 for odd n let k = 7*m^2 and let n=2*q-1; factors to: [m*2^(2q-1)*7^q - 1] * [m*2^(2q-1)*7^q + 1] | colspan="1" rowspan="1" |233, 376, 943, 1132, 1422, 2437 (k = 233 and 1422 at n=1M, other k at n=20.3K) | colspan="1" rowspan="1" |2319 (65184) 3232 (9147) 3019 (7073) 460 (5400) 1688 (4760) 2406 (4634) 2464 (4324) 849 (3129) 1507 (2938) 472 (2414) | colspan="1" rowspan="1" |k = 144, 289, 1681, and 2116 proven composite by condition 1. k = 175 proven composite by condition 2. |- | colspan="1" rowspan="1" |29 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (136) 1 (5) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |30 | colspan="1" rowspan="1" |4928 | colspan="1" rowspan="1" |13, 19, 31, 67 | colspan="1" rowspan="1" |k = 1369: for even n let n=2*q; factors to: (37*30^q - 1) * (37*30^q + 1) odd n: covering set 7, 13, 19 | colspan="1" rowspan="1" |659, 1024, 1580, 1936, 2293, 2916, 3719, 4372, 4897 (all at n=500K) | colspan="1" rowspan="1" |1642 (346592) 239 (337990) 2538 (262614) 249 (199355) 3256 (160619) 225 (158755) 774 (148344) 1873 (50427) 3253 (43291) 1654 (38869) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |31 | colspan="1" rowspan="1" |145 | colspan="1" rowspan="1" |2, 3, 7, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |5, 19, 51, 73, 97 (all at n=6K) | colspan="1" rowspan="1" |123 (1872) 124 (1116) 113 (643) 49 (637) 115 (464) 21 (275) 39 (250) 70 (149) 142 (140) 33 (107) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |32 | colspan="1" rowspan="1" |10 | colspan="1" rowspan="1" |3, 11 | colspan="1" rowspan="1" |All k = m^5 for all n; factors to: (m*2^n - 1) * (m^4*16^n + m^3*8^n + m^2*4^n + m*2^n + 1) | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |3 (11) 2 (6) 9 (3) 8 (2) 5 (2) 7 (1) 6 (1) 4 (1) | colspan="1" rowspan="1" |k = 1 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |33 | colspan="1" rowspan="1" |545 | colspan="1" rowspan="1" |2, 17 | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 4 or 13 mod 17: for even n let k = m^2 and let n = 2*q; factors to: (m*33^q - 1) * (m*33^q + 1) odd n: factor of 17 (Condition 2): All k where k = 33*m^2 and m = = 4 or 13 mod 17: [Reverse condition 1] (Condition 3): All k where k = m^2 and m = = 15 or 17 mod 32: for even n let k = m^2 and let n = 2*q; factors to: (m*33^q - 1) * (m*33^q + 1) odd n: factor of 2 | colspan="1" rowspan="1" |257, 339 (both at n=12K) | colspan="1" rowspan="1" |186 (16770) 254 (3112) 142 (2568) 370 (1628) 272 (1418) 222 (919) 108 (360) 213 (233) 387 (191) 277 (187) | colspan="1" rowspan="1" |k = 16, 169, and 441 proven composite by condition 1. k = 528 proven composite by condition 2. k = 225 and 289 proven composite by condition 3. |- | colspan="1" rowspan="1" |34 | colspan="1" rowspan="1" |6 | colspan="1" rowspan="1" |5, 7 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*34^q - 1) * (m*34^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (13) 5 (2) 3 (1) 2 (1) | colspan="1" rowspan="1" |k = 4 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |35 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (for the k=1 prime, factor N-1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=35&Exp=312&c0=-&EN= 35^312-1]) | colspan="1" rowspan="1" |1 (313) 3 (6) 2 (6) 4 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |36 | colspan="1" rowspan="1" |33791 | colspan="1" rowspan="1" |13, 31, 43, 97 | colspan="1" rowspan="1" |All k = m^2 for all n; factors to: (m*6^n - 1) * (m*6^n + 1) | colspan="1" rowspan="1" |1148, 1555, 2110, 2133, 3699, 4551, 4737, 6236, 6883, 7253, 7362, 7399, 7991, 8250, 8361, 8363, 8472, 9491, 9582, 11014, 12320, 12653, 13641, 14358, 14540, 14836, 14973, 14974, 15228, 15687, 15756, 15909, 16168, 17354, 17502, 17946, 18203, 19035, 19646, 20092, 20186, 20630, 21880, 22164, 22312, 23213, 23901, 23906, 24236, 24382, 24645, 24731, 24887, 25011, 25159, 25161, 25204, 25679, 25788, 26160, 26355, 27161, 29453, 29847, 30970, 31005, 31634, 32302, 33047, 33627 (all at n=10K) | colspan="1" rowspan="1" |13800 (9790) 20485 (9140) 19389 (9119) 20684 (8627) 19907 (8439) 11216 (7524) 28416 (7315) 32380 (7190) 27296 (7115) 10695 (6672) | colspan="1" rowspan="1" |k = 1^2, 2^2, 3^2, 4^2, 5^2, 6^2, 7^2, 8^2, 9^2, 10^2, 11^2, 12^2, 13^2, 14^2, 15^2, 16^2, etc. proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |37 | colspan="1" rowspan="1" |29 | colspan="1" rowspan="1" |2, 5, 7, 13, 67 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (for the k=5 prime, factor N-1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=37&Exp=900&c0=-&EN= 37^900-1]) | colspan="1" rowspan="1" |5 (900) 19 (63) 18 (14) 1 (13) 8 (4) 25 (3) 23 (3) 14 (3) 6 (3) 4 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |38 | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |3, 5, 17 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |11 (766) 9 (43) 7 (7) 1 (3) 12 (2) 8 (2) 5 (2) 2 (2) 10 (1) 6 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |39 | colspan="1" rowspan="1" |9 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*39^q - 1) * (m*39^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven (for the k=1 prime, factor N-1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=39&Exp=348&c0=-&EN= 39^348-1]) | colspan="1" rowspan="1" |1 (349) 7 (2) 3 (2) 2 (2) 8 (1) 6 (1) 5 (1) | colspan="1" rowspan="1" |k = 4 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |40 | colspan="1" rowspan="1" |25462 | colspan="1" rowspan="1" |3, 7, 41, 223 | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 9 or 32 mod 41: for even n let k = m^2 and let n = 2*q; factors to: (m*40^q - 1) * (m*40^q + 1) odd n: factor of 41 (Condition 2): All k where k = 10*m^2 and m = = 18 or 23 mod 41: even n: factor of 41 for odd n let k = 10*m^2 and let n=2*q-1; factors to: [m*2^(3q-1)*5^q - 1] * [m*2^(3q-1)*5^q + 1] | colspan="1" rowspan="1" |157, 534, 618, 709, 739, 787, 862, 1067, 1114, 1174, 1559, 1805, 2254, 2887, 3418, 3650, 4006, 4582, 4673, 4771, 6107, 6463, 6682, 6684, 6946, 7094, 7258, 7282, 7381, 7504, 7702, 7795, 8035, 8461, 8572, 9226, 9347, 9472, 9716, 9748, 9964, 10285, 10615, 10744, 11030, 11470, 11479, 11560, 11847, 12178, 12193, 12250, 12299, 12301, 12568, 12742, 13005, 13022, 13039, 13191, 13624, 13666, 13777, 13939, 14146, 14262, 14494, 15374, 15417, 15496, 15661, 15730, 16579, 16705, 16891, 16932, 17014, 17275, 17344, 17923, 17998, 18949, 19117, 19310, 19606, 19722, 19761, 19825, 19927, 20158, 20212, 20428, 20458, 20583, 20788, 21276, 21321, 21493, 21817, 21895, 22262, 22303, 22344, 22879, 23371, 24268, 24337, 24979 (all at n=5K) | colspan="1" rowspan="1" |20479 (4917) 17536 (4845) 13165 (4713) 14980 (4579) 19751 (4554) 20747 (4471) 19780 (4400) 11971 (4360) 24421 (4047) 21731 (3999) | colspan="1" rowspan="1" |k = 81, 1024, 2500, 5329, 8281, 12996, 17424, and 24025 proven composite by condition 1. k = 3240 and 5290 proven composite by condition 2. |- | colspan="1" rowspan="1" |41 | colspan="1" rowspan="1" |8 | colspan="1" rowspan="1" |3, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |7 (153) 5 (10) 1 (3) 6 (2) 2 (2) 4 (1) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |42 | colspan="1" rowspan="1" |15137 | colspan="1" rowspan="1" |5, 43, 353 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |603, 1049, 1600, 2538, 4299, 4903, 5118, 5978, 6836, 6964, 6971, 7309, 8297, 8341, 9029, 9201, 9633, 9848, 11267, 11781, 11911, 11996, 12125, 12127, 12213, 12598, 13288, 13347, 14884 (k = 1600, 6971 and 14884 at n=8K, other k at n=200K) | colspan="1" rowspan="1" |7051 (188034) 5417 (179220) 13898 (152983) 1633 (128734) 13757 (126934) 7913 (108747) 15024 (104613) 8453 (89184) 7658 (79316) 10923 (61071) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |43 | colspan="1" rowspan="1" |21 | colspan="1" rowspan="1" |2, 11 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |13 (50K) | colspan="1" rowspan="1" |4 (279) 12 (203) 17 (79) 3 (24) 1 (5) 19 (4) 15 (4) 7 (4) 11 (2) 10 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |44 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (5) 2 (4) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |45 | colspan="1" rowspan="1" |93 | colspan="1" rowspan="1" |2, 23 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000920998225 primality certificate for k=53]) | colspan="1" rowspan="1" |24 (153355) 53 (582) 70 (167) 29 (146) 76 (102) 85 (82) 91 (50) 77 (26) 1 (19) 33 (11) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |46 | colspan="1" rowspan="1" |928 | colspan="1" rowspan="1" |3, 7, 103 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |281, 436, 800 (k = 800 at n=500K, other k at n=28K) | colspan="1" rowspan="1" |870 (51699) 86 (26325) 93 (24162) 561 (5011) 576 (3659) 100 (2955) 386 (2425) 338 (1478) 597 (950) 121 (935) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |47 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |4 (1555) 1 (127) 2 (4) 3 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |48 | colspan="1" rowspan="1" |3226 | colspan="1" rowspan="1" |5, 7, 461 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |313, 384, 708, 909, 916, 1093, 1457, 1686, 1877, 1896, 1898, 2071, 2148, 2172, 2402, 2589, 2682, 2927, 2939, 3044, 3067 (all at n=200K) | colspan="1" rowspan="1" |2157 (169491) 2549 (169453) 1478 (167541) 2822 (129611) 2379 (116204) 118 (107422) 692 (103056) 1842 (87175) 953 (81493) 2582 (75696) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |49 | colspan="1" rowspan="1" |81 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" |All k = m^2 for all n; factors to: (m*7^n - 1) * (m*7^n + 1) | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000854476434 primality certificate for k=79]) | colspan="1" rowspan="1" |79 (212) 44 (122) 69 (42) 30 (24) 59 (16) 53 (15) 70 (14) 24 (14) 31 (9) 74 (6) | colspan="1" rowspan="1" |k = 1, 4, 9, 16, 25, 36, 49, and 64 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |50 | colspan="1" rowspan="1" |16 | colspan="1" rowspan="1" |3, 17 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |14 (66) 13 (19) 5 (12) 11 (6) 6 (6) 1 (3) 8 (2) 2 (2) 15 (1) 12 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |51 | colspan="1" rowspan="1" |25 | colspan="1" rowspan="1" |2, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000467236538 primality certificate for k=1]) | colspan="1" rowspan="1" |1 (4229) 23 (96) 3 (8) 12 (4) 14 (3) 4 (3) 22 (2) 19 (2) 18 (2) 15 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |52 | colspan="1" rowspan="1" |25015 | colspan="1" rowspan="1" |3, 7, 53, 379 | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 23 or 30 mod 53: for even n let k = m^2 and let n = 2*q; factors to: (m*52^q - 1) * (m*52^q + 1) odd n: factor of 53 (Condition 2): All k where k = 13*m^2 and m = = 7 or 46 mod 53: even n: factor of 53 for odd n let k = 13*m^2 and let n=2*q-1; factors to: [m*2^(2q-1)*13^q - 1] * [m*2^(2q-1)*13^q + 1] | colspan="1" rowspan="1" |82, 349, 372, 476, 478, 657, 796, 902, 1167, 1234, 1271, 1534, 1589, 1651, 1669, 1801, 1881, 1909, 2035, 2113, 2364, 2437, 2492, 2557, 2643, 2722, 2725, 2769, 3022, 3128, 3199, 3229, 3418, 3559, 3607, 3656, 3764, 3788, 3847, 3870, 4043, 4117, 4239, 4294, 4329, 4366, 4597, 4665, 4754, 4975, 4981, 5037, 5107, 5142, 5158, 5246, 5541, 5575, 5672, 5836, 5882, 6193, 6256, 6308, 6394, 6442, 6493, 6568, 6697, 6835, 6873, 6962, 6981, 6997, 7386, 7399, 7594, 7633, 8163, 8389, 8422, 8488, 8587, 8693, 8744, 8932, 8958, 9055, 9148, 9187, 9223, 9382, 9421, 9624, 9647, 9667, 9682, 9753, 9769, 9799, 9802, 9907, 9967, 10069, 10129, 10173, 10243, 10429, 10462, 10546, 10919, 10996, 11161, 11164, 11299, 11355, 11371, 11394, 11401, 11500, 11767, 11826, 11827, 11854, 12064, 12133, 12304, 12352, 12401, 12423, 12454, 12668, 12688, 12719, 12827, 12931, 13045, 13196, 13198, 13264, 13306, 13357, 13551, 13687, 14309, 14453, 14584, 14647, 14682, 14698, 14786, 14833, 14968, 15010, 15109, 15212, 15265, 15316, 15370, 15574, 15688, 15928, 15937, 16007, 16039, 16087, 16111, 16216, 16293, 16308, 16729, 16748, 16884, 16906, 17197, 17224, 17277, 17311, 17423, 17438, 17734, 17754, 17882, 17989, 18604, 18670, 18757, 18761, 18787, 18871, 18883, 18899, 19026, 19028, 19079, 19102, 19163, 19363, 19556, 19609, 19678, 19821, 19876, 19982, 20088, 20139, 20395, 20616, 20821, 20881, 20883, 20983, 21016, 21148, 21151, 21316, 21413, 21464, 21526, 21537, 21757, 21784, 21796, 21804, 21859, 21866, 21898, 22096, 22146, 22180, 22308, 22312, 22383, 22447, 22471, 22643, 22723, 22738, 22771, 22789, 23215, 23268, 23344, 23377, 23427, 23518, 23531, 23533, 23584, 23692, 23773, 24331, 24403, 24557, 24591, 24911 (all at n=5K) | colspan="1" rowspan="1" |24244 (4987) 24503 (4983) 1357 (4981) 607 (4949) 7603 (4924) 14998 (4896) 14179 (4797) 6434 (4793) 21572 (4673) 5236 (4447) | colspan="1" rowspan="1" |k = 529, 900, 5776, 6889, 16641, and 18496 proven composite by condition 1. k = 637 proven composite by condition 2. |- | colspan="1" rowspan="1" |53 | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |12 (71) 10 (71) 2 (44) 7 (11) 1 (11) 8 (8) 11 (6) 9 (3) 5 (2) 6 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |54 | colspan="1" rowspan="1" |21 | colspan="1" rowspan="1" |5, 11 | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*54^q - 1) * (m*54^q + 1) odd n: factor of 5 (Condition 2): All k where k = 6*m^2 and m = = 1 or 4 mod 5: even n: factor of 5 for odd n let k = 6*m^2 and let n=2*q-1; factors to: [m*2^q*3^(3q-1) - 1] * [m*2^q*3^(3q-1) + 1] | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |20 (8) 19 (6) 10 (4) 17 (3) 1 (3) 14 (2) 7 (2) 3 (2) 18 (1) 16 (1) | colspan="1" rowspan="1" |k = 4 and 9 proven composite by condition 1. k = 6 proven composite by condition 2. |- | colspan="1" rowspan="1" |55 | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |2, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |3 (76) 1 (17) 11 (8) 9 (3) 7 (2) 6 (2) 12 (1) 10 (1) 8 (1) 5 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |56 | colspan="1" rowspan="1" |20 | colspan="1" rowspan="1" |3, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |14 (26) 10 (23) 1 (7) 18 (4) 17 (4) 7 (3) 11 (2) 8 (2) 5 (2) 2 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |57 | colspan="1" rowspan="1" |144 | colspan="1" rowspan="1" |5, 13, 29 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 3 or 5 mod 8: for even n let k = m^2 and let n = 2*q; factors to: (m*57^q - 1) * (m*57^q + 1) odd n: factor of 2 | colspan="1" rowspan="1" |none - proven (the k=87 prime is proven prime by N-1, and [http://factordb.com/cert.php?id=1100000000920998157 primality certificate for the large prime factor of N-1]) | colspan="1" rowspan="1" |87 (242) 54 (157) 100 (109) 59 (83) 115 (34) 124 (31) 88 (27) 63 (22) 139 (20) 38 (20) | colspan="1" rowspan="1" |k = 9, 25, and 121 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |58 | colspan="1" rowspan="1" |547 | colspan="1" rowspan="1" |3, 7, 163 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |71, 130, 169, 178, 319, 456, 493, 499 (k = 71 and 456 at n=100K, other k at n=14K) | colspan="1" rowspan="1" |382 (7188) 400 (5245) 421 (4526) 176 (2854) 473 (1641) 487 (1412) 312 (1079) 334 (724) 53 (645) 457 (492) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |59 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |3 (8) 1 (3) 2 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |60 | colspan="1" rowspan="1" |20558 | colspan="1" rowspan="1" |13, 61, 277 | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 11 or 50 mod 61: for even n let k = m^2 and let n = 2*q; factors to: (m*60^q - 1) * (m*60^q + 1) odd n: factor of 61 (Condition 2): All k where k = 15*m^2 and m = = 22 or 39 mod 61: even n: factor of 61 for odd n let k = 15*m^2 and let n=2*q-1; factors to: [m*2^(2q-1)*15^q - 1] * [m*2^(2q-1)*15^q + 1] | colspan="1" rowspan="1" |36, 1770, 4708, 5317, 5611, 6101, 6162, 6274, 7060, 7870, 8722, 9212, 9454, 9881, 10249, 11101, 12061, 12072, 12098, 12479, 12996, 13297, 13480, 14275, 14851, 15800, 16167, 17185, 17620, 18055, 18965, 18972, 19336, 19394, 19397 (k = 16167 and 18055 at n=8K, other k at n=100K) | colspan="1" rowspan="1" |1024 (90701) 12121 (84208) 15227 (80625) 15185 (79350) 8649 (79159) 20131 (71977) 19457 (68854) 16333 (61172) 18776 (60164) 1486 (58932) | colspan="1" rowspan="1" |k = 121, 2500, 5184, 14641, and 17689 proven composite by condition 1. k = 7260 proven composite by condition 2. |- | colspan="1" rowspan="1" |61 | colspan="1" rowspan="1" |125 | colspan="1" rowspan="1" |2, 31 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |37, 53, 100 (all at n=10K) | colspan="1" rowspan="1" |13 (4134) 77 (3080) 10 (1552) 41 (755) 42 (174) 22 (117) 57 (89) 109 (86) 103 (78) 93 (60) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |62 | colspan="1" rowspan="1" |8 | colspan="1" rowspan="1" |3, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |3 (59) 4 (9) 1 (3) 6 (2) 5 (2) 2 (2) 7 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |63 | colspan="1" rowspan="1" |857 | colspan="1" rowspan="1" |2, 5, 397 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |93, 129, 139, 211, 231, 237, 251, 281, 291, 333, 417, 457, 471, 473, 491, 493, 497, 513, 587, 599, 633, 669, 677, 679, 691, 733, 771, 817, 819, 831 (all at n=2K) | colspan="1" rowspan="1" |65 (1883) 853 (1849) 37 (1615) 64 (1483) 177 (1423) 372 (1320) 821 (1225) 687 (1154) 695 (1144) 271 (1058) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |64 | colspan="1" rowspan="1" |14 | colspan="1" rowspan="1" |5, 13 | colspan="1" rowspan="1" |All k = m^2 for all n; factors to: (m*8^n - 1) * (m*8^n + 1) -or- All k = m^3 for all n; factors to: (m*4^n - 1) * (m^2*16^n + m*4^n + 1) | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |11 (9) 12 (6) 5 (2) 13 (1) 10 (1) 7 (1) 6 (1) 3 (1) 2 (1) | colspan="1" rowspan="1" |k = 1, 4, 8, and 9 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |65 | colspan="1" rowspan="1" |10 | colspan="1" rowspan="1" |3, 11 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (19) 8 (10) 4 (9) 2 (4) 5 (2) 9 (1) 7 (1) 6 (1) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |66 | colspan="1" rowspan="1" |63717671 | colspan="1" rowspan="1" |7, 67, 613, 4423 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |681, 1056, 1205, 1575, 1669, 1944, 2182, 2916, 2949, 3014, 3083, 3148, 3221, 3526, 3684, 3911, 3946, 4423, 5329, 5361, 5897, 5898, 5959, 5972, 6096, 6189, 6263, 6451, 6768, 6796, 7168, 7237, 7357, 7572, 7614, 7927, 8156, 8173, 8348, 8432, 8510, 8825, 8866, 9017, 9111, 9406, 9409, 9781, 9801, 9906, 9998 (for k <= 10K) (all at n=1K) | colspan="1" rowspan="1" |7578 (988) 1252 (956) 2746 (918) 5248 (916) 5476 (873) 5929 (795) 6699 (790) 8843 (780) 5435 (762) 2946 (748) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |67 | colspan="1" rowspan="1" |33 | colspan="1" rowspan="1" |2, 17 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 4 or 13 mod 17: for even n let k = m^2 and let n = 2*q; factors to: (m*67^q - 1) * (m*67^q + 1) odd n: factor of 17 | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000001053748910 primality certificate for k=25]) | colspan="1" rowspan="1" |25 (2829) 2 (768) 23 (42) 21 (27) 1 (19) 31 (10) 19 (8) 18 (7) 13 (7) 11 (6) | colspan="1" rowspan="1" |k = 16 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |68 | colspan="1" rowspan="1" |22 | colspan="1" rowspan="1" |3, 23 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |7 (25395) 5 (13574) 11 (198) 8 (62) 10 (53) 3 (10) 1 (5) 14 (4) 2 (4) 9 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |69 | colspan="1" rowspan="1" |6 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*69^q - 1) * (m*69^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |5 (4) 1 (3) 3 (1) 2 (1) | colspan="1" rowspan="1" |k = 4 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |70 | colspan="1" rowspan="1" |853 | colspan="1" rowspan="1" |13, 29, 71 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |811 (50K) | colspan="1" rowspan="1" |729 (28625) 376 (6484) 496 (4934) 434 (3820) 489 (2096) 278 (1320) 550 (764) 31 (545) 174 (441) 778 (356) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |71 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (52) 1 (3) 3 (2) 4 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |72 | colspan="1" rowspan="1" |293 | colspan="1" rowspan="1" |5, 17, 73 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |4 (1119849) 79 (28009) 291 (26322) 116 (13887) 118 (4599) 67 (4308) 197 (3256) 24 (2648) 11 (2445) 18 (1494) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |73 | colspan="1" rowspan="1" |112 | colspan="1" rowspan="1" |5, 13, 37 | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 6 or 31 mod 37: for even n let k = m^2 and let n = 2*q; factors to: (m*73^q - 1) * (m*73^q + 1) odd n: factor of 37 (Condition 2): All k where k = m^2 and m = = 3 or 5 mod 8: for even n let k = m^2 and let n = 2*q; factors to: (m*73^q - 1) * (m*73^q + 1) odd n: factor of 2 | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000001540581020 primality certificate for k=79], [http://factordb.com/cert.php?id=1100000001540189005 primality certificate for k=101]) | colspan="1" rowspan="1" |79 (9339) 101 (2146) 105 (102) 48 (73) 54 (63) 42 (50) 26 (50) 97 (47) 61 (39) 89 (32) | colspan="1" rowspan="1" |k = 36 proven composite by condition 1. k = 9 and 25 proven composite by condition 2. |- | colspan="1" rowspan="1" |74 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (132) 1 (5) 3 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |75 | colspan="1" rowspan="1" |37 | colspan="1" rowspan="1" |2, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000936512973 primality certificate for k=35]) | colspan="1" rowspan="1" |35 (1844) 16 (119) 18 (54) 30 (41) 3 (16) 22 (15) 5 (9) 17 (5) 4 (5) 23 (4) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |76 | colspan="1" rowspan="1" |34 | colspan="1" rowspan="1" |7, 11 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (41) 27 (40) 20 (22) 25 (11) 15 (11) 30 (7) 21 (4) 19 (4) 13 (4) 10 (4) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |77 | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (14) 1 (3) 12 (2) 11 (2) 8 (2) 5 (2) 3 (2) 10 (1) 9 (1) 7 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |78 | colspan="1" rowspan="1" |90059 | colspan="1" rowspan="1" |5, 79, 1217 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |274, 302, 631, 1816, 2292, 2381, 3872, 3949, 4344, 4383, 4489, 4937, 5057, 5766, 5782, 6077, 6436, 7032, 7800, 8469, 8499, 8649, 8758, 10263, 10924, 10928, 10942, 11044, 11936, 12167, 12187, 12244, 12286, 12332, 12622, 13212, 13287, 13668, 13824, 14059, 14456, 14526, 14932, 15722, 15799, 16451, 16688, 17029, 17039, 17221, 17271, 17732, 17886, 18013, 18663, 19614, 19846, 19909, 19986, 20027, 20182, 20462, 20879, 21197, 21631, 21961, 23052, 23079, 23801, 23899, 24214, 24949, 25061, 25532, 25901, 26377, 26385, 26804, 27021, 27096, 27175, 27256, 27399, 27439, 27842, 29073, 29389, 29668, 29863, 30444, 31046, 31053, 31742, 31836, 31917, 31994, 32705, 33298, 33412, 33671, 33888, 33892, 34728, 35179, 35568, 36233, 36344, 36609, 37024, 38354, 38438, 38711, 38886, 39173, 39901, 40131, 40239, 40289, 40437, 40998, 41079, 41316, 41711, 41748, 42106, 42337, 42896, 43331, 43842, 43886, 44038, 44374, 44634, 44871, 45214, 45221, 45466, 46012, 46187, 46593, 46922, 47004, 47562, 47573, 47636, 47657, 47986, 48004, 48112, 48371, 48973, 48979, 49386, 49611, 49988, 51430, 52042, 52929, 53719, 53761, 54188, 54936, 55245, 55491, 55617, 56563, 56721, 56757, 56904, 57234, 57317, 57611, 57786, 57842, 58402, 58455, 58696, 58854, 59093, 59536, 59774, 60187, 60919, 60978, 61762, 61783, 61937, 62481, 62646, 62854, 63043, 63281, 63351, 64309, 64384, 64744, 65157, 65814, 65885, 66102, 66249, 66991, 67386, 67588, 67593, 67706, 67880, 68027, 68573, 68804, 69630, 69914, 71254, 71338, 72003, 72916, 72997, 73706, 73708, 73734, 73787, 74757, 74823, 75307, 75482, 75857, 75888, 76056, 76392, 76781, 77057, 77594, 78135, 78604, 78835, 78959, 79630, 79633, 79674, 80421, 80725, 80788, 80976, 81208, 81369, 83186, 83739, 84484, 85218, 85506, 85886, 86137, 86164, 86329, 86353, 86446, 86692, 88718, 88817, 88866, 89314, 89538, 89664, 89846 (k = 1 mod 7 and k = 1 mod 11 at n=1K, other k at n=100K) | colspan="1" rowspan="1" |3633 (94500) 68571 (91386) 51476 (88677) 78053 (84433) 58412 (83824) 45661 (73022) 11412 (72798) 72638 (70230) 23462 (69162) 23543 (62677) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |79 | colspan="1" rowspan="1" |9 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*79^q - 1) * (m*79^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (5) 7 (4) 3 (4) 6 (3) 8 (1) 5 (1) 2 (1) | colspan="1" rowspan="1" |k = 4 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |80 | colspan="1" rowspan="1" |253 | colspan="1" rowspan="1" |3, 37, 173 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |10, 31, 214 (all at n=400K) | colspan="1" rowspan="1" |170 (148256) 106 (16237) 154 (9753) 46 (5337) 232 (2997) 157 (2613) 169 (1959) 45 (1156) 218 (776) 244 (653) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |81 | colspan="1" rowspan="1" |74 | colspan="1" rowspan="1" |7, 13, 73 | colspan="1" rowspan="1" |All k = m^2 for all n; factors to: (m*9^n - 1) * (m*9^n + 1) | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000934847239 primality certificate for k=53]) | colspan="1" rowspan="1" |53 (268) 42 (99) 23 (68) 18 (15) 35 (14) 30 (12) 71 (4) 60 (4) 40 (4) 24 (4) | colspan="1" rowspan="1" |k = 1, 4, 9, 16, 25, 36, 49, and 64 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |82 | colspan="1" rowspan="1" |22326 | colspan="1" rowspan="1" |5, 83, 269 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |118, 133, 290, 331, 334, 439, 625, 649, 667, 748, 757, 763, 829, 878, 883, 898, 997, 1163, 1252, 1279, 1327, 1348, 1351, 1531, 1741, 1827, 1936, 1991, 2050, 2157, 2263, 2278, 2419, 2431, 2539, 2543, 2588, 2635, 2668, 2797, 2836, 2896, 2929, 2971, 2974, 3079, 3121, 3156, 3293, 3319, 3436, 3653, 3796, 3817, 4068, 4078, 4083, 4118, 4372, 4399, 4447, 4481, 4483, 4780, 4801, 4867, 4898, 4972, 5053, 5182, 5230, 5311, 5329, 5401, 5560, 5562, 5713, 5893, 5899, 5975, 6028, 6122, 6124, 6143, 6178, 6186, 6226, 6296, 6343, 6418, 6427, 6571, 6631, 6925, 6994, 7054, 7056, 7303, 7386, 7388, 7396, 7474, 7615, 7723, 7801, 7813, 7822, 7884, 7892, 7969, 8065, 8314, 8368, 8384, 8499, 8629, 8761, 8830, 8878, 8891, 8941, 9124, 9166, 9304, 9409, 9461, 9712, 9739, 9967, 9988, 10000, 10036, 10075, 10147, 10162, 10448, 10542, 10891, 10957, 11056, 11086, 11119, 11123, 11271, 11372, 11485, 11533, 11553, 11665, 11728, 11827, 11884, 11929, 12079, 12169, 12202, 12211, 12283, 12547, 12562, 12587, 12791, 13126, 13141, 13358, 13531, 13613, 13768, 13779, 13792, 13862, 13891, 14095, 14109, 14161, 14188, 14242, 14257, 14275, 14349, 14441, 14524, 14531, 14563, 14614, 14687, 14855, 14939, 14941, 14986, 15046, 15136, 15271, 15343, 15349, 15403, 15493, 15508, 15634, 15679, 15682, 15852, 15997, 16024, 16103, 16131, 16242, 16312, 16534, 16633, 16753, 16756, 16767, 16954, 17011, 17401, 17512, 17518, 17761, 17803, 17833, 17878, 18058, 18061, 18431, 18448, 18514, 18538, 18550, 18757, 19093, 19237, 19309, 19372, 19414, 19444, 19519, 19672, 19678, 19930, 19946, 20002, 20050, 20113, 20218, 20251, 20413, 20491, 20578, 20581, 20708, 20773, 20980, 21052, 21088, 21215, 21282, 21334, 21382, 21398, 21433, 21449, 21453, 21454, 21466, 21514, 21541, 21631, 21683, 21762, 21862, 21871, 21913, 22012, 22132, 22162, 22243, 22245 (k = 1 mod 3 at n=1K, other k at n=100K) | colspan="1" rowspan="1" |15978 (99999) 21429 (96772) 18989 (96049) 17592 (83837) 22233 (75716) 12912 (74869) 5811 (72615) 16091 (65850) 18576 (64927) 4482 (63245) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |83 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (8) 1 (5) 3 (2) 4 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |84 | colspan="1" rowspan="1" |16 | colspan="1" rowspan="1" |5, 17 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*84^q - 1) * (m*84^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (17) 14 (8) 11 (7) 8 (4) 12 (3) 15 (1) 13 (1) 10 (1) 7 (1) 6 (1) | colspan="1" rowspan="1" |k = 4 and 9 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |85 | colspan="1" rowspan="1" |173 | colspan="1" rowspan="1" |2, 43 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |61 (8K) | colspan="1" rowspan="1" |169 (6939) 64 (1253) 105 (403) 112 (394) 97 (287) 109 (230) 16 (171) 27 (160) 93 (90) 145 (77) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |86 | colspan="1" rowspan="1" |28 | colspan="1" rowspan="1" |3, 29 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |23 (112) 14 (38) 18 (26) 27 (14) 1 (11) 2 (10) 25 (9) 11 (8) 22 (5) 19 (5) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |87 | colspan="1" rowspan="1" |21 | colspan="1" rowspan="1" |2, 11 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000936225868 primality certificate for k=19]) | colspan="1" rowspan="1" |19 (372) 9 (91) 16 (17) 18 (15) 5 (15) 13 (11) 11 (10) 1 (7) 7 (6) 12 (5) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |88 | colspan="1" rowspan="1" |571 | colspan="1" rowspan="1" |3, 7, 13, 19 | colspan="1" rowspan="1" |k = 400: for even n let n=2*q; factors to: (20*88^q - 1) * (20*88^q + 1) odd n: covering set 3, 7, 13 | colspan="1" rowspan="1" |46, 94, 277, 508 (all at n=10K) | colspan="1" rowspan="1" |464 (20648) 444 (19708) 544 (8904) 380 (8712) 79 (7665) 477 (5816) 212 (5511) 179 (4545) 346 (2969) 68 (2477) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |89 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (60) 3 (5) 1 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |90 | colspan="1" rowspan="1" |27 | colspan="1" rowspan="1" |7, 13 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 5 or 8 mod 13: for even n let k = m^2 and let n = 2*q; factors to: (m*90^q - 1) * (m*90^q + 1) odd n: factor of 13 | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |6 (20) 11 (10) 10 (10) 13 (6) 15 (5) 12 (4) 7 (4) 24 (3) 1 (3) 20 (2) | colspan="1" rowspan="1" |k = 25 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |91 | colspan="1" rowspan="1" |45 | colspan="1" rowspan="1" |2, 23 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000001053779130 primality certificate for k=27], [http://factordb.com/cert.php?id=1100000000651917018 primality certificate for k=1], [http://factordb.com/cert.php?id=1100000000936225921 primality certificate for k=37]) | colspan="1" rowspan="1" |27 (5048) 1 (4421) 37 (159) 15 (14) 43 (6) 39 (6) 31 (6) 24 (5) 20 (4) 36 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |92 | colspan="1" rowspan="1" |32 | colspan="1" rowspan="1" |3, 31 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (for the k=1 prime, factor N-1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=92&Exp=438&c0=-&EN= 92^438-1]) ([http://factordb.com/cert.php?id=1100000000936225965 primality certificate for k=29]) | colspan="1" rowspan="1" |1 (439) 29 (272) 28 (99) 13 (35) 14 (32) 18 (26) 22 (25) 20 (6) 6 (6) 17 (4) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |93 | colspan="1" rowspan="1" |189 | colspan="1" rowspan="1" |2, 47 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |33, 69, 109, 113, 125, 149, 177 (all at n=8K) | colspan="1" rowspan="1" |97 (1179) 29 (496) 92 (476) 46 (434) 121 (271) 141 (262) 101 (142) 122 (126) 85 (86) 166 (66) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |94 | colspan="1" rowspan="1" |39 | colspan="1" rowspan="1" |5, 19 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*94^q - 1) * (m*94^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |29 (1M) | colspan="1" rowspan="1" |16 (21951) 37 (254) 13 (163) 14 (154) 7 (95) 34 (54) 25 (41) 24 (12) 26 (9) 36 (7) | colspan="1" rowspan="1" |k = 4 and 9 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |95 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (7) 3 (2) 2 (2) 4 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |96 | colspan="1" rowspan="1" |38995 | colspan="1" rowspan="1" |7, 67, 97, 1303 | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 22 or 75 mod 97: for even n let k = m^2 and let n = 2*q; factors to: (m*96^q - 1) * (m*96^q + 1) odd n: factor of 97 (Condition 2): All k where k = 6*m^2 and m = = 9 or 88 mod 97: even n: factor of 97 for odd n let k = 6*m^2 and let n=2*q-1; factors to: [m*2^(5q-1)*3^q - 1] * [m*2^(5q-1)*3^q + 1] | colspan="1" rowspan="1" |431, 591, 701, 831, 872, 956, 1006, 1126, 1648, 1681, 1810, 2036, 2386, 2424, 2878, 3001, 3431, 3461, 3671, 3856, 3881, 3956, 3996, 4261, 4351, 4366, 4406, 4451, 4461, 5046, 5836, 5918, 6031, 6261, 6481, 6586, 6670, 6786, 7091, 7116, 7121, 7131, 7249, 7274, 7461, 7801, 8016, 8202, 8291, 8546, 8816, 9022, 9131, 9156, 9326, 9441, 9463, 9476, 9677, 9681, 9921, 10036, 10204, 10375, 10453, 10551, 10651, 10721, 11056, 11156, 11196, 11458, 11553, 11766, 11831, 12676, 12901, 13216, 13231, 13288, 13571, 14011, 14061, 14276, 14517, 14551, 14646, 15341, 15461, 15573, 15596, 16176, 16306, 16392, 16586, 16641, 16645, 17116, 17421, 17636, 17653, 17792, 18311, 19136, 19191, 19246, 19486, 19681, 20091, 20396, 20464, 20502, 20936, 21488, 21776, 22541, 22811, 22846, 22931, 23010, 23161, 23271, 23301, 23570, 23766, 24076, 24216, 24386, 24506, 24831, 24916, 24929, 25306, 25706, 25966, 26038, 26161, 26183, 26571, 26772, 26801, 26846, 27045, 27106, 27126, 27450, 27646, 27700, 27741, 28365, 28558, 28774, 28776, 28921, 29093, 29196, 29561, 29681, 30086, 30120, 30151, 30421, 30581, 30662, 31021, 31136, 31936, 32205, 32881, 33099, 33141, 33391, 33406, 33501, 33621, 33701, 33711, 33951, 33986, 34116, 34236, 34436, 34531, 34921, 35016, 35113, 35271, 35406, 35446, 35781, 35966, 36158, 36551, 36945, 36981, 37031, 37036, 37166, 37222, 37471, 37991, 38156, 38301, 38316, 38986 (k = 1 mod 5 and k = 1 mod 19 at n=1K, other k at n=100K) | colspan="1" rowspan="1" |3769 (92879) 28907 (89447) 13528 (86114) 19882 (82073) 37155 (76817) 9160 (71178) 5179 (66965) 32960 (60312) 7565 (59052) 4754 (56909) | colspan="1" rowspan="1" |k = 484, 5625, 14161, and 29584 proven composite by condition 1. k = 486 proven composite by condition 2. |- | colspan="1" rowspan="1" |97 | colspan="1" rowspan="1" |43 | colspan="1" rowspan="1" |3, 5, 7, 37, 139 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |22 (35.8K) | colspan="1" rowspan="1" |8 (192335) 16 (1627) 4 (621) 28 (184) 1 (17) 34 (16) 32 (9) 27 (8) 37 (5) 31 (5) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |98 | colspan="1" rowspan="1" |10 | colspan="1" rowspan="1" |3, 11 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (13) 5 (10) 7 (3) 4 (3) 8 (2) 2 (2) 9 (1) 6 (1) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |99 | colspan="1" rowspan="1" |9 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*99^q - 1) * (m*99^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |5 (135) 3 (4) 1 (3) 7 (2) 8 (1) 6 (1) 2 (1) | colspan="1" rowspan="1" |k = 4 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |100 | colspan="1" rowspan="1" |211 | colspan="1" rowspan="1" |7, 13, 37 | colspan="1" rowspan="1" |All k = m^2 for all n; factors to: (m*10^n - 1) * (m*10^n + 1) | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000991061498 primality certificate for k=133]) | colspan="1" rowspan="1" |74 (44709) 133 (5496) 102 (209) 193 (155) 203 (133) 95 (96) 109 (68) 55 (56) 98 (45) 37 (36) | colspan="1" rowspan="1" |k = 1, 4, 9, 16, 25, 36, 49, 64, 81, 100, 121, 144, 169, and 196 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |101 | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (for the k=5 prime, factor N-1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=101&Exp=350&c0=-&EN= 101^350-1]) | colspan="1" rowspan="1" |5 (350) 8 (112) 2 (42) 11 (24) 12 (11) 4 (3) 1 (3) 6 (2) 10 (1) 9 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |102 | colspan="1" rowspan="1" |1635 | colspan="1" rowspan="1" |7, 19, 79 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |191, 207, 1082, 1369 (all at n=500K) | colspan="1" rowspan="1" |1451 (188973) 1208 (178632) 653 (117255) 1607 (82644) 254 (58908) 1527 (49462) 1037 (43460) 32 (43302) 1296 (37715) 142 (22025) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |103 | colspan="1" rowspan="1" |25 | colspan="1" rowspan="1" |2, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000936227095 primality certificate for k=19], [http://factordb.com/cert.php?id=1100000000936227106 primality certificate for k=22], [http://factordb.com/cert.php?id=1100000000936227128 primality certificate for k=23]) | colspan="1" rowspan="1" |19 (820) 22 (442) 23 (216) 14 (189) 16 (57) 11 (54) 24 (32) 15 (32) 1 (19) 20 (5) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |104 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (97) 2 (68) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |105 | colspan="1" rowspan="1" |297 | colspan="1" rowspan="1" |2, 37, 149 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 3 or 5 mod 8: for even n let k = m^2 and let n = 2*q; factors to: (m*57^q - 1) * (m*57^q + 1) odd n: factor of 2 | colspan="1" rowspan="1" |73, 137 (both at n=8K) | colspan="1" rowspan="1" |148 (3645) 265 (1666) 162 (294) 255 (222) 154 (139) 145 (119) 80 (91) 68 (56) 66 (47) 223 (21) | colspan="1" rowspan="1" |k = 9, 25, 121, and 169 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |106 | colspan="1" rowspan="1" |13624 | colspan="1" rowspan="1" |3, 19, 199 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |64, 81, 163, 332, 391, 400, 511, 526, 643, 676, 841, 862, 897, 1024, 1223, 1283, 1417, 1546, 1597, 1713, 1869, 2116, 2248, 2389, 2458, 2605, 2623, 2674, 2743, 2780, 2781, 2965, 3241, 3277, 3336, 3425, 3427, 3478, 3481, 3617, 3622, 3646, 3655, 3746, 3883, 4045, 4067, 4096, 4153, 4177, 4219, 4336, 4339, 4416, 4628, 4666, 4696, 4713, 4722, 5135, 5283, 5395, 5468, 5623, 5692, 5707, 5752, 5776, 5872, 5878, 5971, 5992, 6094, 6100, 6220, 6376, 6421, 6547, 6613, 6716, 6736, 6784, 6832, 6955, 7069, 7156, 7202, 7246, 7273, 7297, 7331, 7336, 7345, 7398, 7496, 7540, 7561, 7744, 7894, 7906, 8023, 8181, 8266, 8323, 8371, 8386, 8428, 8521, 8572, 8586, 8637, 8779, 8788, 8861, 8950, 8956, 8962, 8975, 9031, 9096, 9190, 9294, 9415, 9469, 9634, 9736, 9787, 9796, 9808, 9859, 9877, 9973, 10033, 10072, 10117, 10166, 10186, 10271, 10273, 10446, 10627, 10646, 10651, 10660, 10699, 10876, 10894, 11173, 11278, 11299, 11426, 11506, 11833, 11884, 11901, 12066, 12090, 12145, 12352, 12490, 12627, 12851, 12856, 12916, 12970, 12991, 13162, 13174, 13366, 13374, 13378, 13387, 13497, 13516, 13528, 13543 (all at n=2K) | colspan="1" rowspan="1" |913 (1991) 7771 (1952) 13023 (1951) 8561 (1927) 13567 (1850) 12361 (1830) 12910 (1817) 6181 (1800) 2719 (1769) 11639 (1746) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |107 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000987494791 primality certificate for k=3]) | colspan="1" rowspan="1" |2 (21910) 3 (4900) 4 (251) 1 (17) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |108 | colspan="1" rowspan="1" |13406 | colspan="1" rowspan="1" |7, 13, 61, 109 | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 33 or 76 mod 109: for even n let k = m^2 and let n = 2*q; factors to: (m*108^q - 1) * (m*108^q + 1) odd n: factor of 109 (Condition 2): All k where k = 3*m^2 and m = = 20 or 89 mod 109: even n: factor of 109 for odd n let k = 3*m^2 and let n=2*q-1; factors to: [m*2^(2q-1)*3^(3q-1) - 1] * [m*2^(2q-1)*3^(3q-1) + 1] | colspan="1" rowspan="1" |137, 411, 437, 873, 1634, 1769, 1782, 1961, 2508, 2617, 2962, 2963, 3002, 3029, 3474, 3499, 3596, 3646, 4007, 4066, 4084, 4121, 4184, 4328, 4468, 4499, 4744, 4904, 5015, 5142, 5212, 5351, 5625, 5821, 5892, 5923, 5994, 6212, 6284, 6432, 6528, 6570, 6614, 6866, 7107, 7211, 7302, 7304, 7419, 7848, 8037, 8144, 8374, 8383, 8503, 8524, 8638, 8986, 9346, 9852, 10052, 10129, 10136, 10245, 10699, 10926, 11089, 11164, 11278, 11619, 11881, 11918, 12262, 12861, 12863, 13162, 13291, 13297 (k = 5351, 6528, and 13162 at n=6K, other k at n=100K) | colspan="1" rowspan="1" |10322 (88080) 1999 (85188) 7557 (84180) 11882 (81547) 3439 (79524) 4686 (79010) 1159 (77107) 3573 (76352) 1465 (75209) 2148 (75018) | colspan="1" rowspan="1" |k = 1089 and 5776 proven composite by condition 1. k = 1200 proven composite by condition 2. |- | colspan="1" rowspan="1" |109 | colspan="1" rowspan="1" |9 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*109^q - 1) * (m*109^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |8 (19) 1 (17) 5 (2) 2 (2) 7 (1) 6 (1) 3 (1) | colspan="1" rowspan="1" |k = 4 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |110 | colspan="1" rowspan="1" |38 | colspan="1" rowspan="1" |3, 37 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 6 or 31 mod 37: for even n let k = m^2 and let n = 2*q; factors to: (m*110^q - 1) * (m*110^q + 1) odd n: factor of 37 | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |23 (78120) 17 (2598) 37 (1689) 9 (77) 11 (42) 10 (17) 2 (16) 31 (9) 5 (6) 22 (5) | colspan="1" rowspan="1" |k = 36 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |111 | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |2, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (24) 7 (6) 6 (4) 1 (3) 12 (2) 11 (2) 3 (2) 10 (1) 9 (1) 8 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |112 | colspan="1" rowspan="1" |1357 | colspan="1" rowspan="1" |5, 13, 113 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 15 or 98 mod 113: for even n let k = m^2 and let n = 2*q; factors to: (m*112^q - 1) * (m*112^q + 1) odd n: factor of 113 | colspan="1" rowspan="1" |31, 79, 310, 340, 421, 424, 451, 529, 703, 940, 1018, 1051, 1204 (all at n=7.5K) | colspan="1" rowspan="1" |948 (173968) 1268 (50536) 758 (35878) 1353 (7751) 187 (7524) 498 (6038) 9 (5717) 1024 (5681) 619 (5441) 981 (2858) | colspan="1" rowspan="1" |k = 225 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |113 | colspan="1" rowspan="1" |20 | colspan="1" rowspan="1" |3, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |14 (308) 1 (23) 7 (15) 19 (11) 5 (8) 16 (5) 3 (5) 12 (3) 4 (3) 18 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |114 | colspan="1" rowspan="1" |24 | colspan="1" rowspan="1" |5, 23 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*114^q - 1) * (m*114^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |3 (63) 1 (29) 11 (27) 18 (21) 22 (20) 20 (3) 19 (2) 17 (2) 14 (2) 10 (2) | colspan="1" rowspan="1" |k = 4 and 9 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |115 | colspan="1" rowspan="1" |57 | colspan="1" rowspan="1" |2, 29 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |13, 43 (both at n=8K) | colspan="1" rowspan="1" |45 (5227) 4 (4223) 51 (2736) 23 (1116) 53 (165) 21 (127) 35 (50) 15 (38) 39 (28) 32 (28) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |116 | colspan="1" rowspan="1" |14 | colspan="1" rowspan="1" |3, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |9 (249) 5 (156) 11 (118) 1 (59) 2 (32) 13 (15) 10 (11) 12 (2) 8 (2) 7 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |117 | colspan="1" rowspan="1" |149 | colspan="1" rowspan="1" |2, 5, 37 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |5, 17, 33, 141 (all at n=8K) | colspan="1" rowspan="1" |83 (442) 59 (352) 19 (336) 110 (232) 143 (222) 41 (209) 87 (177) 129 (165) 118 (136) 92 (129) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |118 | colspan="1" rowspan="1" |50 | colspan="1" rowspan="1" |7, 17 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |43 (37K) | colspan="1" rowspan="1" |27 (860) 29 (599) 18 (393) 6 (210) 22 (191) 8 (85) 19 (72) 7 (52) 42 (30) 37 (27) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |119 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (28) 3 (6) 1 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |120 | colspan="1" rowspan="1" |166616308 | colspan="1" rowspan="1" |11, 13, 1117, 14281 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |384, 386, 419, 483, 551, 672, 824, 846, 890, 901, 991, 1024, 1077, 1095, 1132, 1134, 1255, 1309, 1385, 1394, 1693, 1797, 1921, 2036, 2133, 2177, 2258, 2354, 2386, 2410, 2452, 2650, 2696, 2716, 3004, 3025, 3123, 3178, 3189, 3214, 3290, 3343, 3347, 3400, 3407, 3433, 3596, 3786, 3994, 4003, 4082, 4320, 4399, 4423, 4460, 4500, 4577, 4676, 4685, 4819, 4830, 4839, 4936, 5105, 5125, 5255, 5378, 5630, 5686, 5730, 6112, 6241, 6332, 6357, 6425, 6581, 6676, 6678, 6755, 6821, 6852, 6951, 6982, 6997, 7008, 7413, 7470, 7523, 7545, 7549, 7789, 7803, 7820, 7910, 7985, 8100, 8205, 8464, 8647, 8810, 8812, 8869, 8922, 8964, 8966, 8997, 9010, 9019, 9057, 9070, 9395, 9564, 9626, 9712, 9889, 9921, 9954, 9993 (for k <= 10K) (all at n=1K) | colspan="1" rowspan="1" |8063 (997) 6434 (976) 2980 (958) 5180 (938) 164 (878) 4234 (876) 7085 (843) 4390 (833) 9354 (829) 2726 (822) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |121 | colspan="1" rowspan="1" |100 | colspan="1" rowspan="1" |3, 7, 37 | colspan="1" rowspan="1" |All k = m^2 for all n; factors to: (m*11^n - 1) * (m*11^n + 1) | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000937362496 primality certificate for k=79]) | colspan="1" rowspan="1" |62 (13101) 79 (4545) 43 (68) 7 (60) 30 (24) 60 (12) 87 (11) 39 (11) 57 (10) 50 (10) | colspan="1" rowspan="1" |k = 1, 4, 9, 16, 25, 36, 49, 64, and 81 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |122 | colspan="1" rowspan="1" |14 | colspan="1" rowspan="1" |3, 5, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |13 (43) 8 (26) 11 (10) 2 (6) 12 (5) 1 (5) 10 (3) 6 (2) 5 (2) 3 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |123 | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |2, 5, 17 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |11 (8K) | colspan="1" rowspan="1" |1 (43) 3 (8) 2 (8) 12 (7) 6 (7) 9 (5) 7 (2) 10 (1) 8 (1) 5 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |124 | colspan="1" rowspan="1" |92881 | colspan="1" rowspan="1" |3, 5, 7, 5167 | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*124^q - 1) * (m*124^q + 1) odd n: factor of 5 (Condition 2): All k where k = 31*m^2 and m = = 1 or 4 mod 5: even n: factor of 5 for odd n let k = 31*m^2 and let n=2*q-1; factors to: [m*2^(2q-1)*31^q - 1] * [m*2^(2q-1)*31^q + 1] | colspan="1" rowspan="1" |101, 136, 146, 175, 179, 199, 204, 236, 259, 271, 301, 328, 364, 389, 434, 441, 459, 469, 561, 586, 589, 599, 604, 614, 616, 631, 661, 741, 766, 806, 844, 894, 901, 922, 931, 951, 971, 974, 1013, 1016, 1019, 1021, 1039, 1043, 1046, 1061, 1081, 1114, 1123, 1149, 1156, 1186, 1229, 1231, 1237, 1246, 1249, 1269, 1288, 1336, 1375, 1376, 1384, 1399, 1461, 1496, 1498, 1499, 1509, 1511, 1519, 1522, 1542, 1636, 1654, 1664, 1711, 1719, 1724, 1731, 1741, 1743, 1754, 1766, 1779, 1783, 1784, 1789, 1814, 1824, 1834, 1861, 1904, 1924, 1926, 1931, 1941, 1954, 1969, 1989, 2029, 2041, 2095, 2101, 2109, 2124, 2131, 2161, 2166, 2191, 2194, 2212, 2296, 2306, 2307, 2344, 2364, 2366, 2377, 2416, 2419, 2436, 2479, 2491, 2497, 2529, 2539, 2559, 2572, 2576, 2616, 2656, 2661, 2664, 2666, 2680, 2686, 2731, 2761, 2789, 2804, 2830, 2854, 2864, 2920, 2931, 2971, 2994, 3024, 3034, 3054, 3067, 3076, 3079, 3081, 3096, 3154, 3196, 3214, 3229, 3247, 3261, 3286, 3294, 3316, 3319, 3324, 3329, 3346, 3382, 3421, 3439, 3579, 3604, 3606, 3646, 3649, 3654, 3679, 3704, 3716, 3730, 3734, 3739, 3752, 3771, 3779, 3786, 3789, 3809, 3821, 3829, 3839, 3866, 3942, 3949, 3964, 3986, 4006, 4015, 4039, 4054, 4066, 4084, 4089, 4091, 4094, 4096, 4129, 4134, 4153, 4207, 4229, 4231, 4234, 4236, 4311, 4319, 4331, 4375, 4376, 4384, 4424, 4429, 4476, 4486, 4506, 4512, 4526, 4546, 4554, 4609, 4646, 4651, 4684, 4714, 4716, 4771, 4786, 4796, 4801, 4811, 4816, 4831, 4854, 4879, 4885, 4909, 4911, 4946, 4961, 4976, 4997, 5009, 5020, 5026, 5032, 5049, 5101, 5116, 5149, 5152, 5164, 5186, 5209, 5224, 5226, 5246, 5269, 5274, 5283, 5314, 5334, 5396, 5404, 5416, 5431, 5459, 5499, 5526, 5539, 5554, 5611, 5626, 5630, 5632, 5679, 5684, 5696, 5699, 5710, 5746, 5751, 5764, 5784, 5830, 5840, 5844, 5911, 5926, 5934, 5946, 5956, 5959, 5974, 5979, 5982, 6000, 6019, 6024, 6049, 6094, 6098, 6106, 6154, 6181, 6184, 6186, 6187, 6189, 6191, 6212, 6214, 6223, 6226, 6246, 6251, 6261, 6309, 6318, 6336, 6361, 6374, 6376, 6381, 6384, 6424, 6434, 6439, 6449, 6466, 6469, 6506, 6514, 6571, 6589, 6625, 6644, 6759, 6799, 6826, 6849, 6856, 6886, 6901, 6919, 6931, 6961, 6971, 6976, 6986, 7006, 7051, 7062, 7066, 7092, 7096, 7104, 7114, 7134, 7144, 7146, 7195, 7221, 7232, 7261, 7274, 7276, 7284, 7301, 7309, 7311, 7329, 7369, 7389, 7396, 7423, 7453, 7456, 7478, 7479, 7494, 7516, 7521, 7522, 7523, 7544, 7551, 7591, 7600, 7616, 7617, 7619, 7674, 7682, 7714, 7739, 7741, 7756, 7762, 7771, 7779, 7801, 7811, 7861, 7884, 7885, 7897, 7909, 7951, 8006, 8041, 8044, 8046, 8111, 8124, 8129, 8137, 8146, 8149, 8161, 8166, 8201, 8203, 8231, 8248, 8249, 8250, 8266, 8286, 8326, 8334, 8339, 8361, 8369, 8383, 8394, 8419, 8429, 8431, 8441, 8454, 8461, 8476, 8479, 8491, 8499, 8524, 8529, 8536, 8551, 8564, 8581, 8606, 8641, 8655, 8674, 8683, 8691, 8719, 8724, 8730, 8779, 8794, 8809, 8811, 8839, 8849, 8854, 8869, 8871, 8934, 8936, 8974, 8979, 8980, 8986, 9001, 9034, 9064, 9069, 9076, 9115, 9136, 9142, 9166, 9172, 9175, 9178, 9199, 9236, 9244, 9247, 9256, 9260, 9264, 9276, 9314, 9334, 9336, 9344, 9349, 9366, 9382, 9401, 9436, 9454, 9459, 9463, 9496, 9516, 9524, 9526, 9551, 9562, 9564, 9571, 9574, 9586, 9634, 9646, 9661, 9728, 9739, 9761, 9799, 9826, 9831, 9844, 9907, 9909, 9931, 9966, 9976 (for k <= 10K) (all at n=1K) | colspan="1" rowspan="1" |1194 (998) 1611 (989) 659 (986) 3996 (985) 6314 (984) 6101 (983) 4903 (978) 3941 (977) 6011 (975) 6179 (972) | colspan="1" rowspan="1" |k = 2^2, 3^2, 7^2, 8^2, 12^2, 13^2, 17^2, 18^2 (etc. pattern repeating every 5m) proven composite by condition 1. k = 31*1^2, 31*4^2, 31*6^2, 31*9^2, 31*11^2, 31*14^2, 31*16^2, 31*19^2 (etc. pattern repeating every 5m) proven composite by condition 2. |- | colspan="1" rowspan="1" |125 | colspan="1" rowspan="1" |8 | colspan="1" rowspan="1" |3, 7 | colspan="1" rowspan="1" |All k = m^3 for all n; factors to: (m*5^n - 1) * (m^2*25^n + m*5^n + 1) | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |6 (24) 7 (5) 3 (3) 5 (2) 2 (2) 4 (1) | colspan="1" rowspan="1" |k = 1 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |126 | colspan="1" rowspan="1" |480821 | colspan="1" rowspan="1" |13, 19, 127, 829 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |406, 1855, 2707, 2744, 3285, 3566, 3573, 3631, 3721, 4416, 4436, 4596, 5081, 5285, 6026, 6041, 6605, 7075, 7107, 7580, 7876, 8061, 8256, 8323, 8336, 8836, 9166, 9524, 9606, 9651, 9936, 11366, 11475, 11493, 11696, 12013, 12416, 12594, 13006, 13016, 13027, 13302, 13389, 13824, 14270, 14831, 15366, 15596, 15752, 15898, 16636, 16974, 17351, 17436, 17826, 17920, 18001, 18058, 18162, 18430, 18571, 18617, 19686, 19996, 20216, 20575, 20907, 20983, 21306, 21316, 22031, 22389, 22790, 22837, 23390, 23466, 23748, 23903, 24001, 24176, 24706, 25106, 25886, 26326, 26490, 27296, 28791, 28928, 29001, 29012, 29551, 29719 (for k <= 30K) (k = 1 mod 5 at n=1K, other k at n=25K) | colspan="1" rowspan="1" |8099 (23965) 24832 (23531) 28659 (23470) 20497 (22584) 21342 (22321) 6990 (21006) 26279 (19646) 18638 (17149) 27730 (16804) 29617 (16038) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |127 | colspan="1" rowspan="1" |2593 | colspan="1" rowspan="1" |2, 5, 17, 137 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |13, 17, 25, 27, 33, 35, 79, 83, 91, 113, 121, 139, 159, 179, 191, 231, 233, 235, 236, 237, 239, 250, 251, 264, 279, 288, 293, 333, 353, 361, 367, 379, 443, 451, 459, 471, 473, 511, 513, 517, 523, 531, 537, 551, 553, 557, 561, 597, 599, 604, 617, 631, 639, 649, 659, 679, 699, 715, 725, 731, 733, 737, 739, 747, 751, 755, 763, 773, 778, 783, 797, 809, 838, 848, 863, 871, 895, 919, 937, 939, 950, 953, 964, 982, 997, 999, 1013, 1019, 1025, 1031, 1037, 1039, 1043, 1051, 1106, 1107, 1117, 1119, 1127, 1157, 1173, 1185, 1196, 1199, 1211, 1231, 1232, 1233, 1245, 1253, 1259, 1279, 1288, 1291, 1313, 1327, 1333, 1335, 1337, 1347, 1353, 1359, 1371, 1377, 1401, 1407, 1417, 1421, 1429, 1432, 1439, 1473, 1481, 1491, 1513, 1525, 1539, 1549, 1551, 1573, 1577, 1579, 1589, 1593, 1595, 1597, 1599, 1611, 1612, 1618, 1631, 1639, 1641, 1661, 1677, 1693, 1699, 1709, 1711, 1731, 1732, 1737, 1751, 1771, 1792, 1793, 1803, 1837, 1839, 1903, 1911, 1921, 1928, 1933, 1936, 1939, 1943, 1951, 1957, 1959, 1999, 2013, 2017, 2032, 2039, 2045, 2072, 2073, 2079, 2092, 2097, 2099, 2129, 2155, 2168, 2179, 2191, 2197, 2215, 2231, 2247, 2253, 2273, 2279, 2303, 2313, 2339, 2367, 2377, 2389, 2411, 2427, 2431, 2433, 2479, 2501, 2543, 2548, 2559, 2565, 2573, 2583 (all at n=1K) | colspan="1" rowspan="1" |667 (1000) 1775 (994) 2497 (989) 2199 (972) 1759 (936) 2015 (910) 343 (904) 1113 (899) 1962 (893) 1543 (872) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |128 | colspan="1" rowspan="1" |44 | colspan="1" rowspan="1" |3, 43 | colspan="1" rowspan="1" |All k = m^7 for all n; factors to: (m*2^n - 1) * (m^6*64^n + m^5*32^n + m^4*16^n + m^3*8^n + m^2*4^n + m*2^n + 1) | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |29 (211192) 23 (2118) 26 (1442) 37 (699) 16 (459) 42 (246) 35 (98) 30 (66) 36 (59) 12 (46) | colspan="1" rowspan="1" |k = 1 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |129 | colspan="1" rowspan="1" |14 | colspan="1" rowspan="1" |5, 13 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*129^q - 1) * (m*129^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |12 (228) 1 (5) 5 (3) 7 (2) 13 (1) 11 (1) 10 (1) 8 (1) 6 (1) 3 (1) | colspan="1" rowspan="1" |k = 4 and 9 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |130 | colspan="1" rowspan="1" |2563 | colspan="1" rowspan="1" |3, 7, 811 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |64, 247, 253, 254, 302, 597, 739, 799, 877, 918, 961, 1003, 1129, 1159, 1178, 1255, 1258, 1423, 1702, 1754, 1773, 1807, 1849, 2227, 2304, 2311, 2319, 2381, 2479, 2494, 2536 (all at n=2K) | colspan="1" rowspan="1" |148 (1894) 1555 (1886) 1049 (1881) 2242 (1850) 2326 (1749) 1114 (1724) 523 (1670) 1796 (1650) 557 (1525) 1483 (1490) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |131 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (4) 1 (3) 3 (2) 4 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |132 | colspan="1" rowspan="1" |20 | colspan="1" rowspan="1" |7, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |18 (62) 1 (47) 3 (38) 8 (11) 19 (9) 4 (3) 13 (2) 7 (2) 6 (2) 17 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |133 | colspan="1" rowspan="1" |17 | colspan="1" rowspan="1" |2, 5, 29 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (13) 11 (5) 2 (4) 12 (3) 9 (3) 7 (3) 4 (3) 13 (2) 5 (2) 16 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |134 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (5) 2 (2) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |135 | colspan="1" rowspan="1" |33 | colspan="1" rowspan="1" |2, 17 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 4 or 13 mod 17: for even n let k = m^2 and let n = 2*q; factors to: (m*135^q - 1) * (m*135^q + 1) odd n: factor of 17 | colspan="1" rowspan="1" |none - proven (for the k=1 prime, factor N-1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=135&Exp=1170&c0=-&EN= 135^1170-1]) (the k=25 prime is proven prime by N-1, and [http://factordb.com/cert.php?id=1100000002391995274 primality certificate for the large prime factor of N-1]) ([http://factordb.com/cert.php?id=1100000002345322913 primality certificate for k=27], [http://factordb.com/cert.php?id=1100000001544061523 primality certificate for k=29]) | colspan="1" rowspan="1" |27 (3250) 32 (2091) 1 (1171) 29 (697) 18 (569) 25 (317) 7 (26) 26 (13) 17 (11) 23 (6) | colspan="1" rowspan="1" |k = 16 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |136 | colspan="1" rowspan="1" |22195 | colspan="1" rowspan="1" |3, 7, 43, 137 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 37 or 100 mod 137: for even n let k = m^2 and let n = 2*q; factors to: (m*136^q - 1) * (m*136^q + 1) odd n: factor of 137 | colspan="1" rowspan="1" |testing not started | colspan="1" rowspan="1" |testing not started | colspan="1" rowspan="1" |k = 1369 and 10000 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |137 | colspan="1" rowspan="1" |17 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 3 or 5 mod 8: for even n let k = m^2 and let n = 2*q; factors to: (m*137^q - 1) * (m*137^q + 1) odd n: factor of 2 | colspan="1" rowspan="1" |11, 13, 15 (all at n=2K) | colspan="1" rowspan="1" |16 (231) 3 (27) 5 (12) 1 (11) 10 (5) 14 (4) 12 (2) 8 (2) 2 (2) 7 (1) | colspan="1" rowspan="1" |k = 9 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |138 | colspan="1" rowspan="1" |1806 | colspan="1" rowspan="1" |5, 13, 139 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |408, 688, 831, 1074, 1743 (all at n=300K) | colspan="1" rowspan="1" |421 (272919) 773 (249730) 372 (103160) 1368 (66926) 1087 (55582) 1258 (54256) 557 (52295) 359 (47249) 291 (35886) 9 (35685) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |139 | colspan="1" rowspan="1" |6 | colspan="1" rowspan="1" |5, 7 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*139^q - 1) * (m*139^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven (for the k=1 prime, factor N-1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=139&Exp=162&c0=-&EN= 139^162-1]) | colspan="1" rowspan="1" |1 (163) 3 (114) 5 (1) 2 (1) | colspan="1" rowspan="1" |k = 4 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |140 | colspan="1" rowspan="1" |46 | colspan="1" rowspan="1" |3, 47 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |38 (448) 11 (108) 1 (79) 5 (30) 29 (18) 32 (16) 14 (16) 33 (12) 40 (9) 41 (8) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |141 | colspan="1" rowspan="1" |285 | colspan="1" rowspan="1" |2, 71 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000002577778137 primality certificate for k=201], [http://factordb.com/cert.php?id=1100000002342316027 primality certificate for k=93], [http://factordb.com/cert.php?id=1100000002342318636 primality certificate for k=197], [http://factordb.com/cert.php?id=1100000002342316742 primality certificate for k=133], [http://factordb.com/cert.php?id=1100000002342217475 primality certificate for k=16], [http://factordb.com/cert.php?id=1100000002342318867 primality certificate for k=203], [http://factordb.com/cert.php?id=1100000002342320668 primality certificate for k=283], [http://factordb.com/cert.php?id=1100000002342315669 primality certificate for k=73], [http://factordb.com/cert.php?id=1100000002342317299 primality certificate for k=147]) | colspan="1" rowspan="1" |201 (5279) 93 (1860) 197 (1052) 133 (818) 16 (573) 203 (250) 283 (244) 73 (237) 147 (209) 144 (171) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |142 | colspan="1" rowspan="1" |12 | colspan="1" rowspan="1" |11, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000651919336 primality certificate for k=1]) | colspan="1" rowspan="1" |1 (1231) 3 (26) 11 (14) 8 (7) 6 (3) 4 (3) 10 (2) 9 (1) 7 (1) 5 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |143 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |3 (16) 1 (3) 2 (2) 4 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |144 | colspan="1" rowspan="1" |59 | colspan="1" rowspan="1" |5, 29 | colspan="1" rowspan="1" |All k = m^2 for all n; factors to: (m*12^n - 1) * (m*12^n + 1) | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |39 (964) 30 (519) 23 (134) 46 (97) 58 (35) 2 (24) 57 (20) 15 (10) 54 (8) 34 (8) | colspan="1" rowspan="1" |k = 1, 4, 9, 16, 25, 36, and 49 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |145 | colspan="1" rowspan="1" |1169 | colspan="1" rowspan="1" |2, 73 | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 27 or 46 mod 73: for even n let k = m^2 and let n = 2*q; factors to: (m*145^q - 1) * (m*145^q + 1) odd n: factor of 73 (Condition 2): All k where k = m^2 and m = = 7 or 9 mod 16: for even n let k = m^2 and let n = 2*q; factors to: (m*145^q - 1) * (m*145^q + 1) odd n: factor of 2 | colspan="1" rowspan="1" |72, 113, 181, 303, 450, 523, 673, 769, 865, 1094, 1160 (all at n=2K) | colspan="1" rowspan="1" |8 (6368) 863 (1480) 838 (1460) 257 (1269) 1025 (1223) 347 (737) 817 (730) 641 (723) 685 (589) 759 (575) | colspan="1" rowspan="1" |k = 729 proven composite by condition 1. k = 49, 81, 529, and 625 proven composite by condition 2. |- | colspan="1" rowspan="1" |146 | colspan="1" rowspan="1" |8 | colspan="1" rowspan="1" |3, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |5 (30) 2 (16) 1 (7) 4 (5) 3 (3) 6 (2) 7 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |147 | colspan="1" rowspan="1" |73 | colspan="1" rowspan="1" |2, 37 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 6 or 31 mod 37: for even n let k = m^2 and let n = 2*q; factors to: (m*147^q - 1) * (m*147^q + 1) odd n: factor of 37 | colspan="1" rowspan="1" |49, 51, 55, 58, 59, 63 (all at n=2K) | colspan="1" rowspan="1" |11 (2042) 33 (619) 64 (169) 19 (140) 38 (131) 71 (114) 12 (112) 48 (96) 22 (48) 15 (46) | colspan="1" rowspan="1" |k = 36 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |148 | colspan="1" rowspan="1" |1936 | colspan="1" rowspan="1" |5, 13, 149 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 44 or 105 mod 149: for even n let k = m^2 and let n = 2*q; factors to: (m*148^q - 1) * (m*148^q + 1) odd n: factor of 149 | colspan="1" rowspan="1" |215, 256, 304, 346, 367, 448, 577, 580, 595, 636, 691, 694, 746, 801, 831, 898, 934, 967, 1015, 1048, 1052, 1134, 1204, 1234, 1249, 1256, 1258, 1307, 1341, 1351, 1426, 1489, 1516, 1594, 1600, 1604, 1621, 1743, 1750, 1852, 1901 (all at n=2K) | colspan="1" rowspan="1" |1554 (1991) 1312 (1967) 1381 (1942) 597 (1895) 417 (1891) 1357 (1890) 541 (1762) 281 (1738) 1228 (1657) 1841 (1586) | colspan="1" rowspan="1" |No k's proven composite by algebraic factors. |- | colspan="1" rowspan="1" |149 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (7) 2 (4) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |150 | colspan="1" rowspan="1" |49074 | colspan="1" rowspan="1" |7, 31, 103, 151 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |206, 841, 1509, 1962, 3229, 4682, 5245, 5890, 6039, 6353, 6494, 7851, 9061, 9260, 11324, 11477, 11516, 12839, 14373, 16309, 16404, 16424, 16977, 17603, 18859, 19027, 19191, 19226, 20468, 20988, 22238, 22349, 22977, 23396, 23706, 23944, 24614, 24852, 25488, 25704, 25829, 26685, 27032, 28389, 28822, 30050, 30993, 31738, 31812, 33521, 34429, 34707, 35066, 35344, 36709, 36994, 37137, 39108, 39141, 39712, 39736, 40020, 42012, 42128, 43060, 43789, 44346, 44645, 44832, 46257, 46616, 47717, 48138 (k = 30993 and 31738 at n=2K, other k at n=100K) | colspan="1" rowspan="1" |17554 (99646) 32797 (97430) 32399 (96963) 37966 (96107) 10505 (93910) 42643 (93875) 5674 (92155) 6492 (90168) 32135 (90000) 31409 (89441) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |151 | colspan="1" rowspan="1" |37 | colspan="1" rowspan="1" |2, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |9, 25 (both at n=2K) | colspan="1" rowspan="1" |3 (716) 34 (45) 29 (25) 22 (20) 4 (15) 27 (14) 1 (13) 16 (9) 13 (9) 23 (8) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |152 | colspan="1" rowspan="1" |16 | colspan="1" rowspan="1" |3, 17 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (with probable primes that have not been certified: k = 1) | colspan="1" rowspan="1" |14 (343720) 1 (270217) 2 (796) 13 (23) 11 (14) 5 (12) 10 (5) 3 (3) 15 (2) 8 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |153 | colspan="1" rowspan="1" |34 | colspan="1" rowspan="1" |7, 11 | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 3 or 5 mod 8: for even n let k = m^2 and let n = 2*q; factors to: (m*153^q - 1) * (m*153^q + 1) odd n: factor of 2 (Condition 2): All k where k = 17*m^2 and m = = 1 or 7 mod 8: even n: factor of 2 for odd n let k = 17*m^2 and let n=2*q-1; factors to: [m*3^(2q-1)*17^q - 1] * [m*3^(2q-1)*17^q + 1] | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |12 (21659) 21 (70) 27 (44) 22 (23) 32 (8) 15 (5) 20 (4) 4 (3) 1 (3) 30 (2) | colspan="1" rowspan="1" |k = 9 and 25 proven composite by condition 1. k = 17 proven composite by condition 2. |- | colspan="1" rowspan="1" |154 | colspan="1" rowspan="1" |61 | colspan="1" rowspan="1" |5, 31 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*154^q - 1) * (m*154^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000001544063272 primality certificate for k=19]) | colspan="1" rowspan="1" |6 (1989) 39 (326) 19 (324) 24 (106) 14 (78) 29 (62) 54 (30) 36 (7) 31 (7) 21 (7) | colspan="1" rowspan="1" |k = 4, 9, and 49 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |155 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (3) 3 (2) 2 (2) 4 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |156 | colspan="1" rowspan="1" |unknown (>10^9, <=2113322677) | colspan="1" rowspan="1" |unknown | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 28 or 129 mod 157: for even n let k = m^2 and let n = 2*q; factors to: (m*156^q - 1) * (m*156^q + 1) odd n: factor of 157 (Condition 2): All k where k = 39*m^2 and m = = 56 or 101 mod 157: even n: factor of 157 for odd n let k = 39*m^2 and let n=2*q-1; factors to: [m*2^(2q-1)*39^q - 1] * [m*2^(2q-1)*39^q + 1] | colspan="1" rowspan="1" |testing not started | colspan="1" rowspan="1" |testing not started | colspan="1" rowspan="1" |k = 28^2, 129^2, 185^2, 286^2 (etc. pattern repeating every 157m) proven composite by condition 1. k = 39*56^2, 39*101^2, 39*213^2, 39*258^2 (etc. pattern repeating every 157m) proven composite by condition 2. |- | colspan="1" rowspan="1" |157 | colspan="1" rowspan="1" |17 | colspan="1" rowspan="1" |2, 5, 29 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |8 (56) 15 (49) 4 (45) 7 (32) 1 (17) 13 (10) 14 (7) 16 (5) 5 (4) 12 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |158 | colspan="1" rowspan="1" |52 | colspan="1" rowspan="1" |3, 53 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |29, 44 (both at n=500K) | colspan="1" rowspan="1" |47 (273942) 34 (5223) 46 (147) 41 (94) 38 (74) 39 (49) 7 (39) 9 (35) 20 (34) 8 (20) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |159 | colspan="1" rowspan="1" |9 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*159^q - 1) * (m*159^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000001559095607 primality certificate for k=3]) | colspan="1" rowspan="1" |3 (2160) 8 (22) 1 (13) 7 (6) 6 (1) 5 (1) 2 (1) | colspan="1" rowspan="1" |k = 4 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |160 | colspan="1" rowspan="1" |22 | colspan="1" rowspan="1" |7, 23 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |20 (7570) 12 (11) 6 (8) 1 (7) 5 (3) 4 (3) 13 (2) 10 (2) 2 (2) 21 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |161 | colspan="1" rowspan="1" |65 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000002344047954 primality certificate for k=55]) | colspan="1" rowspan="1" |52 (549) 50 (328) 32 (316) 2 (228) 55 (153) 49 (103) 40 (67) 53 (46) 59 (36) 20 (26) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |162 | colspan="1" rowspan="1" |3259 | colspan="1" rowspan="1" |5, 163, 181 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |274, 302, 456, 1205, 1358, 1588, 1828, 2118, 2178, 2297, 2423, 2703, 2841, 2997, 3144, 3249 (k = 2118 and 2841 at n=300K, other k at n=2K) | colspan="1" rowspan="1" |2018 (194314) 2954 (95124) 1308 (82803) 1607 (28018) 58 (13758) 2809 (12303) 423 (8898) 3098 (8723) 653 (8335) 1781 (8327) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |163 | colspan="1" rowspan="1" |81 | colspan="1" rowspan="1" |2, 41 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |11, 37, 39, 57, 64 (all at n=2K) | colspan="1" rowspan="1" |4 (2285) 45 (1863) 75 (1000) 41 (955) 42 (775) 46 (249) 2 (84) 29 (37) 63 (36) 72 (24) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |164 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (3) 2 (2) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |165 | colspan="1" rowspan="1" |79 | colspan="1" rowspan="1" |7, 13, 43 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |65 (15K) | colspan="1" rowspan="1" |53 (1174) 45 (184) 49 (171) 6 (86) 44 (71) 60 (67) 50 (41) 78 (29) 16 (17) 41 (13) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |166 | colspan="1" rowspan="1" |4174 | colspan="1" rowspan="1" |3, 7, 13, 167 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |79, 187, 196, 222, 322, 337, 387, 424, 472, 556, 565, 571, 610, 615, 640, 759, 888, 946, 982, 1033, 1057, 1087, 1249, 1321, 1550, 1609, 1759, 1846, 1849, 1942, 1963, 2003, 2047, 2071, 2096, 2152, 2170, 2302, 2313, 2362, 2501, 2526, 2554, 2566, 2588, 2614, 2673, 2809, 3166, 3234, 3349, 3418, 3467, 3481, 3493, 3501, 3502, 3508, 3526, 3541, 3642, 3736, 3899, 3962, 3991, 4006, 4134 (all at n=2K) | colspan="1" rowspan="1" |3106 (1861) 1969 (1823) 1789 (1796) 1602 (1770) 4042 (1732) 823 (1698) 919 (1651) 3424 (1597) 2802 (1583) 2929 (1528) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |167 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |4 (1865) 2 (8) 3 (6) 1 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |168 | colspan="1" rowspan="1" |4744 | colspan="1" rowspan="1" |5, 13, 17, 73 | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 5 or 8 mod 13: for even n let k = m^2 and let n = 2*q; factors to: (m*168^q - 1) * (m*168^q + 1) odd n: factor of 13 (Condition 2): All k where k = 42*m^2 and m = = 3 or 10 mod 13: even n: factor of 13 for odd n let k = 42*m^2 and let n=2*q-1; factors to: [m*2^(2q-1)*42^q - 1] * [m*2^(2q-1)*42^q + 1] | colspan="1" rowspan="1" |53, 495, 584, 586, 948, 1364, 1416, 1429, 1512, 1626, 1741, 1743, 1754, 1938, 2172, 2237, 2263, 2599, 2627, 2848, 2852, 3067, 3106, 3119, 3238, 3314, 3407, 3574, 3678, 3769, 3795, 3797, 3844, 4016, 4328, 4382, 4549, 4614, 4642, 4668, 4707, 4723 (k = 2172 at n=2K, other k at n=100K) | colspan="1" rowspan="1" |1689 (68676) 3309 (63795) 4471 (54466) 4185 (53498) 2846 (50670) 1717 (38259) 1829 (34296) 2885 (34186) 2942 (33546) 2523 (31457) | colspan="1" rowspan="1" |k = 25, 64, 324, 441, 961, 1156, 1936, 2209, 3249, and 3600 proven composite by condition 1. k = 378 and 4200 proven composite by condition 2. |- | colspan="1" rowspan="1" |169 | colspan="1" rowspan="1" |16 | colspan="1" rowspan="1" |5, 17 | colspan="1" rowspan="1" |All k = m^2 for all n; factors to: (m*13^n - 1) * (m*13^n + 1) | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |14 (2) 13 (2) 3 (2) 15 (1) 12 (1) 11 (1) 10 (1) 8 (1) 7 (1) 6 (1) | colspan="1" rowspan="1" |k = 1, 4, and 9 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |170 | colspan="1" rowspan="1" |20 | colspan="1" rowspan="1" |3, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (166428) 8 (15422) 18 (360) 11 (108) 5 (38) 1 (17) 13 (13) 9 (7) 7 (3) 4 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |171 | colspan="1" rowspan="1" |85 | colspan="1" rowspan="1" |2, 43 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |15, 51, 75 (all at n=2K) | colspan="1" rowspan="1" |5 (2925) 1 (181) 11 (138) 68 (83) 42 (72) 7 (68) 3 (60) 73 (51) 61 (45) 23 (32) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |172 | colspan="1" rowspan="1" |235 | colspan="1" rowspan="1" |3, 7, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |22, 127, 133, 184, 219 (k = 219 at n=300K, other k at n=2K) | colspan="1" rowspan="1" |30 (1160) 196 (749) 164 (603) 139 (573) 200 (468) 230 (231) 148 (103) 103 (95) 100 (89) 217 (80) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |173 | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |11 (6K) | colspan="1" rowspan="1" |5 (54) 7 (15) 2 (4) 10 (3) 1 (3) 12 (2) 8 (2) 6 (2) 3 (2) 9 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |174 | colspan="1" rowspan="1" |6 | colspan="1" rowspan="1" |5, 7 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*174^q - 1) * (m*174^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000670865877 primality certificate for k=1]) | colspan="1" rowspan="1" |1 (3251) 5 (2) 3 (1) 2 (1) | colspan="1" rowspan="1" |k = 4 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |175 | colspan="1" rowspan="1" |21 | colspan="1" rowspan="1" |2, 11 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (the k=10 prime is proven prime by N+1, and for the large prime factor of N+1, factor N-1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=175&Exp=136&c0=-&EN= 175^136-1]) ([http://factordb.com/cert.php?id=1100000001573905066 primality certificate for k=11]) | colspan="1" rowspan="1" |11 (3048) 10 (136) 3 (90) 16 (17) 5 (13) 18 (10) 15 (8) 14 (7) 1 (5) 19 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |176 | colspan="1" rowspan="1" |58 | colspan="1" rowspan="1" |3, 59 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |34 (79) 26 (20) 22 (19) 53 (16) 50 (12) 32 (12) 29 (12) 25 (9) 4 (9) 43 (7) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |177 | colspan="1" rowspan="1" |209 | colspan="1" rowspan="1" |2, 5, 13 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 7 or 9 mod 16: for even n let k = m^2 and let n = 2*q; factors to: (m*177^q - 1) * (m*177^q + 1) odd n: factor of 2 | colspan="1" rowspan="1" |25, 161, 193, 197 (all at n=2K) | colspan="1" rowspan="1" |64 (340147) 36 (2957) 44 (1711) 163 (963) 97 (609) 33 (431) 179 (383) 200 (288) 58 (219) 172 (200) | colspan="1" rowspan="1" |k = 49 and 81 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |178 | colspan="1" rowspan="1" |22 | colspan="1" rowspan="1" |3, 5, 7, 13, 97 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |4 (13K) | colspan="1" rowspan="1" |19 (13655) 11 (177) 6 (118) 21 (89) 14 (44) 3 (14) 17 (12) 13 (8) 7 (4) 16 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |179 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (19) 3 (16) 2 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |180 | colspan="1" rowspan="1" |7674582 | colspan="1" rowspan="1" |7, 31, 181, 1051 | colspan="1" rowspan="1" |(Condition 1): All k where k = m^2 and m = = 19 or 162 mod 181: for even n let k = m^2 and let n = 2*q; factors to: (m*180^q - 1) * (m*180^q + 1) odd n: factor of 181 (Condition 2): All k where k = 5*m^2 and m = = 67 or 114 mod 181: even n: factor of 181 for odd n let k = 5*m^2 and let n=2*q-1; factors to: [m*6^(2q-1)*5^q - 1] * [m*6^(2q-1)*5^q + 1] | colspan="1" rowspan="1" |testing not started | colspan="1" rowspan="1" |testing not started | colspan="1" rowspan="1" |k = 19^2, 162^2, 200^2, 343^2 (etc. pattern repeating every 181m) proven composite by condition 1. k = 5*67^2, 5*114^2, 5*248^2, 5*295^2 (etc. pattern repeating every 181m) proven composite by condition 2. |- | colspan="1" rowspan="1" |181 | colspan="1" rowspan="1" |25 | colspan="1" rowspan="1" |2, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |5, 21 (k = 5 at n=6K, k = 21 at n=2K) | colspan="1" rowspan="1" |14 (29) 1 (17) 12 (8) 24 (5) 10 (5) 9 (5) 15 (3) 20 (2) 13 (2) 6 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |182 | colspan="1" rowspan="1" |62 | colspan="1" rowspan="1" |3, 61 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (for the k=1 prime, factor N-1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=182&Exp=166&c0=-&EN= 182^166-1]) | colspan="1" rowspan="1" |43 (502611) 26 (990) 29 (632) 54 (329) 7 (209) 1 (167) 44 (152) 58 (127) 47 (122) 59 (96) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |183 | colspan="1" rowspan="1" |45 | colspan="1" rowspan="1" |2, 23 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (for the k=1 prime, factor N-1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=183&Exp=222&c0=-&EN= 183^222-1]) (the k=37 prime is proven prime by N-1, and [http://factordb.com/cert.php?id=1100000002509732036 primality certificate for the large prime factor of N-1]) ([http://factordb.com/cert.php?id=1100000002509731461 primality certificate for k=13], [http://factordb.com/cert.php?id=1100000002509731825 primality certificate for k=23], [http://factordb.com/cert.php?id=1100000002509731671 primality certificate for k=17]) | colspan="1" rowspan="1" |13 (581) 23 (534) 1 (223) 17 (175) 37 (155) 15 (42) 27 (40) 26 (37) 21 (27) 42 (11) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |184 | colspan="1" rowspan="1" |36 | colspan="1" rowspan="1" |5, 37 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*184^q - 1) * (m*184^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven (with probable primes that have not been certified: k = 1) | colspan="1" rowspan="1" |1 (16703) 28 (85) 7 (32) 16 (21) 11 (15) 19 (10) 24 (8) 14 (8) 22 (7) 34 (6) | colspan="1" rowspan="1" |k = 4 and 9 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |185 | colspan="1" rowspan="1" |17 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 3 or 5 mod 8: for even n let k = m^2 and let n = 2*q; factors to: (m*185^q - 1) * (m*185^q + 1) odd n: factor of 2 | colspan="1" rowspan="1" |1 (66.3K) | colspan="1" rowspan="1" |10 (6783) 12 (8) 8 (8) 14 (4) 11 (4) 5 (4) 16 (3) 15 (2) 2 (2) 13 (1) | colspan="1" rowspan="1" |k = 9 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |186 | colspan="1" rowspan="1" |67 | colspan="1" rowspan="1" |11, 17 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 4 or 13 mod 17: for even n let k = m^2 and let n = 2*q; factors to: (m*186^q - 1) * (m*186^q + 1) odd n: factor of 17 | colspan="1" rowspan="1" |36 (13K) | colspan="1" rowspan="1" |12 (112717) 32 (388) 43 (44) 51 (32) 44 (14) 35 (13) 52 (11) 58 (9) 42 (7) 1 (7) | colspan="1" rowspan="1" |k = 16 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |187 | colspan="1" rowspan="1" |51 | colspan="1" rowspan="1" |2, 5, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |13, 27, 33, 39 (all at n=2K) | colspan="1" rowspan="1" |17 (1125) 7 (510) 43 (136) 11 (110) 31 (74) 48 (71) 1 (37) 10 (16) 18 (12) 23 (10) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |188 | colspan="1" rowspan="1" |8 | colspan="1" rowspan="1" |3, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |6 (950) 5 (40) 7 (7) 1 (3) 2 (2) 4 (1) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |189 | colspan="1" rowspan="1" |9 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*189^q - 1) * (m*189^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |6 (3) 2 (3) 1 (3) 5 (2) 8 (1) 7 (1) 3 (1) | colspan="1" rowspan="1" |k = 4 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |190 | colspan="1" rowspan="1" |626861 | colspan="1" rowspan="1" |13, 89, 191, 1753 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |testing not started | colspan="1" rowspan="1" |testing not started | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |191 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (970) 1 (17) 4 (5) 3 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |192 | colspan="1" rowspan="1" |13897 | colspan="1" rowspan="1" |5, 73, 193 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 81 or 112 mod 193: for even n let k = m^2 and let n = 2*q; factors to: (m*192^q - 1) * (m*192^q + 1) odd n: factor of 193 | colspan="1" rowspan="1" |253, 311, 593, 894, 898, 1268, 1422, 1704, 2118, 2264, 2315, 2324, 2396, 2441, 2909, 3092, 3282, 3303, 3323, 3719, 3859, 4038, 4062, 4078, 4104, 4164, 4247, 4304, 4372, 4426, 4618, 4679, 5132, 5173, 5523, 5547, 5584, 5731, 5758, 5761, 5789, 5967, 5984, 6083, 6175, 6177, 6205, 6261, 6263, 6297, 6353, 6354, 6484, 6547, 6558, 6746, 6789, 6889, 6939, 7096, 7407, 7528, 7549, 7591, 7756, 7889, 7913, 7931, 7984, 8187, 8214, 8248, 8347, 8361, 8382, 8493, 8537, 8988, 9091, 9111, 9208, 9402, 9689, 9883, 10037, 10063, 10162, 10349, 10396, 10423, 10488, 10657, 10817, 10988, 11002, 11213, 11488, 11933, 12132, 12157, 12234, 12317, 12424, 12716, 12782, 12797, 12906, 12983, 12984, 13358, 13484, 13605, 13623, 13738, 13798 (k = 5731 and 8214 at n=2K, other k at n=100K) | colspan="1" rowspan="1" |10909 (89859) 2486 (88582) 49 (88335) 2258 (86531) 7511 (85174) 12732 (85108) 12807 (84820) 9344 (83216) 1023 (78795) 2423 (77515) | colspan="1" rowspan="1" |k = 6561 and 12544 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |193 | colspan="1" rowspan="1" |484 | colspan="1" rowspan="1" |3, 5, 7, 13, 97 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 22 or 75 mod 97: for even n let k = m^2 and let n = 2*q; factors to: (m*193^q - 1) * (m*193^q + 1) odd n: factor of 97 | colspan="1" rowspan="1" |30, 58, 95, 106, 116, 134, 169, 184, 207, 226, 272, 302, 348, 379, 449, 463 (all at n=2K) | colspan="1" rowspan="1" |466 (1986) 431 (1794) 297 (1700) 387 (1638) 93 (1473) 136 (1018) 121 (849) 408 (725) 256 (417) 135 (413) | colspan="1" rowspan="1" |No k's proven composite by algebraic factors. |- | colspan="1" rowspan="1" |194 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (42) 3 (3) 1 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |195 | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |2, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |6 (38) 1 (11) 11 (4) 4 (3) 7 (2) 3 (2) 12 (1) 10 (1) 9 (1) 8 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |196 | colspan="1" rowspan="1" |1267 | colspan="1" rowspan="1" |3, 61, 211 | colspan="1" rowspan="1" |All k = m^2 for all n; factors to: (m*14^n - 1) * (m*14^n + 1) | colspan="1" rowspan="1" |198, 202, 223, 423, 562, 617, 647, 735, 808, 976, 1183 (all at n=2K) | colspan="1" rowspan="1" |5 (9849) 947 (1797) 807 (1630) 973 (1574) 342 (1548) 1111 (1455) 865 (649) 877 (639) 1087 (541) 962 (485) | colspan="1" rowspan="1" |k = 1^2, 2^2, 3^2, 4^2, 5^2, 6^2, 7^2, 8^2, 9^2, 10^2, 11^2, 12^2, 13^2, 14^2, 15^2, 16^2, etc. proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |197 | colspan="1" rowspan="1" |10 | colspan="1" rowspan="1" |3, 11 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000001562317156 primality certificate for k=7]) | colspan="1" rowspan="1" |7 (249) 1 (31) 5 (10) 8 (4) 3 (4) 2 (2) 9 (1) 6 (1) 4 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |198 | colspan="1" rowspan="1" |3662 | colspan="1" rowspan="1" |7, 13, 433 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |81, 172, 424, 464, 484, 529, 991, 1037, 1054, 1262, 1283, 1792, 1856, 1920, 2253, 2272, 2304, 2445, 2577, 2787, 2811, 2934, 3103, 3207, 3305, 3329, 3342, 3602, 3649 (all at n=100K) | colspan="1" rowspan="1" |2661 (95399) 1284 (73379) 807 (50662) 2791 (48837) 2187 (43879) 2388 (43718) 848 (40132) 947 (36807) 3420 (35891) 1922 (31592) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |199 | colspan="1" rowspan="1" |9 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" |All k where k = m^2 and m = = 2 or 3 mod 5: for even n let k = m^2 and let n = 2*q; factors to: (m*199^q - 1) * (m*199^q + 1) odd n: factor of 5 | colspan="1" rowspan="1" |none - proven (for the k=1 prime, factor N-1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=199&Exp=576&c0=-&EN= 199^576-1]) | colspan="1" rowspan="1" |1 (577) 7 (104) 3 (24) 8 (5) 5 (3) 6 (1) 2 (1) | colspan="1" rowspan="1" |k = 4 proven composite by partial algebraic factors. |- | colspan="1" rowspan="1" |200 | colspan="1" rowspan="1" |68 | colspan="1" rowspan="1" |3, 67 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (with probable primes that have not been certified: k = 1) | colspan="1" rowspan="1" |38 (131900) 58 (102363) 53 (45666) 51 (44252) 23 (31566) 19 (29809) 1 (17807) 13 (12053) 37 (597) 62 (126) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |256 | colspan="1" rowspan="1" |100 | colspan="1" rowspan="1" |3, 7, 13 | colspan="1" rowspan="1" |All k = m^2 for all n; factors to: (m*16^n - 1) * (m*16^n + 1) | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |74 (319) 47 (228) 42 (224) 92 (143) 68 (87) 61 (54) 35 (28) 65 (24) 70 (18) 75 (17) | colspan="1" rowspan="1" |k = 1, 4, 9, 16, 25, 36, 49, 64, and 81 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |512 | colspan="1" rowspan="1" |14 | colspan="1" rowspan="1" |3, 5, 13 | colspan="1" rowspan="1" |All k = m^3 for all n; factors to: (m*8^n - 1) * (m^2*64^n + m*8^n + 1) | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |4 (2215) 13 (2119) 9 (7) 11 (6) 6 (6) 5 (2) 3 (2) 2 (2) 12 (1) 10 (1) | colspan="1" rowspan="1" |k = 1 and 8 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |1024 | colspan="1" rowspan="1" |81 | colspan="1" rowspan="1" |5, 41 | colspan="1" rowspan="1" |All k = m^2 for all n; factors to: (m*32^n - 1) * (m*32^n + 1) -or- All k = m^5 for all n; factors to: (m*4^n - 1) * (m^4*256^n + m^3*64^n + m^2*16^n + m*4^n + 1) | colspan="1" rowspan="1" |29, 31, 56, 61 (k = 29 at n=1M, other k at n=3K) | colspan="1" rowspan="1" |74 (666084) 39 (4070) 43 (2290) 13 (1167) 78 (424) 65 (93) 69 (54) 3 (47) 71 (41) 44 (36) | colspan="1" rowspan="1" |k = 1, 4, 9, 16, 25, 32, 36, 49, and 64 proven composite by full algebraic factors. |} ohh27b10pao3y8h4cej4psq40exphtu 2 284274 2408099 2398552 2022-07-20T03:48:51Z Jtwsaddress42 234843 wikitext text/x-wiki * {{cite journal | last= Brown | first= Herbert C. | year= 1979 | title= From Little Acorns To Tall Oaks - From Boranes Through Organoboranes (Nobel Lecture) | journal= Science | volume= 210 | number= 4469 | pages= 485-492 | publication-date= October 31, 1980 | pmid= 17841388 | doi= 10.1126/science.210.4469.485 | url= https://www.science.org/doi/10.1126/science.210.4469.485}} * {{cite journal | last1= Brown | first1= Herbert C. | last2= Mead | first2= Edward J. | last3= Rao | first3= B.C. Subra | year= 1955 | title= A Study Of Solvents For Sodium Borohydride And The Effect Of Solvent And The Metal Ion On Borohydride Reductions | series= Organic and Biological Chemistry | journal= Journal Of The American Chemical Society | volume= 77 | number= 23 | pages= 6209-6213 | publication-date= December 5, 1955 | doi= 10.1021/ja01628a044 | url= https://pubs.acs.org/doi/10.1021/ja01628a044}} * {{cite journal | last1= Brown | first1= Herbert C. | last2= Schwier | first2= John R. | last3= Singaram | first3= Bakthan | year= 1978 | title= Simple synthesis of monoisopinocampheylborane of high optical purity | journal= The Journal of Organic Chemistry | volume= 43 | number= 22 | pages= 4395–4397 | publication-date= October 1, 1978 | doi= 10.1021/jo00416a042 | url= https://pubs.acs.org/doi/abs/10.1021/jo00416a042 }} * {{cite journal | last1= Brown | first1= Herbert C. | last2= Singaram | first2= Bakthan | year= 1987 | title= Organoboranes For Synthesis - Substitution With Retention | journal= Pure And Applied Chemistry | volume= 59 | number= 7 | pages= 879-894 | doi= 10.1351/pac198759070879 | url= https://www.degruyter.com/document/doi/10.1351/pac198759070879/html }} qktq1rjjmj3brrzidpqxr86k0ufj51s 2 285215 2408089 2406254 2022-07-20T03:01:38Z Jtwsaddress42 234843 /* Singaram, Bakthan */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} [[File:Bakthan Singaram.jpg|thumb|Bakthan Singaram]] === [[w:Bakthan Singaram|Singaram, Bakthan]] === '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=singaram UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department - Faculty Professor Emerti] * <u>[https://singaram.chemistry.ucsc.edu/ Singaram Research Group]</u> - Singaram Research Group (SRG) at the University of California, Santa Cruz is headed by [[w:Bakthan Singaram|Professor Bakthan Singaram]] and specializes in Boron-based organic chemistry. A primary goal of the Singaram lab is the development of novel chiral catalysts from terpenes, amino acids, and other biological and organic compounds. Bakthan is an expert in organic synthesis, organoborane chemistry, heterocyclic chemistry, organometallic chemistry, asymmetric synthesis, biosensors, and natural products chemistry. ** [https://www.sigmaaldrich.com/US/en/collections/professor-product-portal/singaram Sigma Alrich Portal] <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Singaram et al.}} <br />{{RoundBoxBottom}} <hr /> kht2cc4z8masav0qhxihd4s1rf2sdi9 2408095 2408089 2022-07-20T03:25:44Z Jtwsaddress42 234843 /* Singaram, Bakthan */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} [[File:Bakthan Singaram.jpg|thumb|Bakthan Singaram]] === [[w:Bakthan Singaram|Singaram, Bakthan]] === '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=singaram UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department - Faculty Professor Emerti] * <u>[https://singaram.chemistry.ucsc.edu/ Singaram Research Group]</u> - Singaram Research Group (SRG) at the University of California, Santa Cruz is headed by [[w:Bakthan Singaram|Professor Bakthan Singaram]] and specializes in Boron-based organic chemistry. A primary goal of the Singaram lab is the development of novel chiral catalysts from terpenes, amino acids, and other biological and organic compounds. Bakthan is an expert in organic synthesis, organoborane chemistry, heterocyclic chemistry, organometallic chemistry, asymmetric synthesis, biosensors, and natural products chemistry. ** [https://www.sigmaaldrich.com/US/en/collections/professor-product-portal/singaram Sigma Alrich Portal] <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Singaram et al.}} <br /><hr /> '''TarBX Reactions'''<br /> [[File:TarBX Reactions.png|640px|TarBX Reactions]] {{RoundBoxBottom}} <hr /> tgp1oboe6ubj4a0b8skh038reobjpid 2408096 2408095 2022-07-20T03:26:29Z Jtwsaddress42 234843 /* Singaram, Bakthan */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} [[File:Bakthan Singaram.jpg|thumb|Bakthan Singaram]] === [[w:Bakthan Singaram|Singaram, Bakthan]] === '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=singaram UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department - Faculty Professor Emerti] * <u>[https://singaram.chemistry.ucsc.edu/ Singaram Research Group]</u> - Singaram Research Group (SRG) at the University of California, Santa Cruz is headed by [[w:Bakthan Singaram|Professor Bakthan Singaram]] and specializes in Boron-based organic chemistry. A primary goal of the Singaram lab is the development of novel chiral catalysts from terpenes, amino acids, and other biological and organic compounds. Bakthan is an expert in organic synthesis, organoborane chemistry, heterocyclic chemistry, organometallic chemistry, asymmetric synthesis, biosensors, and natural products chemistry. ** [https://www.sigmaaldrich.com/US/en/collections/professor-product-portal/singaram Sigma Alrich Portal] <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Singaram et al.}} <br /><hr /> {| align= center |'''TarBX Reactions'''<br /> [[File:TarBX Reactions.png|640px|TarBX Reactions]] <br /> |} {{RoundBoxBottom}} <hr /> 4nmquf8j782bu1jcp0tqwrz5bjm1l9f 2408097 2408096 2022-07-20T03:32:29Z Jtwsaddress42 234843 /* Singaram, Bakthan */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} [[File:Bakthan Singaram.jpg|thumb|Bakthan Singaram]] === [[w:Bakthan Singaram|Singaram, Bakthan]] === '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=singaram UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department - Faculty Professor Emerti] * <u>[https://singaram.chemistry.ucsc.edu/ Singaram Research Group]</u> - Singaram Research Group (SRG) at the University of California, Santa Cruz is headed by [[w:Bakthan Singaram|Professor Bakthan Singaram]] and specializes in Boron-based organic chemistry. A primary goal of the Singaram lab is the development of novel chiral catalysts from terpenes, amino acids, and other biological and organic compounds. Bakthan is an expert in organic synthesis, organoborane chemistry, heterocyclic chemistry, organometallic chemistry, asymmetric synthesis, biosensors, and natural products chemistry. ** [https://www.sigmaaldrich.com/US/en/collections/professor-product-portal/singaram Sigma Alrich Portal] <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Singaram et al.}} <br /><hr /> {| align= center |'''TarBX Reactions'''<br /> [[File:TarBX Reactions.png|640px|TarBX Reactions]] <br /> |} <hr /> {| align= center |'''LAB Reactions'''<br /> [[File:LAB Reagent.png|640px|LAB Reagent]]<br /> |} <hr /> {| align= center |'''Glucose Sensing Quencher-Dye System'''<br /> [[File:BoronicAcidDye.png|640px|BoronicAcidDye]]<br /> |} {{RoundBoxBottom}} <hr /> e8imbpkinrc13mcjbr6s33l9sbn3g7j 2408100 2408097 2022-07-20T03:54:50Z Jtwsaddress42 234843 /* Singaram, Bakthan */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} [[File:Bakthan Singaram.jpg|thumb|Bakthan Singaram]] === [[w:Bakthan Singaram|Singaram, Bakthan]] === [[File:Structural formula of (+)-Diisopinocampheylborane.svg|thumb|(+)-Diisopinocampheylborane]] '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=singaram UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department - Faculty Professor Emerti] * <u>[https://singaram.chemistry.ucsc.edu/ Singaram Research Group]</u> - Singaram Research Group (SRG) at the University of California, Santa Cruz is headed by [[w:Bakthan Singaram|Professor Bakthan Singaram]] and specializes in Boron-based organic chemistry. A primary goal of the Singaram lab is the development of novel chiral catalysts from terpenes, amino acids, and other biological and organic compounds. Bakthan is an expert in organic synthesis, organoborane chemistry, heterocyclic chemistry, organometallic chemistry, asymmetric synthesis, biosensors, and natural products chemistry. ** [https://www.sigmaaldrich.com/US/en/collections/professor-product-portal/singaram Sigma Alrich Portal] <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Singaram et al.}} <br /><hr /> {| align= center |'''TarBX Reactions'''<br /> [[File:TarBX Reactions.png|640px|TarBX Reactions]] <br /> |} <hr /> {| align= center |'''LAB Reactions'''<br /> [[File:LAB Reagent.png|640px|LAB Reagent]]<br /> |} <hr /> {| align= center |'''Glucose Sensing Quencher-Dye System'''<br /> [[File:BoronicAcidDye.png|640px|BoronicAcidDye]]<br /> |} {{RoundBoxBottom}} <hr /> 2u4cd9hwjk7o3gszn4cb9qc8pdvxnin 2408101 2408100 2022-07-20T03:55:18Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Bakthan Singaram|Singaram, Bakthan]] === [[File:Bakthan Singaram.jpg|thumb|Bakthan Singaram]] [[File:Structural formula of (+)-Diisopinocampheylborane.svg|thumb|(+)-Diisopinocampheylborane]] '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=singaram UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department - Faculty Professor Emerti] * <u>[https://singaram.chemistry.ucsc.edu/ Singaram Research Group]</u> - Singaram Research Group (SRG) at the University of California, Santa Cruz is headed by [[w:Bakthan Singaram|Professor Bakthan Singaram]] and specializes in Boron-based organic chemistry. A primary goal of the Singaram lab is the development of novel chiral catalysts from terpenes, amino acids, and other biological and organic compounds. Bakthan is an expert in organic synthesis, organoborane chemistry, heterocyclic chemistry, organometallic chemistry, asymmetric synthesis, biosensors, and natural products chemistry. ** [https://www.sigmaaldrich.com/US/en/collections/professor-product-portal/singaram Sigma Alrich Portal] <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Singaram et al.}} <br /><hr /> {| align= center |'''TarBX Reactions'''<br /> [[File:TarBX Reactions.png|640px|TarBX Reactions]] <br /> |} <hr /> {| align= center |'''LAB Reactions'''<br /> [[File:LAB Reagent.png|640px|LAB Reagent]]<br /> |} <hr /> {| align= center |'''Glucose Sensing Quencher-Dye System'''<br /> [[File:BoronicAcidDye.png|640px|BoronicAcidDye]]<br /> |} {{RoundBoxBottom}} <hr /> 8nkbppgg7mgo5qnahdi8bjoukv8dltf 0 285232 2408023 2406335 2022-07-19T14:52:07Z 210.242.153.201 wikitext text/x-wiki == Definition == For the original Sierpinski problem, it is finding and proving the smallest k such that k×bⁿ+1 is not prime for all integers n ≥ 1 and GCD(k+1, b-1)=1. === Extended definiton === Finding and proving the smallest k such that (k×bⁿ+1)/GCD(k+1, b-1) is not prime for all integers n ≥ 1. === Notes === All n must be >= 1. k-values that make a full covering set with all or partial algebraic factors are excluded from the conjectures. k-values that are a multiple of base (b) and where (k+1)/gcd(k+1,b-1) is not prime are included in the conjectures but excluded from testing. Such k-values will have the same prime as k / b. == Table == {| class="wikitable" | colspan="1" rowspan="1" |Base | colspan="1" rowspan="1" |Conjectured smallest Sierpinski k | colspan="1" rowspan="1" |Covering set | colspan="1" rowspan="1" |k's that make a full covering set with all or partial algebraic factors | colspan="1" rowspan="1" |Remaining k to find prime (n testing limit) | colspan="1" rowspan="1" |Top 10 k's with largest first primes: k (n) (sorted by n only) | colspan="1" rowspan="1" |Comments |- | colspan="1" rowspan="1" |2 | colspan="1" rowspan="1" |78557 | colspan="1" rowspan="1" |3, 5, 7, 13, 19, 37, 73 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |21181, 22699, 24737, 55459, 65536, 67607 (k = 65536 at n=8.589G, other k at n=37M) | colspan="1" rowspan="1" |10223 (31172165) 19249 (13018586) 27653 (9167433) 28433 (7830457) 33661 (7031232) 5359 (5054502) 4847 (3321063) 54767 (1337287) 69109 (1157446) 65567 (1013803) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |3 | colspan="1" rowspan="1" |11047 | colspan="1" rowspan="1" |2, 5, 7, 13, 73 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1187, 1801, 3007, 3047, 3307, 5321, 5743, 5893, 6427, 6569, 6575, 7927, 8161, 8227, 8467, 8609, 8863, 8987, 9263, 9449 (all at n=16.3K) | colspan="1" rowspan="1" |621 (20820) 3061 (15772) 10243 (9731) 2747 (7097) 10207 (6089) 823 (6087) 10741 (6028) 821 (5512) 5147 (5153) 9721 (5040) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |419 | colspan="1" rowspan="1" |3, 5, 7, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |186 (10458) 94 (291) 176 (228) 129 (207) 89 (167) 86 (108) 174 (103) 369 (71) 101 (66) 293 (58) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |7 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |4 (2) 3 (2) 6 (1) 5 (1) 2 (1) 1 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |6 | colspan="1" rowspan="1" |174308 | colspan="1" rowspan="1" |7, 13, 31, 37, 97 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1296, 1814, 9589, 12179, 13215, 14505, 22139, 23864, 29014, 43429, 49874, 50252, 57189, 62614, 67894, 73814, 76441, 80389, 87284, 87289, 87800, 97131, 100899, 112783, 117454, 122704, 124874, 127688, 132614, 135199, 139959, 145984, 151719, 152209, 166753, 168610 (k = 1296 at n=268.4M, k = 1814 at n=200K, other k = 4 mod 5 at n=33.5K, other k at n=4M) | colspan="1" rowspan="1" |124125 (2018254) 139413 (1279992) 33706 (910462) 125098 (896696) 31340 (833096) 59506 (780877) 10107 (559967) 113966 (511831) 172257 (349166) 121736 (298935) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |7 | colspan="1" rowspan="1" |209 | colspan="1" rowspan="1" |2, 3, 5, 13, 43 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000887911448 primality certificate for k=141]) | colspan="1" rowspan="1" |141 (1044) 121 (252) 101 (216) 21 (124) 181 (80) 173 (48) 87 (47) 145 (46) 77 (44) 187 (35) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |8 | colspan="1" rowspan="1" |47 | colspan="1" rowspan="1" |3, 5, 13 | colspan="1" rowspan="1" |All k = m^3 for all n; factors to: (m*2^n + 1) * (m^2*4^n - m*2^n + 1) | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |31 (20) 46 (4) 40 (4) 37 (4) 28 (4) 16 (4) 13 (4) 45 (3) 38 (3) 36 (3) | colspan="1" rowspan="1" |k = 1, 8, and 27 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |9 | colspan="1" rowspan="1" |31 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |26 (6) 21 (4) 24 (3) 17 (3) 28 (2) 23 (2) 16 (2) 11 (2) 10 (2) 7 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |10 | colspan="1" rowspan="1" |989 | colspan="1" rowspan="1" |3, 7, 11, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |100, 269 (k = 100 at n=2.147G, k = 269 at n=100K) | colspan="1" rowspan="1" |804 (5470) 342 (338) 485 (230) 912 (215) 815 (190) 378 (188) 494 (135) 640 (120) 737 (117) 603 (107) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |11 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |4 (2) 1 (2) 3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |12 | colspan="1" rowspan="1" |521 | colspan="1" rowspan="1" |5, 13, 29 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |12 (33.55M) | colspan="1" rowspan="1" |404 (714558) 378 (2388) 261 (644) 407 (367) 354 (291) 37 (199) 30 (144) 88 (113) 17 (78) 274 (74) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |15 | colspan="1" rowspan="1" |2, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (for the k=11 prime, factor N-1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=13&Exp=564&c0=-&EN= 13^564-1]) | colspan="1" rowspan="1" |11 (564) 8 (4) 13 (3) 3 (2) 2 (2) 14 (1) 12 (1) 10 (1) 9 (1) 7 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |14 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (2) 3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |15 | colspan="1" rowspan="1" |673029 | colspan="1" rowspan="1" |2, 17, 113, 1489 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |225, 341, 343, 641, 965, 1205, 1827, 2263, 2323, 2403, 2445, 2461, 2471, 2531, 2813, 3347, 3625, 3797, 3935, 3959, 4045, 4169, 4355, 4665, 4733, 5169, 5793, 5891, 5983, 6061, 6331, 6553, 6661, 6775, 6849, 7087, 7693, 7711, 7773, 7975, 7979, 8017, 8161, 8181, 8271, 8603, 8881, 9215, 9643, 9767, 9783, 9857 (for k <= 10K) (k = 225 at n=524K, other k at n=1.5K) | colspan="1" rowspan="1" |6598 (11715) 6476 (1522) 5529 (1446) 6313 (1276) 7763 (1179) 4787 (1129) 219 (1129) 5975 (1099) 7957 (1082) 5653 (1064) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |16 | colspan="1" rowspan="1" |38 | colspan="1" rowspan="1" |3, 7, 13 | colspan="1" rowspan="1" |All k=4*q^4 for all n: let k=4*q^4 and let m=q*2^n; factors to: (2*m^2 + 2m + 1) * (2*m^2 - 2m + 1) | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000001707231 primality certificate for k=23]) | colspan="1" rowspan="1" |23 (1074) 33 (7) 35 (4) 18 (4) 10 (3) 5 (3) 32 (2) 31 (2) 30 (2) 24 (2) | colspan="1" rowspan="1" |k = 4 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |17 | colspan="1" rowspan="1" |31 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |10 (1356) 7 (190) 2 (47) 29 (41) 20 (13) 23 (9) 4 (6) 16 (4) 1 (4) 30 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |18 | colspan="1" rowspan="1" |398 | colspan="1" rowspan="1" |5, 13, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |18 (33.55M) | colspan="1" rowspan="1" |122 (292318) 381 (24108) 291 (2415) 37 (457) 362 (258) 123 (236) 183 (171) 363 (163) 209 (79) 318 (78) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |19 | colspan="1" rowspan="1" |9 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |5 (78) 6 (14) 4 (3) 1 (2) 8 (1) 7 (1) 3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |20 | colspan="1" rowspan="1" |8 | colspan="1" rowspan="1" |3, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |6 (15) 7 (2) 4 (2) 1 (2) 5 (1) 3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |21 | colspan="1" rowspan="1" |23 | colspan="1" rowspan="1" |2, 11 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |12 (10) 21 (3) 19 (2) 11 (2) 8 (2) 3 (2) 22 (1) 20 (1) 18 (1) 17 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |22 | colspan="1" rowspan="1" |2253 | colspan="1" rowspan="1" |5, 23, 97 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |22, 1754, 1772, 1862, 2186, 2232 (k = 22 at n=16.77M, other k at n=16.8K) | colspan="1" rowspan="1" |1611 (738988) 1908 (355313) 942 (18359) 740 (18137) 1496 (17480) 461 (16620) 953 (5596) 1793 (4121) 1161 (3720) 346 (3180) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |23 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |4 (342) 1 (4) 3 (3) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |24 | colspan="1" rowspan="1" |30651 | colspan="1" rowspan="1" |5, 7, 13, 73, 79 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |656, 1099, 1816, 1851, 1864, 2164, 2351, 2529, 2586, 3404, 3526, 3609, 4346, 4606, 4894, 5129, 5316, 5324, 5386, 5889, 5974, 7276, 7746, 7844, 8054, 8091, 8161, 9279, 9304, 9701, 9721, 10026, 10156, 10326, 10531, 11346, 12626, 12969, 12991, 13716, 14006, 14604, 15921, 17334, 17819, 17876, 18006, 18204, 18911, 19031, 19094, 20219, 20676, 20731, 21459, 21849, 22289, 22356, 22479, 23844, 23874, 24784, 25964, 25966, 26279, 27344, 29091, 29349, 29464, 29566, 29601 (k = 22 mod 23 at n=11.3K, other k at n=400K) | colspan="1" rowspan="1" |13984 (397259) 3846 (383526) 23981 (360062) 8369 (359371) 3706 (353908) 12799 (353083) 29009 (338099) 28099 (332519) 21526 (329368) 26804 (266195) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |25 | colspan="1" rowspan="1" |79 | colspan="1" rowspan="1" |2, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |71 (10K) | colspan="1" rowspan="1" |61 (3104) 40 (518) 59 (48) 77 (27) 68 (15) 47 (9) 12 (9) 51 (7) 66 (6) 57 (5) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |26 | colspan="1" rowspan="1" |221 | colspan="1" rowspan="1" |3, 7, 19, 37 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |65, 155 (both at n=1M) | colspan="1" rowspan="1" |32 (318071) 217 (11454) 95 (1683) 178 (1154) 138 (827) 157 (308) 175 (276) 211 (98) 149 (87) 197 (71) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |27 | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |2, 7 | colspan="1" rowspan="1" |All k = m^3 for all n; factors to: (m*3^n + 1) * (m^2*9^n - m*3^n + 1) | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |9 (10) 7 (3) 12 (2) 5 (2) 2 (2) 11 (1) 10 (1) 6 (1) 4 (1) 3 (1) | colspan="1" rowspan="1" |k = 1 and 8 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |28 | colspan="1" rowspan="1" |4554 | colspan="1" rowspan="1" |5, 29, 157 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |871, 3104, 4552 (k = 3104 at n=25.5K, k = 871 and 4552 at n=1M) | colspan="1" rowspan="1" |3394 (427262) 4233 (331135) 2377 (104621) 146 (47316) 1291 (22811) 2203 (13911) 1565 (8607) 1797 (5681) 1043 (5459) 2467 (4956) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |29 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |3 (2) 1 (2) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |30 | colspan="1" rowspan="1" |867 | colspan="1" rowspan="1" |7, 13, 19, 31 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |278, 588 (both at n=1M) | colspan="1" rowspan="1" |699 (11837) 242 (5064) 659 (4936) 311 (1760) 559 (1654) 557 (1463) 740 (1135) 12 (1023) 83 (644) 293 (361) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |31 | colspan="1" rowspan="1" |239 | colspan="1" rowspan="1" |2, 3, 7, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 51, 73, 77, 107, 117, 149, 181, 209 (k = 1 at n=524K, k = 51 at n=37K, other k at n=6K) | colspan="1" rowspan="1" |43 (21053) 189 (5570) 191 (1553) 5 (1026) 113 (178) 121 (118) 145 (78) 37 (64) 33 (62) 205 (60) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |32 | colspan="1" rowspan="1" |10 | colspan="1" rowspan="1" |3, 11 | colspan="1" rowspan="1" |All k = m^5 for all n; factors to: (m*2^n + 1) * (m^4*16^n - m^3*8^n + m^2*4^n - m*2^n + 1) | colspan="1" rowspan="1" |4 (1.717G) | colspan="1" rowspan="1" |9 (13) 7 (4) 5 (3) 2 (3) 8 (1) 6 (1) 3 (1) | colspan="1" rowspan="1" |k = 1 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |33 | colspan="1" rowspan="1" |511 | colspan="1" rowspan="1" |2, 17 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |67, 203 (both at n=12K) | colspan="1" rowspan="1" |36 (23615) 407 (10961) 154 (6846) 319 (5043) 288 (4583) 418 (780) 11 (593) 305 (561) 251 (495) 63 (347) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |34 | colspan="1" rowspan="1" |6 | colspan="1" rowspan="1" |5, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |5 (12) 1 (4) 4 (1) 3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |35 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |4 (42) 1 (2) 3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |36 | colspan="1" rowspan="1" |1886 | colspan="1" rowspan="1" |13, 31, 37, 43 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1296, 1814 (k = 1296 at n=134.2M, k = 1814 at n=100K) | colspan="1" rowspan="1" |960 (1571) 716 (1554) 526 (698) 1000 (542) 223 (480) 1096 (407) 1570 (352) 667 (302) 1115 (280) 1669 (240) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |37 | colspan="1" rowspan="1" |39 | colspan="1" rowspan="1" |2, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |37 (524K) | colspan="1" rowspan="1" |19 (5310) 18 (461) 17 (12) 36 (9) 35 (6) 33 (6) 3 (6) 31 (5) 32 (4) 11 (4) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |38 | colspan="1" rowspan="1" |14 | colspan="1" rowspan="1" |3, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (16.77M) | colspan="1" rowspan="1" |2 (2729) 9 (21) 4 (10) 8 (7) 10 (4) 7 (4) 3 (3) 13 (2) 12 (1) 11 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |39 | colspan="1" rowspan="1" |9 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |6 (2) 5 (2) 1 (2) 8 (1) 7 (1) 4 (1) 3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |40 | colspan="1" rowspan="1" |47723 | colspan="1" rowspan="1" |3, 7, 41, 223 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1169, 1229, 1415, 1600, 2215, 2294, 2338, 2543, 2789, 2951, 2957, 3050, 3281, 3689, 3812, 3935, 4224, 4388, 4468, 4565, 4675, 4742, 4820, 5003, 5042, 5126, 5372, 5944, 6689, 7051, 7092, 7586, 7934, 8255, 8283, 8362, 8363, 8792, 8978, 9090, 9101, 9221, 9224, 9731, 9964, 10187, 10661, 10762, 11112, 11195, 11438, 11645, 11684, 12422, 12668, 12955, 13025, 13193, 13283, 13406, 13445, 13970, 15104, 15263, 15284, 15374, 15579, 15581, 15989, 16235, 16319, 16445, 16481, 16768, 16850, 17465, 17477, 17957, 18146, 18164, 18285, 18365, 18572, 18692, 18695, 18818, 19202, 19213, 19280, 19394, 19884, 20124, 20198, 20267, 20318, 20870, 20894, 20951, 20963, 21032, 21196, 21407, 21895, 22671, 22961, 23123, 23201, 23371, 23741, 23984, 24221, 24437, 24476, 24594, 25667, 26198, 26387, 26815, 26855, 27182, 27389, 27430, 28332, 28496, 28578, 28619, 29045, 29108, 29150, 29291, 29603, 29642, 30236, 30269, 30503, 30505, 30751, 31079, 31088, 31220, 31226, 31489, 31538, 31770, 31928, 32512, 32555, 32637, 32678, 32717, 33065, 33211, 33344, 33662, 33764, 33785, 33929, 34029, 34646, 34709, 34808, 35333, 35375, 35382, 35384, 35417, 35507, 35546, 35552, 35822, 35828, 35837, 35894, 35999, 36101, 36185, 36368, 36824, 37229, 37268, 37577, 37703, 38324, 38828, 38951, 39115, 39230, 39722, 40667, 41411, 41450, 41479, 41696, 41819, 42106, 43174, 43295, 43787, 43830, 43892, 43994, 44238, 44279, 44546, 44732, 44894, 46370, 46698, 46709, 46925, 47272, 47276, 47559, 47684 (all at n=5K) | colspan="1" rowspan="1" |14555 (4988) 39119 (4945) 21026 (4919) 20402 (4907) 39525 (4904) 8624 (4892) 15417 (4860) 25501 (4717) 27948 (4710) 5477 (4683) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |41 | colspan="1" rowspan="1" |8 | colspan="1" rowspan="1" |3, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (16) 4 (6) 6 (3) 7 (2) 5 (1) 3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |42 | colspan="1" rowspan="1" |13372 | colspan="1" rowspan="1" |5, 43, 353 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |42, 988, 1117, 1421, 3226, 4127, 5503, 6707, 8298, 8601, 9074, 11093, 11717, 11738, 11912, 12256, 13283 (k = 42 at n=16.77M, k = 13283 at n=10K, other k at n=800K) | colspan="1" rowspan="1" |8343 (560662) 12001 (312245) 12042 (277646) 4643 (143933) 4297 (142044) 4731 (141968) 3897 (136780) 10009 (132629) 2794 (126595) 8300 (116404) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |43 | colspan="1" rowspan="1" |21 | colspan="1" rowspan="1" |2, 11 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (for the k=13 prime, factor N-1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=43&Exp=580&c0=-&EN= 43^580-1]) ([http://factordb.com/cert.php?id=1100000000899429028 primality certificate for k=9]) | colspan="1" rowspan="1" |13 (580) 9 (498) 3 (171) 5 (38) 17 (34) 15 (23) 1 (8) 18 (3) 16 (3) 14 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |44 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (16) 3 (9) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |45 | colspan="1" rowspan="1" |47 | colspan="1" rowspan="1" |2, 23 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |24 (18522) 15 (55) 42 (36) 3 (28) 35 (22) 8 (8) 30 (5) 38 (3) 23 (3) 20 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |46 | colspan="1" rowspan="1" |881 | colspan="1" rowspan="1" |3, 7, 103 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |563, 845 (both at n=35K) | colspan="1" rowspan="1" |283 (21198) 17 (4920) 140 (2105) 619 (2005) 278 (1788) 347 (1287) 729 (1006) 95 (446) 229 (443) 871 (405) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |47 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (175) 1 (8) 4 (2) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |48 | colspan="1" rowspan="1" |1219 | colspan="1" rowspan="1" |7, 13, 61, 181 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |36, 62, 153, 561, 622, 1114, 1168 (all at n=500K) | colspan="1" rowspan="1" |937 (309725) 701 (284564) 1077 (216501) 1086 (136352) 1121 (133656) 29 (133042) 841 (84732) 1099 (81106) 359 (35671) 1028 (22619) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |49 | colspan="1" rowspan="1" |31 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |24 (165) 21 (62) 22 (39) 11 (26) 16 (10) 29 (9) 9 (3) 26 (2) 20 (2) 15 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |50 | colspan="1" rowspan="1" |16 | colspan="1" rowspan="1" |3, 17 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (16.77M) | colspan="1" rowspan="1" |7 (516) 4 (10) 11 (9) 10 (4) 13 (2) 9 (2) 15 (1) 14 (1) 12 (1) 8 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |51 | colspan="1" rowspan="1" |25 | colspan="1" rowspan="1" |2, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |5 (6) 24 (5) 21 (4) 13 (4) 10 (3) 3 (3) 17 (2) 16 (2) 14 (2) 9 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |52 | colspan="1" rowspan="1" |28674 | colspan="1" rowspan="1" |5, 53, 541 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |52, 113, 158, 266, 311, 317, 419, 584, 674, 743, 863, 902, 973, 1043, 1292, 1376, 1483, 1502, 1538, 1591, 1658, 1727, 1808, 1907, 2174, 2384, 2386, 2570, 2624, 2711, 2813, 2978, 3181, 3232, 3254, 3418, 3671, 3746, 4133, 4135, 4241, 4292, 4706, 4901, 4928, 4967, 5281, 5282, 5405, 5570, 5573, 5619, 5624, 5693, 5711, 5776, 5882, 5988, 6011, 6125, 6147, 6149, 6239, 6536, 6572, 6687, 6770, 6891, 7058, 7089, 7147, 7207, 7262, 7283, 7313, 7397, 7400, 7577, 7580, 7737, 7739, 7998, 8054, 8638, 8681, 8693, 8990, 9083, 9134, 9243, 9329, 9356, 9421, 9433, 9437, 9602, 9737, 9848, 9943, 9977, 10004, 10013, 10188, 10246, 10328, 10451, 10487, 10493, 10499, 10548, 10586, 10601, 10641, 10652, 10667, 10679, 10739, 10916, 10919, 10999, 11078, 11146, 11516, 11553, 11684, 11714, 11747, 11771, 11798, 11818, 12191, 12197, 12461, 12471, 12533, 12721, 12779, 12918, 13043, 13171, 13251, 13277, 13514, 13673, 13697, 13784, 13799, 13842, 13952, 14132, 14256, 14849, 14888, 15110, 15157, 15282, 15422, 15424, 15474, 15636, 15637, 15659, 15901, 16058, 16133, 16273, 16535, 16559, 16738, 16749, 16802, 16853, 16961, 17012, 17027, 17054, 17120, 17277, 17279, 17383, 17491, 17712, 17723, 17809, 17996, 18072, 18328, 18449, 18458, 18526, 18602, 18632, 18797, 18816, 18951, 19043, 19081, 19121, 19157, 19178, 19241, 19319, 19352, 19397, 19403, 19451, 19493, 19556, 19646, 19721, 19751, 19768, 19959, 19980, 19982, 20192, 20351, 20459, 20475, 20526, 20722, 20840, 20897, 20936, 20975, 21246, 21272, 21347, 21353, 21359, 21517, 21851, 21902, 22055, 22169, 22332, 22418, 22430, 22526, 22701, 22709, 22719, 22739, 22791, 23062, 23531, 23558, 23586, 23612, 23663, 23705, 23743, 23774, 23844, 23871, 23902, 23987, 24257, 24273, 24328, 24347, 24452, 24456, 24464, 24547, 24563, 24697, 24866, 24911, 25227, 25229, 25236, 25439, 25492, 25494, 25653, 25704, 25865, 25943, 26078, 26261, 26287, 26498, 26658, 26660, 26744, 26771, 26858, 26923, 26966, 27082, 27122, 27327, 27527, 27572, 27623, 27877, 28142, 28193, 28198, 28462, 28493, 28661 (all at n=5K) | colspan="1" rowspan="1" |14129 (4891) 19634 (4877) 8132 (4875) 42 (4822) 3827 (4716) 15656 (4640) 6044 (4635) 21167 (4604) 10861 (4597) 20987 (4571) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |53 | colspan="1" rowspan="1" |7 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |4 (2.075M) | colspan="1" rowspan="1" |6 (143) 5 (9) 1 (8) 3 (4) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |54 | colspan="1" rowspan="1" |21 | colspan="1" rowspan="1" |5, 11 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |19 (103) 16 (30) 13 (7) 12 (4) 4 (3) 20 (2) 18 (2) 11 (2) 6 (2) 1 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |55 | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |2, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (524K) | colspan="1" rowspan="1" |10 (9) 9 (2) 8 (2) 5 (2) 4 (2) 12 (1) 11 (1) 7 (1) 6 (1) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |56 | colspan="1" rowspan="1" |20 | colspan="1" rowspan="1" |3, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |4 (78) 19 (70) 13 (6) 7 (6) 3 (5) 16 (2) 15 (2) 10 (2) 1 (2) 18 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |57 | colspan="1" rowspan="1" |47 | colspan="1" rowspan="1" |2, 5, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |14 (14955) 39 (74) 27 (44) 46 (20) 30 (14) 31 (7) 38 (5) 25 (5) 16 (5) 6 (5) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |58 | colspan="1" rowspan="1" |488 | colspan="1" rowspan="1" |3, 7, 163 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |58, 122, 176, 222, 431, 437, 461 (k = 58 at n=16.77M, k = 222 at n=125K, other k at n=14.9K) | colspan="1" rowspan="1" |178 (25524) 297 (11508) 266 (9040) 241 (1964) 296 (1892) 393 (1831) 106 (1795) 228 (1603) 20 (1340) 392 (1222) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |59 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (3) 1 (2) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |60 | colspan="1" rowspan="1" |16957 | colspan="1" rowspan="1" |13, 61, 277 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |60, 853, 1646, 2075, 4025, 4406, 4441, 5064, 6772, 7262, 7931, 10226, 11406, 12323, 13785, 14958, 15007, 15452, 15676, 16050 (k = 60 at n=16.77M, other k at n=500K) | colspan="1" rowspan="1" |14066 (324990) 16014 (227010) 5767 (201439) 12927 (191870) 11441 (180105) 8923 (109088) 13846 (90979) 2497 (88149) 10405 (77541) 6465 (37209) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |61 | colspan="1" rowspan="1" |63 | colspan="1" rowspan="1" |2, 31 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000922457360 primality certificate for k=62], [http://factordb.com/cert.php?id=1100000000922387890 primality certificate for k=43], [http://factordb.com/cert.php?id=1100000000922387835 primality certificate for k=23]) | colspan="1" rowspan="1" |62 (3698) 43 (2788) 23 (1659) 10 (165) 19 (70) 32 (18) 25 (16) 36 (12) 57 (11) 26 (11) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |62 | colspan="1" rowspan="1" |8 | colspan="1" rowspan="1" |3, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (16.77M) | colspan="1" rowspan="1" |7 (308) 2 (43) 3 (12) 4 (2) 6 (1) 5 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |63 | colspan="1" rowspan="1" |1589 | colspan="1" rowspan="1" |2, 5, 397 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 83, 101, 103, 113, 143, 185, 223, 237, 267, 307, 309, 335, 343, 367, 381, 391, 411, 425, 467, 471, 487, 509, 549, 587, 603, 637, 643, 645, 673, 677, 681, 687, 689, 701, 789, 807, 821, 825, 827, 881, 903, 937, 951, 963, 983, 989, 1021, 1043, 1047, 1063, 1067, 1103, 1263, 1267, 1283, 1321, 1341, 1401, 1461, 1463, 1467, 1481, 1523, 1553, 1563, 1581 (k = 1 at n=524K, other k at n=2K) | colspan="1" rowspan="1" |1108 (12351) 888 (2698) 9 (2162) 1174 (1989) 1201 (1904) 1367 (1861) 1189 (1846) 1027 (1693) 581 (1596) 1433 (1554) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |64 | colspan="1" rowspan="1" |14 | colspan="1" rowspan="1" |5, 13 | colspan="1" rowspan="1" |All k = m^3 for all n; factors to: (m*4^n + 1) * (m^2*16^n - m*4^n + 1) | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000315647263 primality certificate for k=11]) | colspan="1" rowspan="1" |11 (3222) 13 (2) 6 (2) 12 (1) 10 (1) 9 (1) 7 (1) 5 (1) 4 (1) 3 (1) | colspan="1" rowspan="1" |k = 1 and 8 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |65 | colspan="1" rowspan="1" |10 | colspan="1" rowspan="1" |3, 11 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |6 (5) 7 (2) 4 (2) 3 (2) 1 (2) 9 (1) 8 (1) 5 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |66 | colspan="1" rowspan="1" |21314443 | colspan="1" rowspan="1" |7, 17, 37, 67, 73, 4357 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |269, 470, 537, 1198, 1408, 1449, 2076, 2257, 2464, 2605, 2614, 2624, 2815, 3284, 3899, 4153, 4155, 4175, 4356, 4689, 4769, 4820, 4883, 5024, 5200, 5334, 5361, 5442, 5765, 5805, 5857, 6031, 6289, 6634, 6835, 7216, 7374, 7818, 8024, 8304, 9312 (for k <= 10K) (all at n=1K) | colspan="1" rowspan="1" |1511 (999) 1674 (863) 5269 (831) 4490 (774) 6969 (764) 2014 (758) 6105 (658) 7285 (645) 3149 (627) 7669 (616) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |67 | colspan="1" rowspan="1" |26 | colspan="1" rowspan="1" |3, 7, 31 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 17, 21 (k = 1 at n=524K, other k at n=10K) | colspan="1" rowspan="1" |6 (4532) 11 (209) 12 (135) 7 (135) 19 (21) 5 (6) 2 (6) 22 (3) 16 (3) 25 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |68 | colspan="1" rowspan="1" |22 | colspan="1" rowspan="1" |3, 23 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 17 (k = 1 at n=16.77M, k = 17 at n=1M) | colspan="1" rowspan="1" |12 (656921) 11 (3947) 8 (319) 16 (36) 5 (29) 13 (26) 19 (6) 10 (6) 4 (6) 18 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |69 | colspan="1" rowspan="1" |6 | colspan="1" rowspan="1" |5, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |3 (2) 1 (2) 5 (1) 4 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |70 | colspan="1" rowspan="1" |11077 | colspan="1" rowspan="1" |13, 29, 71 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |70, 89, 178, 212, 283, 285, 434, 545, 581, 629, 881, 1300, 1373, 1436, 1490, 1559, 1565, 1694, 1871, 1916, 1946, 1955, 2129, 2176, 2351, 2354, 2379, 2419, 2705, 2756, 3154, 3317, 3329, 3336, 3362, 3407, 3452, 3530, 3647, 3762, 3764, 3929, 3944, 4025, 4061, 4119, 4166, 4188, 4193, 4250, 4331, 4351, 4454, 4913, 5145, 5169, 5204, 5231, 5348, 5429, 5540, 5594, 5608, 5609, 5798, 5857, 5894, 5953, 5975, 6133, 6167, 6218, 6410, 6518, 6530, 6582, 6743, 7145, 7325, 7365, 7552, 7578, 7691, 7736, 7811, 7907, 7974, 7994, 8003, 8015, 8045, 8153, 8159, 8201, 8234, 8306, 8348, 8351, 8377, 8406, 8423, 8465, 8477, 8637, 8907, 8945, 9231, 9268, 9323, 9428, 9471, 9515, 9586, 9693, 9712, 9751, 9758, 10009, 10051, 10089, 10193, 10271, 10291, 10399, 10438, 10544, 10574, 10718, 10997, 11003 (all at n=1K) | colspan="1" rowspan="1" |3479 (998) 7345 (994) 10793 (976) 4155 (970) 1040 (965) 4343 (936) 2471 (936) 5578 (932) 4208 (926) 2877 (907) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |71 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |4 (22) 2 (3) 1 (2) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |72 | colspan="1" rowspan="1" |731 | colspan="1" rowspan="1" |5, 61, 73 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |72 (16.77M) | colspan="1" rowspan="1" |493 (480933) 647 (60536) 489 (20201) 559 (9626) 395 (8171) 444 (6071) 499 (2998) 292 (2779) 649 (2658) 521 (1208) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |73 | colspan="1" rowspan="1" |47 | colspan="1" rowspan="1" |2, 5, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (with probable primes that have not been certified: k = 14) ([http://factordb.com/cert.php?id=1100000000955319214 primality certificate for k=21], [http://factordb.com/cert.php?id=1100000000933743766 primality certificate for k=39]) | colspan="1" rowspan="1" |14 (21369) 21 (1531) 39 (350) 16 (40) 8 (28) 13 (23) 25 (10) 17 (9) 36 (7) 38 (6) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |74 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (2) 3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |75 | colspan="1" rowspan="1" |37 | colspan="1" rowspan="1" |2, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000955319204 primality certificate for k=11]) | colspan="1" rowspan="1" |11 (3071) 28 (129) 17 (128) 18 (57) 12 (57) 5 (48) 1 (32) 33 (18) 35 (11) 9 (6) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |76 | colspan="1" rowspan="1" |34 | colspan="1" rowspan="1" |7, 11 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |29 (84) 22 (16) 1 (16) 23 (12) 19 (6) 15 (6) 33 (4) 8 (4) 20 (3) 13 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |77 | colspan="1" rowspan="1" |7 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (524K) | colspan="1" rowspan="1" |4 (6098) 2 (3) 3 (2) 6 (1) 5 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |78 | colspan="1" rowspan="1" |96144 | colspan="1" rowspan="1" |5, 79, 1217 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |78, 1143, 2371, 3317, 3513, 4346, 4820, 4897, 5136, 5294, 5531, 5686, 5862, 6103, 6353, 6859, 7188, 7594, 8373, 9558, 9652, 9694, 9701, 9953, 10348, 10723, 11003, 11219, 12244, 12251, 13353, 13508, 13768, 14566, 14832, 15126, 15777, 15899, 16071, 16273, 16591, 17588, 17761, 18248, 18776, 19501, 19828, 19931, 20146, 20206, 20754, 21171, 21284, 21453, 21489, 21884, 21972, 22279, 22662, 23337, 23341, 23953, 24254, 24672, 24877, 24886, 24912, 25044, 25171, 25199, 26069, 26212, 26515, 26592, 27059, 27124, 27537, 27663, 28202, 28423, 28518, 28597, 29303, 29322, 29497, 29784, 30572, 30967, 31030, 32073, 32633, 33094, 33193, 33318, 33732, 34208, 34522, 34528, 34712, 34998, 35244, 35433, 35628, 35709, 36014, 36497, 37068, 37456, 37773, 37795, 37842, 38009, 38393, 38401, 39724, 40361, 40844, 41239, 41271, 41634, 42671, 43214, 43493, 43609, 43693, 43770, 44428, 44631, 45268, 45345, 45352, 45582, 45584, 45779, 46213, 46374, 46927, 47053, 48012, 48113, 48173, 48187, 48824, 49139, 49149, 49482, 50441, 51148, 51428, 51501, 51981, 52238, 52541, 52744, 53503, 53703, 53721, 54263, 54273, 54438, 54669, 54942, 55026, 56091, 56199, 57276, 57303, 57694, 58409, 58582, 59373, 59611, 60513, 60906, 60987, 61417, 61648, 61777, 62033, 62567, 62663, 62964, 63596, 63666, 64542, 64712, 65253, 65727, 65887, 67070, 67591, 67941, 68011, 68053, 68697, 69173, 70943, 70982, 71168, 71203, 71609, 71730, 71952, 72225, 73943, 74051, 74249, 74367, 74733, 75019, 75492, 76394, 77182, 77209, 77573, 77972, 78826, 79001, 79127, 79749, 79949, 80046, 80263, 80343, 80737, 80739, 80897, 81731, 81864, 82556, 83419, 83502, 83978, 84013, 84818, 85133, 85714, 86267, 86281, 86371, 86503, 86687, 87016, 87156, 87328, 87559, 87614, 87691, 87821, 88321, 88479, 88619, 89039, 89214, 89352, 89429, 89836, 90481, 91009, 91125, 91496, 92826, 93587, 93624, 93722, 93774, 93873, 93981, 94114, 94758, 95354, 95670 (k = 78 at n=16.77M, k = 6 mod 7 and k = 10 mod 11 at n=1K, other k at n=100K) | colspan="1" rowspan="1" |31738 (98568) 83107 (95785) 25281 (83932) 22344 (83678) 12325 (83516) 78211 (82952) 74928 (80731) 34346 (78373) 60908 (70199) 46424 (66623) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |79 | colspan="1" rowspan="1" |9 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (for the k=3 prime, factor N+1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=79&Exp=875&c0=%2B&EN= 79^875+1]) (for the k=5 prime, factor N-1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=79&Exp=162&c0=-&EN= 79^162-1]) | colspan="1" rowspan="1" |3 (875) 5 (162) 6 (2) 1 (2) 8 (1) 7 (1) 4 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |80 | colspan="1" rowspan="1" |1039 | colspan="1" rowspan="1" |3, 7, 13, 43, 173 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |86, 92, 166, 370, 393, 472, 556, 623, 692, 778, 818, 947, 968 (k = 947 at n=4K, other k at n=500K) | colspan="1" rowspan="1" |628 (491322) 295 (404886) 326 (398799) 188 (142291) 433 (121106) 770 (107149) 857 (106007) 787 (48156) 1024 (46306) 233 (36917) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |81 | colspan="1" rowspan="1" |575 | colspan="1" rowspan="1" |2, 41 | colspan="1" rowspan="1" |All k=4*q^4 for all n: let k=4*q^4 and let m=q*3^n; factors to: (2*m^2 + 2m + 1) * (2*m^2 - 2m + 1) | colspan="1" rowspan="1" |239, 335, 514 (all at n=5K) | colspan="1" rowspan="1" |558 (51992) 311 (7834) 75 (3309) 569 (2937) 439 (2097) 284 (1455) 41 (1223) 389 (871) 34 (734) 317 (518) | colspan="1" rowspan="1" |k = 4, 64, and 324 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |82 | colspan="1" rowspan="1" |19587 | colspan="1" rowspan="1" |5, 7, 13, 37, 83 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |74, 122, 167, 470, 839, 848, 1121, 1226, 1251, 1319, 1327, 1376, 1427, 1433, 1493, 1514, 1559, 1716, 1733, 1798, 1908, 2024, 2066, 2159, 2251, 2339, 2352, 2461, 2491, 2708, 2939, 2989, 3041, 3236, 3239, 3332, 3377, 3474, 3572, 3593, 3641, 3656, 3746, 3896, 3962, 4133, 4142, 4151, 4232, 4379, 4384, 4454, 4542, 4898, 5064, 5251, 5279, 5396, 5477, 5483, 5516, 5612, 5703, 5721, 5747, 5867, 5893, 5975, 6059, 6226, 6497, 6641, 6761, 6764, 6912, 6953, 7127, 7160, 7201, 7266, 7541, 7718, 7856, 7884, 7969, 7982, 8135, 8301, 8384, 8467, 8532, 8609, 8657, 8742, 8797, 8909, 9038, 9169, 9335, 9380, 9419, 9437, 9461, 9476, 9638, 9776, 9788, 9812, 9836, 9842, 9851, 9911, 9941, 9954, 10049, 10127, 10154, 10304, 10448, 10553, 10577, 10586, 10802, 10958, 11080, 11087, 11177, 11408, 11612, 11621, 11666, 11702, 11704, 11761, 11783, 11834, 11957, 11963, 11984, 12008, 12036, 12119, 12347, 12451, 12491, 12532, 12548, 12554, 12638, 12737, 12744, 12856, 12866, 12938, 12947, 12949, 13121, 13246, 13268, 13283, 13343, 13607, 13613, 13777, 14192, 14473, 14609, 14621, 14639, 14676, 14681, 14692, 14873, 14941, 14984, 15032, 15122, 15146, 15203, 15271, 15296, 15356, 15551, 15854, 15869, 15937, 15953, 16088, 16133, 16267, 16269, 16423, 16433, 16442, 16502, 16601, 16682, 16733, 16811, 16847, 17029, 17078, 17112, 17174, 17177, 17369, 17393, 17798, 17813, 17846, 17921, 18332, 18342, 18457, 18548, 18566, 18626, 18944, 18965, 18971, 19061, 19181, 19421 (k = 2 mod 3 at n=1K, other k at n=100K) | colspan="1" rowspan="1" |5652 (96054) 7288 (94205) 5101 (88245) 5977 (85004) 9676 (84109) 17692 (82887) 17091 (82407) 19134 (82154) 18168 (71000) 19098 (69654) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |83 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 3 (k = 1 at n=524K, k = 3 at n=8K) | colspan="1" rowspan="1" |4 (5870) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |84 | colspan="1" rowspan="1" |16 | colspan="1" rowspan="1" |5, 17 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |14 (47) 15 (6) 10 (5) 2 (4) 11 (2) 7 (2) 6 (2) 3 (2) 1 (2) 13 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |85 | colspan="1" rowspan="1" |87 | colspan="1" rowspan="1" |2, 43 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |70 (1586) 65 (125) 43 (62) 20 (57) 68 (12) 37 (12) 38 (11) 73 (7) 34 (7) 83 (6) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |86 | colspan="1" rowspan="1" |28 | colspan="1" rowspan="1" |3, 29 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 8 (k = 1 at n=16.77M, k = 8 at n=1M) | colspan="1" rowspan="1" |6 (40) 24 (23) 17 (17) 7 (12) 19 (6) 4 (6) 27 (4) 25 (2) 22 (2) 21 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |87 | colspan="1" rowspan="1" |21 | colspan="1" rowspan="1" |2, 11 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |12 (1214) 8 (112) 17 (16) 1 (16) 7 (7) 5 (6) 16 (4) 10 (3) 14 (2) 13 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |88 | colspan="1" rowspan="1" |26 | colspan="1" rowspan="1" |3, 7, 19, 31 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000936509845 primality certificate for k=8]) | colspan="1" rowspan="1" |8 (1094) 14 (83) 12 (9) 6 (7) 3 (4) 23 (3) 21 (3) 11 (3) 25 (2) 22 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |89 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (524K) | colspan="1" rowspan="1" |3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |90 | colspan="1" rowspan="1" |27 | colspan="1" rowspan="1" |7, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |14 (14) 8 (14) 22 (6) 19 (6) 5 (6) 16 (4) 12 (3) 23 (2) 21 (2) 15 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |91 | colspan="1" rowspan="1" |45 | colspan="1" rowspan="1" |2, 23 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (524K) | colspan="1" rowspan="1" |33 (52) 35 (45) 9 (36) 7 (17) 37 (12) 36 (9) 29 (8) 43 (7) 41 (6) 16 (6) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |92 | colspan="1" rowspan="1" |32 | colspan="1" rowspan="1" |3, 31 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (16.77M) | colspan="1" rowspan="1" |31 (416) 25 (308) 8 (109) 17 (59) 29 (47) 24 (38) 10 (24) 16 (12) 7 (6) 23 (5) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |93 | colspan="1" rowspan="1" |95 | colspan="1" rowspan="1" |2, 47 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |62, 67, 87, 93 (k = 62 at n=100K, k = 93 and n=524K, other k at n=8K) | colspan="1" rowspan="1" |19 (4362) 36 (3936) 43 (2994) 31 (527) 6 (520) 3 (156) 79 (69) 71 (41) 63 (31) 18 (24) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |94 | colspan="1" rowspan="1" |39 | colspan="1" rowspan="1" |5, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000936109552 primality certificate for k=17]) | colspan="1" rowspan="1" |17 (581) 9 (263) 11 (90) 31 (54) 2 (51) 16 (26) 23 (22) 34 (19) 30 (12) 38 (11) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |95 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |3 (9) 4 (6) 1 (2) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |96 | colspan="1" rowspan="1" |68869 | colspan="1" rowspan="1" |13, 97, 709 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |194, 939, 969, 994, 1169, 1177, 1262, 1514, 1844, 2146, 2424, 2545, 2868, 2952, 3028, 3364, 3624, 3699, 3784, 4019, 4164, 4239, 4549, 5140, 5239, 5262, 5764, 5959, 6009, 6074, 6304, 6389, 6569, 6668, 6671, 6769, 6882, 6934, 7132, 7246, 7312, 7539, 7569, 8009, 8069, 8226, 8634, 8796, 9020, 9064, 9309, 9489, 9589, 9619, 9799, 10089, 10139, 10574, 10669, 10739, 10844, 10849, 10939, 11154, 11159, 11361, 11549, 11634, 11659, 11738, 11974, 12029, 12054, 12417, 12706, 12999, 13044, 13519, 13773, 13899, 14169, 14279, 14299, 14494, 14646, 15194, 15208, 15228, 15448, 16073, 16279, 16349, 16799, 17009, 17029, 17264, 17362, 17517, 17564, 17909, 18189, 18231, 18254, 18916, 19109, 19254, 19289, 19304, 19683, 19884, 19934, 20064, 20324, 20369, 20494, 20584, 20599, 20733, 21194, 21234, 21679, 22309, 22419, 22569, 22604, 22699, 22999, 23174, 23629, 24015, 24049, 24259, 24490, 24724, 25459, 25575, 25829, 25995, 26229, 26379, 26424, 26577, 26846, 26899, 26941, 27219, 27299, 27334, 27514, 27644, 27682, 27849, 28939, 29039, 29278, 29411, 29574, 30360, 30459, 30484, 30509, 30689, 30779, 31461, 31621, 31979, 32138, 32239, 32300, 32319, 32369, 32384, 32432, 32609, 32664, 32714, 33034, 33175, 33229, 34119, 34267, 34469, 34744, 35071, 35296, 35309, 35404, 35794, 36304, 36824, 36834, 37129, 37829, 38134, 38219, 38546, 38609, 38739, 39164, 39187, 39309, 39386, 39719, 39777, 39983, 40014, 40724, 41339, 41614, 41674, 41709, 41779, 41806, 41905, 42004, 42179, 42199, 42291, 42374, 42394, 42444, 42629, 42901, 42954, 42979, 43194, 43389, 43494, 43739, 43909, 43914, 44136, 44384, 44539, 44611, 44634, 45009, 45589, 45774, 46134, 46214, 46344, 46409, 46444, 46658, 46684, 47139, 47143, 47164, 47238, 47259, 47344, 47644, 48010, 48214, 48307, 48404, 48479, 48504, 48582, 48744, 48749, 48914, 49017, 49249, 49859, 50079, 50194, 50224, 50387, 50549, 50709, 50929, 51099, 51159, 51399, 51414, 51797, 51827, 52019, 52034, 52209, 53004, 53079, 53465, 53519, 53624, 54016, 54254, 54509, 54994, 55049, 55774, 55959, 56044, 56229, 56719, 56854, 56919, 56939, 57037, 57114, 57264, 57520, 57524, 57968, 58199, 58215, 58356, 58644, 59189, 59519, 59654, 59684, 59799, 59945, 59947, 60014, 60194, 60269, 60464, 60624, 60917, 61014, 61034, 61384, 61524, 61699, 61773, 62024, 62774, 62884, 62954, 63029, 63439, 63504, 63509, 63799, 63809, 63939, 64454, 64484, 64644, 64700, 64789, 64871, 64982, 65019, 65089, 65164, 65229, 65239, 65379, 65399, 65573, 65606, 65668, 65749, 65864, 66039, 66096, 66119, 66349, 66559, 66664, 66734, 66749, 66929, 67159, 67174, 67373, 67976, 68004, 68169, 68192, 68274, 68339, 68384, 68444, 68532, 68752, 68774 (k = 4 mod 5 and k = 18 mod 19 at n=1K, other k at n=100K) | colspan="1" rowspan="1" |14825 (91707) 64312 (89580) 59132 (85620) 41452 (85565) 32762 (81344) 21533 (81235) 26773 (74392) 13872 (73620) 4461 (73443) 16780 (72065) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |97 | colspan="1" rowspan="1" |127 | colspan="1" rowspan="1" |2, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 27, 43, 62, 83, 116, 120, 123 (k = 1 at n=524K, k = 120 at n=100K, other k at n=2K) | colspan="1" rowspan="1" |64 (7474) 22 (2182) 122 (660) 68 (593) 26 (224) 87 (167) 24 (158) 113 (104) 41 (89) 17 (64) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |98 | colspan="1" rowspan="1" |10 | colspan="1" rowspan="1" |3, 11 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (16.77M) | colspan="1" rowspan="1" |4 (294) 8 (119) 6 (32) 7 (8) 3 (2) 9 (1) 5 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |99 | colspan="1" rowspan="1" |9 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (524K) | colspan="1" rowspan="1" |5 (14) 8 (10) 6 (6) 7 (1) 4 (1) 3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |100 | colspan="1" rowspan="1" |62 | colspan="1" rowspan="1" |3, 7, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |31 (168) 38 (29) 59 (24) 34 (13) 36 (8) 17 (6) 52 (5) 3 (5) 60 (4) 46 (4) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |101 | colspan="1" rowspan="1" |7 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (192275) 3 (22) 5 (3) 4 (2) 1 (2) 6 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |102 | colspan="1" rowspan="1" |293 | colspan="1" rowspan="1" |7, 19, 79 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |122, 178, 236 (all at n=360K) | colspan="1" rowspan="1" |46 (50451) 278 (10941) 94 (6421) 12 (2739) 73 (2040) 131 (1112) 202 (610) 56 (499) 48 (305) 271 (300) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |103 | colspan="1" rowspan="1" |25 | colspan="1" rowspan="1" |2, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |7 (8K) | colspan="1" rowspan="1" |13 (7010) 20 (476) 11 (81) 23 (51) 14 (34) 21 (16) 5 (16) 2 (8) 8 (7) 1 (4) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |104 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (16.77M) | colspan="1" rowspan="1" |2 (1233) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |105 | colspan="1" rowspan="1" |319 | colspan="1" rowspan="1" |2, 53 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000001053697575 primality certificate for k=191], [http://factordb.com/cert.php?id=1100000000936113242 primality certificate for k=39], [http://factordb.com/cert.php?id=1100000000936113332 primality certificate for k=183]) | colspan="1" rowspan="1" |191 (5045) 36 (675) 39 (348) 264 (275) 183 (210) 150 (193) 80 (177) 164 (146) 167 (140) 204 (105) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |106 | colspan="1" rowspan="1" |2387 | colspan="1" rowspan="1" |3, 19, 199 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |69, 110, 164, 259, 412, 449, 635, 748, 812, 929, 1088, 1190, 1429, 1511, 1607, 1628, 1823, 1925, 1985, 2018, 2075, 2177, 2189, 2216, 2279 (all at n=2K) | colspan="1" rowspan="1" |1559 (1975) 436 (1949) 679 (1818) 198 (1699) 2119 (1685) 1160 (1564) 2036 (1312) 887 (1307) 1703 (1305) 1835 (1303) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |107 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (524K) | colspan="1" rowspan="1" |4 (32586) 3 (165) 2 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |108 | colspan="1" rowspan="1" |26270 | colspan="1" rowspan="1" |7, 13, 109, 127 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |108, 127, 156, 211, 217, 653, 998, 1267, 1271, 1854, 2252, 2393, 2399, 2724, 2842, 2915, 2942, 2976, 3098, 3563, 3571, 3925, 3938, 4162, 4311, 4391, 4468, 4623, 4699, 5013, 5117, 5251, 5778, 5794, 5849, 5924, 5994, 6686, 7211, 7478, 8401, 8623, 8642, 8828, 9127, 9482, 9578, 9941, 10188, 10202, 10245, 10574, 10689, 10973, 11008, 11028, 11321, 11335, 11703, 11833, 11909, 12172, 12209, 12427, 12534, 13081, 13299, 13316, 13844, 13861, 14044, 14134, 14691, 14932, 15207, 15638, 15912, 15913, 15926, 16042, 16122, 16240, 16569, 16896, 17267, 17616, 18319, 18638, 19098, 19158, 19294, 19318, 19839, 19948, 19966, 20303, 20687, 20929, 21181, 21262, 21511, 21532, 21581, 21818, 21908, 22008, 22182, 22194, 22259, 22266, 22562, 22706, 23066, 23327, 23543, 23838, 24078, 24088, 24103, 24529, 24756, 24767, 24853, 25062, 25068, 25071, 25319, 25546, 25607, 25763, 25973, 26234, 26256 (k = 108 at n=16.77M, other k at n=100K) | colspan="1" rowspan="1" |7612 (99261) 7304 (94930) 15874 (94153) 8034 (93577) 2874 (91402) 20666 (91335) 7631 (90728) 9187 (90213) 6759 (89530) 21101 (88027) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |109 | colspan="1" rowspan="1" |19 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (524K) | colspan="1" rowspan="1" |3 (6) 4 (3) 18 (2) 16 (2) 12 (2) 11 (2) 6 (2) 5 (2) 17 (1) 15 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |110 | colspan="1" rowspan="1" |38 | colspan="1" rowspan="1" |3, 37 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |20 (933) 34 (356) 11 (161) 13 (124) 19 (66) 25 (58) 2 (51) 22 (42) 28 (12) 18 (11) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |111 | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |2, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |8 (62) 1 (16) 9 (8) 11 (5) 6 (3) 12 (2) 5 (2) 10 (1) 7 (1) 4 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |112 | colspan="1" rowspan="1" |2261 | colspan="1" rowspan="1" |5, 13, 113 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |209, 269, 467, 941, 1292, 1412, 1463, 1499, 1517, 1604, 1613, 1664, 1696, 1937 (k = 1696 at n=1M, other k at n=6.9K) | colspan="1" rowspan="1" |1780 (62794) 547 (8124) 953 (6802) 677 (5723) 1920 (5333) 2082 (5308) 1712 (4836) 813 (4616) 8 (4526) 1217 (3872) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |113 | colspan="1" rowspan="1" |20 | colspan="1" rowspan="1" |3, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |17 (8K) | colspan="1" rowspan="1" |4 (2958) 13 (1336) 19 (50) 18 (47) 8 (47) 16 (40) 12 (4) 3 (4) 1 (4) 15 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |114 | colspan="1" rowspan="1" |24 | colspan="1" rowspan="1" |5, 23 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (32) 12 (15) 3 (12) 22 (11) 11 (10) 9 (5) 16 (4) 23 (3) 19 (3) 15 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |115 | colspan="1" rowspan="1" |57 | colspan="1" rowspan="1" |2, 29 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |17, 47 (both at n=8K) | colspan="1" rowspan="1" |30 (47376) 50 (798) 38 (94) 46 (79) 23 (51) 5 (44) 53 (38) 40 (38) 49 (14) 37 (12) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |116 | colspan="1" rowspan="1" |14 | colspan="1" rowspan="1" |3, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |12 (47) 9 (8) 4 (6) 10 (4) 7 (4) 5 (3) 13 (2) 6 (2) 1 (2) 11 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |117 | colspan="1" rowspan="1" |119 | colspan="1" rowspan="1" |2, 59 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |59, 117 (k = 59 at n=8K, k = 117 at n=524K) | colspan="1" rowspan="1" |58 (460033) 75 (1428) 11 (1164) 77 (311) 2 (286) 81 (264) 47 (227) 67 (182) 4 (101) 51 (76) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |118 | colspan="1" rowspan="1" |50 | colspan="1" rowspan="1" |7, 17 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |48 (740K) | colspan="1" rowspan="1" |43 (106) 36 (96) 18 (80) 33 (67) 3 (46) 15 (22) 29 (10) 21 (7) 35 (6) 46 (5) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |119 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (4) 3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |120 | colspan="1" rowspan="1" |374876369 | colspan="1" rowspan="1" |11, 13, 1117, 14281 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |56, 89, 208, 219, 307, 309, 426, 540, 560, 694, 714, 727, 991, 1024, 1167, 1616, 1658, 1662, 1689, 1833, 1946, 1969, 1970, 2023, 2078, 2157, 2223, 2279, 2377, 2395, 2509, 2519, 2881, 3161, 3257, 3301, 3321, 3345, 3387, 3510, 3561, 3598, 3607, 3774, 3805, 3814, 3827, 3860, 3893, 3950, 4212, 4333, 4367, 4456, 4610, 4724, 4762, 4852, 4993, 5069, 5191, 5347, 5433, 5543, 5553, 5665, 5763, 5875, 5894, 5928, 6029, 6084, 6447, 6478, 6502, 6715, 6718, 6984, 7097, 7195, 7248, 7284, 7379, 7589, 7998, 8051, 8161, 8189, 8293, 8304, 8359, 8382, 8427, 8514, 8636, 8669, 8678, 8693, 8876, 8931, 8933, 8957, 9041, 9043, 9058, 9109, 9140, 9195, 9318, 9351, 9494, 9513, 9637, 9721, 9890 (for k <= 10K) (all at n=1K) | colspan="1" rowspan="1" |8389 (969) 6546 (954) 3195 (951) 3466 (908) 7479 (899) 3359 (897) 4437 (870) 8584 (843) 6382 (803) 738 (790) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |121 | colspan="1" rowspan="1" |27 | colspan="1" rowspan="1" |7, 19, 37 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |23 (102) 24 (72) 7 (6) 17 (5) 10 (5) 2 (5) 25 (4) 21 (4) 19 (4) 16 (4) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |122 | colspan="1" rowspan="1" |40 | colspan="1" rowspan="1" |3, 41 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 34 (k = 1 at n=16.77M, k = 34 at n=1M) | colspan="1" rowspan="1" |37 (1622) 31 (1236) 16 (764) 2 (755) 25 (674) 23 (389) 17 (371) 4 (358) 5 (135) 28 (108) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |123 | colspan="1" rowspan="1" |55 | colspan="1" rowspan="1" |2, 17, 89 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 3, 41 (k = 1 at n=524K, other k at n=8K) | colspan="1" rowspan="1" |19 (59) 38 (42) 47 (29) 13 (28) 34 (19) 28 (19) 8 (16) 54 (15) 15 (15) 53 (14) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |124 | colspan="1" rowspan="1" |31001 | colspan="1" rowspan="1" |3, 5, 7, 5167 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |54, 61, 76, 83, 89, 96, 114, 121, 146, 171, 206, 209, 221, 239, 251, 344, 362, 376, 381, 386, 411, 416, 431, 446, 449, 516, 519, 526, 530, 576, 581, 601, 635, 646, 647, 656, 661, 669, 670, 676, 684, 731, 766, 794, 804, 809, 831, 836, 841, 872, 896, 911, 971, 976, 1019, 1031, 1051, 1054, 1076, 1111, 1124, 1129, 1136, 1166, 1190, 1229, 1251, 1254, 1259, 1264, 1284, 1298, 1324, 1326, 1336, 1369, 1421, 1446, 1460, 1461, 1471, 1474, 1477, 1499, 1519, 1535, 1536, 1551, 1569, 1586, 1591, 1601, 1604, 1647, 1657, 1676, 1686, 1700, 1721, 1727, 1734, 1741, 1779, 1801, 1814, 1829, 1844, 1864, 1910, 1955, 2021, 2034, 2036, 2045, 2055, 2067, 2069, 2096, 2097, 2109, 2114, 2129, 2159, 2163, 2179, 2216, 2234, 2266, 2306, 2316, 2354, 2374, 2375, 2406, 2414, 2429, 2436, 2446, 2462, 2504, 2507, 2539, 2559, 2561, 2565, 2621, 2639, 2646, 2651, 2716, 2726, 2734, 2799, 2821, 2834, 2840, 2844, 2861, 2864, 2874, 2901, 2906, 2934, 2981, 2999, 3019, 3032, 3041, 3049, 3053, 3071, 3144, 3161, 3164, 3181, 3229, 3236, 3242, 3251, 3281, 3285, 3296, 3299, 3316, 3329, 3351, 3405, 3442, 3470, 3471, 3491, 3494, 3533, 3554, 3561, 3574, 3631, 3659, 3674, 3684, 3714, 3726, 3736, 3737, 3758, 3779, 3806, 3824, 3854, 3869, 3881, 3890, 3911, 3916, 3921, 3941, 3961, 3981, 3986, 3994, 4021, 4049, 4086, 4089, 4124, 4127, 4131, 4153, 4162, 4191, 4196, 4226, 4231, 4254, 4297, 4306, 4314, 4352, 4375, 4388, 4406, 4414, 4421, 4454, 4476, 4489, 4500, 4506, 4520, 4521, 4529, 4541, 4546, 4589, 4594, 4604, 4629, 4719, 4739, 4751, 4764, 4769, 4799, 4849, 4891, 4910, 4926, 4936, 4952, 4961, 4964, 4973, 4974, 5001, 5041, 5048, 5049, 5108, 5114, 5121, 5149, 5154, 5189, 5191, 5231, 5244, 5279, 5289, 5300, 5316, 5321, 5326, 5364, 5366, 5369, 5375, 5381, 5384, 5414, 5440, 5462, 5474, 5481, 5489, 5519, 5543, 5551, 5579, 5581, 5596, 5651, 5663, 5681, 5696, 5697, 5701, 5721, 5723, 5738, 5744, 5771, 5781, 5799, 5801, 5816, 5819, 5825, 5839, 5840, 5851, 5876, 5884, 5909, 5919, 5939, 5951, 5976, 5981, 6024, 6026, 6036, 6041, 6046, 6059, 6099, 6146, 6151, 6161, 6164, 6166, 6196, 6201, 6211, 6219, 6224, 6241, 6269, 6296, 6310, 6323, 6329, 6366, 6383, 6386, 6394, 6401, 6409, 6410, 6411, 6416, 6486, 6494, 6496, 6511, 6514, 6536, 6539, 6559, 6596, 6620, 6621, 6644, 6646, 6647, 6654, 6659, 6665, 6686, 6689, 6691, 6712, 6729, 6731, 6746, 6749, 6751, 6761, 6789, 6794, 6806, 6821, 6864, 6881, 6891, 6904, 6908, 6926, 6949, 6956, 6959, 6962, 6971, 7004, 7006, 7016, 7034, 7036, 7071, 7074, 7079, 7081, 7146, 7169, 7204, 7216, 7227, 7239, 7259, 7269, 7271, 7276, 7301, 7319, 7324, 7331, 7359, 7369, 7376, 7391, 7424, 7439, 7446, 7451, 7454, 7472, 7484, 7486, 7499, 7523, 7544, 7559, 7565, 7586, 7601, 7609, 7639, 7656, 7664, 7666, 7671, 7691, 7739, 7744, 7761, 7796, 7801, 7831, 7851, 7868, 7881, 7886, 7931, 7949, 7979, 7981, 8014, 8017, 8034, 8042, 8054, 8114, 8141, 8146, 8192, 8213, 8219, 8221, 8231, 8274, 8279, 8291, 8296, 8321, 8323, 8351, 8354, 8381, 8396, 8417, 8423, 8424, 8429, 8516, 8519, 8526, 8531, 8532, 8579, 8634, 8641, 8651, 8666, 8681, 8711, 8714, 8741, 8771, 8776, 8780, 8786, 8829, 8831, 8876, 8916, 8921, 8930, 8936, 8939, 8966, 8978, 8982, 9006, 9024, 9026, 9038, 9069, 9099, 9106, 9118, 9138, 9161, 9166, 9173, 9187, 9209, 9214, 9216, 9226, 9244, 9261, 9267, 9269, 9286, 9302, 9314, 9319, 9411, 9479, 9483, 9509, 9521, 9536, 9594, 9596, 9598, 9599, 9641, 9651, 9681, 9687, 9743, 9754, 9785, 9791, 9831, 9836, 9865, 9866, 9901, 9911, 9914, 9949, 9971 (for k <= 10K) (all at n=1K) | colspan="1" rowspan="1" |1646 (998) 8094 (997) 1886 (996) 1926 (994) 2987 (985) 7193 (981) 3276 (974) 6974 (973) 6951 (966) 2801 (960) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |125 | colspan="1" rowspan="1" |7 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" |All k = m^3 for all n; factors to: (m*5^n + 1) * (m^2*25^n - m*5^n + 1) | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |4 (2) 3 (2) 6 (1) 5 (1) 2 (1) | colspan="1" rowspan="1" |k = 1 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |126 | colspan="1" rowspan="1" |766700 | colspan="1" rowspan="1" |13, 19, 127, 829 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |259, 1084, 1117, 1154, 2708, 2922, 3735, 3982, 5093, 5099, 5392, 5529, 5587, 6059, 6478, 6772, 7817, 8150, 8304, 8659, 8759, 8779, 8829, 9268, 9429, 9474, 9624, 10072, 10540, 11008, 11429, 12094, 12414, 12750, 12757, 12799, 12900, 13111, 13129, 13264, 13274, 13309, 14299, 14390, 14538, 14598, 15402, 15454, 15781, 15876, 15883, 16312, 17300, 18119, 18394, 18594, 18795, 19421, 19479, 19484, 19499, 19559, 19894, 20326, 20394, 20609, 20914, 21083, 21369, 21679, 21694, 21999, 22582, 24023, 24119, 24543, 24764, 25399, 25624, 25739, 25757, 25913, 26374, 26441, 27179, 27884, 27948, 28222, 28374, 28602, 28729, 29590 (for k <= 30K) (k = 4 mod 5 at n=1K, other k at n=25K) | colspan="1" rowspan="1" |26532 (23264) 27765 (22565) 15493 (22097) 25722 (20095) 29405 (19897) 28188 (17368) 25575 (17359) 26036 (15264) 27433 (14598) 12965 (14155) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |127 | colspan="1" rowspan="1" |6343 | colspan="1" rowspan="1" |2, 5, 17, 137 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 37, 67, 103, 121, 134, 138, 139, 141, 153, 172, 177, 189, 201, 205, 215, 223, 237, 247, 263, 267, 301, 311, 343, 367, 381, 383, 387, 398, 409, 413, 425, 447, 452, 465, 469, 474, 487, 495, 525, 527, 529, 543, 569, 582, 601, 629, 645, 647, 649, 657, 659, 673, 681, 691, 701, 707, 727, 733, 763, 781, 790, 797, 807, 809, 818, 819, 837, 847, 849, 887, 895, 901, 903, 907, 909, 925, 927, 941, 954, 1011, 1021, 1023, 1043, 1075, 1079, 1103, 1109, 1121, 1123, 1147, 1161, 1165, 1167, 1169, 1173, 1193, 1199, 1201, 1229, 1232, 1237, 1239, 1243, 1244, 1261, 1303, 1309, 1322, 1329, 1343, 1351, 1357, 1362, 1379, 1381, 1383, 1403, 1417, 1423, 1425, 1427, 1431, 1439, 1441, 1461, 1463, 1466, 1472, 1483, 1487, 1494, 1515, 1543, 1544, 1547, 1549, 1553, 1557, 1565, 1574, 1581, 1583, 1603, 1607, 1615, 1621, 1641, 1649, 1686, 1691, 1719, 1723, 1741, 1742, 1747, 1753, 1754, 1765, 1783, 1785, 1793, 1801, 1808, 1815, 1827, 1841, 1849, 1861, 1875, 1887, 1917, 1921, 1954, 1961, 1981, 1987, 1997, 2001, 2022, 2027, 2041, 2055, 2083, 2089, 2109, 2123, 2147, 2152, 2156, 2167, 2177, 2181, 2189, 2211, 2229, 2235, 2241, 2261, 2263, 2265, 2285, 2287, 2330, 2335, 2336, 2341, 2375, 2401, 2403, 2409, 2429, 2441, 2461, 2521, 2523, 2531, 2537, 2551, 2603, 2607, 2625, 2627, 2636, 2649, 2657, 2661, 2687, 2701, 2721, 2729, 2741, 2744, 2749, 2778, 2801, 2803, 2809, 2847, 2861, 2863, 2867, 2869, 2887, 2894, 2907, 2908, 2909, 2915, 2921, 2929, 2949, 2961, 2963, 2977, 2981, 2987, 2988, 2993, 3001, 3005, 3041, 3045, 3061, 3069, 3089, 3093, 3095, 3099, 3107, 3121, 3129, 3133, 3141, 3143, 3169, 3181, 3199, 3209, 3221, 3241, 3243, 3276, 3283, 3297, 3303, 3309, 3313, 3325, 3327, 3329, 3345, 3363, 3377, 3381, 3392, 3401, 3407, 3419, 3421, 3449, 3455, 3461, 3489, 3501, 3521, 3526, 3527, 3533, 3543, 3545, 3549, 3563, 3603, 3641, 3646, 3647, 3703, 3741, 3743, 3747, 3763, 3779, 3790, 3807, 3811, 3812, 3815, 3821, 3823, 3829, 3896, 3923, 3929, 3947, 3981, 3986, 3987, 3995, 3996, 4001, 4007, 4021, 4029, 4031, 4039, 4045, 4063, 4073, 4079, 4081, 4087, 4112, 4125, 4135, 4157, 4164, 4167, 4181, 4185, 4193, 4201, 4207, 4229, 4241, 4247, 4261, 4281, 4289, 4309, 4323, 4327, 4329, 4339, 4364, 4373, 4381, 4382, 4385, 4416, 4421, 4437, 4447, 4455, 4469, 4481, 4503, 4517, 4521, 4527, 4531, 4547, 4573, 4587, 4609, 4614, 4617, 4643, 4645, 4667, 4677, 4684, 4701, 4705, 4742, 4761, 4781, 4809, 4819, 4823, 4829, 4849, 4867, 4887, 4891, 4896, 4909, 4957, 4968, 4969, 4975, 4987, 4995, 5005, 5009, 5016, 5023, 5025, 5041, 5057, 5061, 5067, 5069, 5091, 5101, 5119, 5123, 5149, 5165, 5172, 5187, 5189, 5201, 5205, 5226, 5238, 5247, 5249, 5267, 5273, 5283, 5321, 5327, 5331, 5343, 5347, 5363, 5368, 5379, 5381, 5387, 5391, 5399, 5415, 5429, 5435, 5441, 5443, 5457, 5461, 5469, 5477, 5485, 5487, 5488, 5503, 5507, 5529, 5531, 5534, 5543, 5547, 5549, 5563, 5577, 5583, 5589, 5606, 5609, 5615, 5618, 5619, 5622, 5623, 5627, 5638, 5665, 5668, 5674, 5678, 5687, 5697, 5701, 5707, 5713, 5721, 5723, 5735, 5747, 5761, 5767, 5799, 5807, 5813, 5823, 5837, 5841, 5859, 5861, 5863, 5867, 5887, 5888, 5903, 5923, 5929, 5941, 5955, 5957, 5966, 5981, 5996, 6015, 6021, 6041, 6047, 6048, 6057, 6081, 6085, 6087, 6111, 6114, 6121, 6149, 6209, 6221, 6231, 6237, 6245, 6261, 6269, 6275, 6277 (all at n=1K) | colspan="1" rowspan="1" |2163 (985) 2837 (982) 6065 (980) 2479 (975) 3525 (972) 365 (968) 5541 (964) 5654 (963) 6129 (950) 2267 (947) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |128 | colspan="1" rowspan="1" |44 | colspan="1" rowspan="1" |3, 43 | colspan="1" rowspan="1" |All k = m^7 for all n; factors to: (m*2^n + 1) * (m^6*64^n - m^5*32^n + m^4*16^n - m^3*8^n + m^2*4^n - m*2^n + 1) | colspan="1" rowspan="1" |16, 40 (k = 16 at n=4.908G, k = 40 at n=1.2857M) | colspan="1" rowspan="1" |41 (39271) 42 (13001) 20 (473) 28 (322) 38 (291) 19 (178) 25 (64) 3 (27) 17 (21) 31 (20) | colspan="1" rowspan="1" |k = 1 proven composite by full algebraic factors. k = 8 and 32 have no possible prime. |- | colspan="1" rowspan="1" |129 | colspan="1" rowspan="1" |14 | colspan="1" rowspan="1" |5, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |6 (16796) 4 (19) 9 (15) 2 (6) 1 (4) 11 (2) 5 (2) 13 (1) 12 (1) 10 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |130 | colspan="1" rowspan="1" |1049 | colspan="1" rowspan="1" |3, 7, 31, 131 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |37, 50, 71, 227, 341, 414, 545, 794, 809, 920, 1013 (all at n=2K) | colspan="1" rowspan="1" |992 (1751) 458 (1399) 773 (1303) 593 (917) 944 (880) 83 (695) 278 (662) 272 (614) 1046 (612) 290 (543) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |131 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |4 (2) 1 (2) 3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |132 | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |5, 7, 17 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |6 (5) 1 (4) 7 (3) 12 (2) 9 (2) 8 (2) 4 (2) 2 (2) 11 (1) 10 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |133 | colspan="1" rowspan="1" |59 | colspan="1" rowspan="1" |2, 5, 29 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |23, 51 (both at n=2K) | colspan="1" rowspan="1" |19 (806) 57 (174) 38 (43) 48 (18) 43 (12) 58 (10) 45 (8) 41 (8) 27 (8) 8 (7) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |134 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |3 (4) 1 (2) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |135 | colspan="1" rowspan="1" |33 | colspan="1" rowspan="1" |2, 17 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 17 (k = 1 at n=524K, k = 17 at n=2K) | colspan="1" rowspan="1" |21 (1154) 7 (213) 10 (54) 25 (38) 20 (28) 32 (13) 3 (9) 28 (8) 8 (8) 5 (4) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |136 | colspan="1" rowspan="1" |29180 | colspan="1" rowspan="1" |53, 137, 349 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |testing not started | colspan="1" rowspan="1" |testing not started | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |137 | colspan="1" rowspan="1" |22 | colspan="1" rowspan="1" |3, 23 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 5, 17 (k = 1 at n=524K, other k at n=2K) | colspan="1" rowspan="1" |2 (327) 10 (102) 14 (93) 16 (48) 11 (19) 4 (18) 13 (4) 7 (4) 12 (3) 19 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |138 | colspan="1" rowspan="1" |2781 | colspan="1" rowspan="1" |5, 13, 139 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |138, 211, 344, 678, 1188, 1444, 1494, 1818, 2371, 2627 (k = 138 at n=16.77M, other k at n=500K) | colspan="1" rowspan="1" |2636 (469911) 2189 (345010) 2354 (314727) 1019 (274533) 1789 (271671) 141 (244616) 2416 (214921) 866 (212835) 2062 (192750) 47 (136218) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |139 | colspan="1" rowspan="1" |6 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |5 (6) 2 (5) 3 (3) 1 (2) 4 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |140 | colspan="1" rowspan="1" |46 | colspan="1" rowspan="1" |3, 47 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |8 (1M) | colspan="1" rowspan="1" |16 (251178) 34 (136) 29 (103) 38 (79) 13 (64) 28 (44) 11 (37) 44 (31) 10 (24) 14 (23) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |141 | colspan="1" rowspan="1" |143 | colspan="1" rowspan="1" |2, 71 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |19, 27, 64, 107 (all at n=2K) | colspan="1" rowspan="1" |123 (312) 95 (109) 7 (99) 46 (75) 129 (73) 39 (53) 77 (47) 17 (45) 15 (25) 93 (24) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |142 | colspan="1" rowspan="1" |12 | colspan="1" rowspan="1" |11, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |10 (407) 7 (23) 2 (4) 1 (4) 5 (3) 3 (2) 11 (1) 9 (1) 8 (1) 6 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |143 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (524K) | colspan="1" rowspan="1" |3 (183) 4 (10) 2 (5) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |144 | colspan="1" rowspan="1" |59 | colspan="1" rowspan="1" |5, 29 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (16.77M) | colspan="1" rowspan="1" |34 (3061) 37 (1154) 6 (782) 31 (102) 55 (88) 30 (72) 35 (42) 17 (39) 46 (16) 40 (15) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |145 | colspan="1" rowspan="1" |1023 | colspan="1" rowspan="1" |2, 73 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |18, 58, 94, 220, 221, 367, 458, 539, 628, 719, 729, 783, 795, 802, 863, 904 (all at n=2K) | colspan="1" rowspan="1" |72 (769) 559 (734) 490 (632) 335 (586) 940 (512) 951 (506) 336 (448) 8 (401) 989 (397) 176 (396) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |146 | colspan="1" rowspan="1" |8 | colspan="1" rowspan="1" |3, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |5 (3) 7 (2) 4 (2) 1 (2) 6 (1) 3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |147 | colspan="1" rowspan="1" |73 | colspan="1" rowspan="1" |2, 37 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 17, 19, 35, 47, 63 (k = 1 at n=524K, other k at n=2K) | colspan="1" rowspan="1" |66 (520) 65 (434) 69 (226) 43 (201) 2 (154) 37 (152) 61 (136) 25 (128) 14 (115) 54 (62) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |148 | colspan="1" rowspan="1" |3128 | colspan="1" rowspan="1" |5, 13, 149 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |43, 98, 148, 168, 246, 299, 302, 359, 392, 413, 416, 464, 563, 641, 684, 728, 768, 776, 802, 876, 941, 953, 963, 1091, 1093, 1101, 1103, 1136, 1166, 1185, 1295, 1322, 1379, 1418, 1427, 1496, 1559, 1611, 1633, 1638, 1652, 1669, 1799, 1808, 1877, 1901, 2064, 2072, 2107, 2162, 2207, 2361, 2417, 2548, 2573, 2576, 2716, 2745, 2852, 2933, 2978, 2981, 2996, 3029, 3033, 3038, 3071, 3112 (all at n=2K) | colspan="1" rowspan="1" |2369 (1947) 338 (1947) 1781 (1829) 134 (1783) 2467 (1709) 1256 (1705) 1571 (1696) 1787 (1677) 1586 (1644) 1676 (1541) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |149 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (524K) | colspan="1" rowspan="1" |2 (3) 3 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |150 | colspan="1" rowspan="1" |49074 | colspan="1" rowspan="1" |7, 31, 103, 151 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |343, 1553, 3980, 4578, 5254, 5413, 5891, 6041, 7342, 7506, 7724, 8787, 8906, 10256, 10699, 11434, 11465, 11475, 12232, 13591, 14265, 16046, 17366, 18806, 19256, 19480, 20235, 20537, 20789, 20988, 21388, 22045, 22604, 23307, 24765, 24914, 25364, 26478, 26909, 27320, 27502, 29265, 29446, 30501, 30654, 31666, 33674, 34594, 35391, 35484, 36265, 36774, 40232, 40839, 41073, 42128, 42734, 43093, 43200, 43275, 44242, 44441, 45161, 46649, 46660, 47111, 48168, 48354, 48617 (all at n=100K) | colspan="1" rowspan="1" |2529 (95448) 25295 (93740) 43789 (91123) 30505 (91058) 15402 (88775) 610 (87338) 41663 (83930) 22810 (81558) 26349 (75650) 22237 (72247) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |151 | colspan="1" rowspan="1" |37 | colspan="1" rowspan="1" |2, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (524K) | colspan="1" rowspan="1" |15 (925) 25 (166) 32 (63) 20 (40) 8 (19) 19 (11) 17 (10) 30 (8) 7 (7) 33 (6) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |152 | colspan="1" rowspan="1" |16 | colspan="1" rowspan="1" |3, 17 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |11 (837) 6 (27) 4 (18) 13 (8) 1 (8) 9 (7) 12 (4) 2 (3) 10 (2) 7 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |153 | colspan="1" rowspan="1" |15 | colspan="1" rowspan="1" |2, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |13 (79) 3 (4) 1 (4) 12 (2) 9 (2) 8 (2) 7 (2) 14 (1) 11 (1) 10 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |154 | colspan="1" rowspan="1" |61 | colspan="1" rowspan="1" |5, 31 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (for the k=16 prime, factor N-1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=154&Exp=252&c0=-&EN= 154^252-1]) | colspan="1" rowspan="1" |40 (9256) 16 (252) 36 (138) 44 (89) 31 (88) 37 (79) 59 (17) 43 (15) 9 (15) 26 (8) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |155 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 4 (k = 1 at n=524K, k = 4 at n=1.5M) | colspan="1" rowspan="1" |3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |156 | colspan="1" rowspan="1" |unknown (>10^9, <=18406311208) | colspan="1" rowspan="1" |unknown | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |testing not started | colspan="1" rowspan="1" |testing not started | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |157 | colspan="1" rowspan="1" |47 | colspan="1" rowspan="1" |2, 5, 17 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |15, 17, 23 (all at n=2K) | colspan="1" rowspan="1" |18 (3873) 29 (1650) 38 (492) 44 (449) 30 (132) 35 (92) 20 (63) 46 (49) 40 (33) 41 (27) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |158 | colspan="1" rowspan="1" |52 | colspan="1" rowspan="1" |3, 53 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |8 (123475) 48 (24191) 32 (13401) 38 (10519) 27 (4966) 20 (1633) 37 (1034) 4 (874) 43 (178) 47 (141) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |159 | colspan="1" rowspan="1" |9 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000956052198 primality certificate for k=5]) | colspan="1" rowspan="1" |5 (234) 4 (29) 8 (5) 2 (3) 6 (2) 1 (2) 7 (1) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |160 | colspan="1" rowspan="1" |22 | colspan="1" rowspan="1" |7, 23 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |20 (2K) | colspan="1" rowspan="1" |18 (27) 14 (5) 16 (4) 9 (4) 8 (4) 7 (4) 6 (3) 15 (2) 12 (2) 5 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |161 | colspan="1" rowspan="1" |95 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 47, 79 (k = 1 at n=524K, other k at n=2K) | colspan="1" rowspan="1" |5 (5627) 4 (4650) 53 (1603) 26 (57) 40 (52) 91 (48) 13 (44) 61 (40) 19 (40) 83 (39) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |162 | colspan="1" rowspan="1" |6193 | colspan="1" rowspan="1" |5, 13, 37, 61, 163 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |363, 685, 916, 1248, 1438, 2358, 2603, 2609, 2757, 2841, 2874, 2953, 3002, 3096, 3562, 3856, 3961, 4297, 4409, 4654, 4831, 4871, 5039, 5102, 5242, 5706, 5869, 6002 (k = 6 mod 7 and k = 22 mod 23 at n=2K, other k at n=300K) | colspan="1" rowspan="1" |6102 (230090) 2212 (227663) 3052 (200790) 1764 (76926) 3496 (60128) 1250 (58127) 933 (55381) 2163 (49760) 2377 (47102) 1398 (33797) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |163 | colspan="1" rowspan="1" |81 | colspan="1" rowspan="1" |2, 41 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |8, 12, 38, 41, 63, 73 (k = 8 at n=6K, k = 12 at n=500K, other k at n=2K) | colspan="1" rowspan="1" |66 (107651) 6 (1303) 27 (409) 17 (374) 21 (236) 23 (175) 65 (148) 69 (134) 61 (84) 53 (50) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |164 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |3 (4) 1 (4) 2 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |165 | colspan="1" rowspan="1" |167 | colspan="1" rowspan="1" |2, 83 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |43 (2K) | colspan="1" rowspan="1" |80 (1104) 143 (703) 87 (589) 131 (300) 82 (273) 34 (269) 103 (137) 23 (135) 75 (74) 13 (40) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |166 | colspan="1" rowspan="1" |335 | colspan="1" rowspan="1" |3, 7, 13, 167 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |29, 137, 141, 166, 208, 209, 243, 269, 326 (all at n=2K) | colspan="1" rowspan="1" |101 (1049) 113 (318) 225 (277) 334 (156) 149 (132) 191 (129) 230 (99) 107 (86) 123 (84) 95 (81) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |167 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |2 (6547) 1 (16) 4 (10) 3 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |168 | colspan="1" rowspan="1" |9244 | colspan="1" rowspan="1" |5, 13, 17, 73 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 77, 248, 298, 467, 469, 740, 818, 901, 1236, 1377, 1437, 1886, 1998, 2183, 2211, 2378, 2406, 2731, 2770, 2963, 2991, 3057, 3514, 3654, 3717, 3977, 4161, 4174, 4224, 4226, 4382, 4441, 4499, 4517, 4616, 4746, 4913, 5303, 5381, 5474, 5526, 5539, 5680, 5812, 5981, 6083, 6124, 6166, 6241, 6319, 6356, 6382, 6772, 6787, 6824, 6967, 7032, 7099, 7123, 7292, 7422, 7541, 7697, 7708, 7736, 7916, 8164, 8293, 8334, 8971, 9138 (k = 1 at n=16.77M, k = 4174 at n=2K, other k at n=100K) | colspan="1" rowspan="1" |1561 (97864) 1398 (80456) 5942 (77280) 4432 (73477) 8072 (68617) 7188 (62211) 3394 (55546) 2614 (54002) 7240 (50425) 6892 (48868) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |169 | colspan="1" rowspan="1" |16 | colspan="1" rowspan="1" |5, 17 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (for the k=11 prime, factor N-1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=169&Exp=282&c0=-&EN= 169^282-1]) | colspan="1" rowspan="1" |11 (282) 7 (8) 14 (3) 10 (2) 8 (2) 6 (2) 5 (2) 1 (2) 15 (1) 13 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |170 | colspan="1" rowspan="1" |20 | colspan="1" rowspan="1" |3, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |7 (178) 5 (175) 19 (36) 17 (21) 13 (4) 3 (3) 2 (3) 16 (2) 10 (2) 4 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |171 | colspan="1" rowspan="1" |85 | colspan="1" rowspan="1" |2, 43 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |23, 29, 31, 39, 45, 73 (all at n=2K) | colspan="1" rowspan="1" |30 (229506) 17 (370) 69 (212) 71 (127) 77 (98) 79 (65) 58 (36) 84 (31) 37 (18) 57 (14) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |172 | colspan="1" rowspan="1" |62 | colspan="1" rowspan="1" |3, 7, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000003279055153 primality certificate for k=26], [http://factordb.com/cert.php?id=1100000003279088136 primality certificate for k=59]) | colspan="1" rowspan="1" |26 (287) 52 (259) 59 (214) 22 (108) 17 (84) 54 (35) 51 (35) 48 (26) 40 (23) 19 (15) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |173 | colspan="1" rowspan="1" |7 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (16) 4 (10) 3 (2) 6 (1) 5 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |174 | colspan="1" rowspan="1" |6 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |4 (1M) | colspan="1" rowspan="1" |1 (4) 3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |175 | colspan="1" rowspan="1" |21 | colspan="1" rowspan="1" |2, 11 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |5 (64) 15 (59) 20 (36) 11 (9) 9 (8) 14 (7) 13 (6) 18 (3) 10 (3) 2 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |176 | colspan="1" rowspan="1" |58 | colspan="1" rowspan="1" |3, 59 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |55 (2K) | colspan="1" rowspan="1" |32 (3591) 37 (3088) 35 (995) 50 (213) 10 (146) 49 (108) 28 (24) 46 (16) 31 (14) 27 (14) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |177 | colspan="1" rowspan="1" |79 | colspan="1" rowspan="1" |2, 5, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000003283553198 primality certificate for k=77]) | colspan="1" rowspan="1" |12 (3810) 77 (646) 8 (64) 33 (54) 41 (40) 67 (36) 24 (30) 15 (18) 48 (14) 63 (13) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |178 | colspan="1" rowspan="1" |569 | colspan="1" rowspan="1" |3, 13, 19 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |32, 41, 83, 96, 126, 128, 136, 155, 167, 178, 194, 212, 217, 251, 278, 283, 284, 357, 359, 372, 382, 383, 398, 407, 458, 468, 474, 480, 506, 550, 566 (all at n=2K) | colspan="1" rowspan="1" |433 (1888) 362 (1821) 410 (1626) 488 (1248) 353 (1207) 331 (1028) 363 (1018) 8 (956) 214 (889) 442 (840) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |179 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (524K) | colspan="1" rowspan="1" |3 (1) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |180 | colspan="1" rowspan="1" |1679679 | colspan="1" rowspan="1" |7, 31, 181, 1051 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |testing not started | colspan="1" rowspan="1" |testing not started | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |181 | colspan="1" rowspan="1" |15 | colspan="1" rowspan="1" |2, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |8 (10) 11 (6) 13 (5) 12 (3) 14 (2) 4 (2) 3 (2) 2 (2) 1 (2) 10 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |182 | colspan="1" rowspan="1" |23 | colspan="1" rowspan="1" |3, 5, 53 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 8 (k = 1 at n=16.77M, k = 8 at n=1M) | colspan="1" rowspan="1" |9 (263) 19 (90) 4 (70) 2 (15) 13 (12) 20 (5) 18 (4) 16 (4) 7 (4) 17 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |183 | colspan="1" rowspan="1" |45 | colspan="1" rowspan="1" |2, 23 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 5, 9, 41 (k = 1 at n=524K, other k at n=2K) | colspan="1" rowspan="1" |24 (298) 33 (198) 38 (112) 11 (59) 29 (58) 12 (48) 14 (46) 3 (35) 37 (32) 13 (24) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |184 | colspan="1" rowspan="1" |36 | colspan="1" rowspan="1" |5, 37 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (k=20 prime currently has no primality certificate) | colspan="1" rowspan="1" |20 (1298) 16 (298) 23 (70) 6 (40) 4 (29) 32 (16) 3 (11) 12 (10) 29 (9) 10 (9) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |185 | colspan="1" rowspan="1" |23 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |10, 22 (k = 10 at n=1M, k = 22 at n=2K) | colspan="1" rowspan="1" |19 (540) 4 (414) 6 (170) 13 (98) 1 (8) 21 (3) 17 (3) 9 (3) 2 (3) 16 (2) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |186 | colspan="1" rowspan="1" |67 | colspan="1" rowspan="1" |11, 17 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1, 34 (k = 1 at n=16.77M, k = 34 at n=2K) | colspan="1" rowspan="1" |65 (18879) 56 (300) 24 (258) 35 (134) 16 (107) 40 (98) 52 (72) 45 (58) 54 (29) 50 (25) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |187 | colspan="1" rowspan="1" |47 | colspan="1" rowspan="1" |2, 5, 13 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |5, 9, 29, 47, 51, 53, 61 (all at n=2K) | colspan="1" rowspan="1" |49 (938) 23 (801) 59 (141) 27 (71) 41 (68) 31 (55) 67 (47) 65 (46) 15 (43) 50 (24) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |188 | colspan="1" rowspan="1" |8 | colspan="1" rowspan="1" |3, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |4 (26) 1 (16) 2 (9) 7 (2) 3 (2) 6 (1) 5 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |189 | colspan="1" rowspan="1" |19 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (524K) | colspan="1" rowspan="1" |18 (171175) 16 (42) 6 (34) 8 (7) 11 (4) 3 (4) 9 (3) 10 (2) 5 (2) 17 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |190 | colspan="1" rowspan="1" |2157728 | colspan="1" rowspan="1" |13, 191, 2777 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |testing not started | colspan="1" rowspan="1" |testing not started | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |191 | colspan="1" rowspan="1" |5 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |3 (6K) | colspan="1" rowspan="1" |1 (32) 4 (6) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |192 | colspan="1" rowspan="1" |7879 | colspan="1" rowspan="1" |5, 7, 13, 31, 101 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |712, 787, 1031, 1157, 1234, 1369, 1388, 1627, 1806, 1828, 1899, 1929, 1931, 1965, 2311, 2313, 2461, 2482, 2521, 2537, 2672, 2807, 2928, 2988, 3020, 3346, 3604, 3827, 3929, 4024, 4054, 4672, 4768, 4826, 4859, 5010, 5059, 5147, 5262, 5373, 5752, 5927, 5958, 5982, 6133, 6257, 6474, 6523, 6968, 6995, 7152, 7414, 7437, 7528, 7600, 7666, 7822 (k = 2482 at n=2K, other k at n=100K) | colspan="1" rowspan="1" |1122 (89238) 5594 (86270) 5675 (74618) 3473 (69049) 4566 (67168) 2829 (63997) 6878 (60430) 5375 (54124) 6898 (52349) 7586 (49923) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |193 | colspan="1" rowspan="1" |2687 | colspan="1" rowspan="1" |2, 3, 5, 7, 37 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |5, 24, 63, 68, 98, 122, 131, 150, 167, 188, 193, 203, 264, 271, 290, 293, 299, 320, 333, 367, 371, 412, 413, 419, 486, 527, 542, 545, 586, 608, 632, 678, 680, 719, 722, 731, 733, 775, 790, 819, 821, 831, 852, 962, 971, 977, 1010, 1013, 1028, 1034, 1046, 1050, 1064, 1066, 1069, 1091, 1097, 1112, 1141, 1153, 1156, 1163, 1187, 1195, 1201, 1262, 1274, 1294, 1333, 1340, 1349, 1355, 1357, 1393, 1403, 1412, 1418, 1427, 1437, 1446, 1451, 1456, 1464, 1466, 1469, 1487, 1504, 1517, 1613, 1623, 1653, 1676, 1679, 1753, 1784, 1796, 1832, 1844, 1873, 1916, 1922, 1928, 1943, 1946, 1970, 1977, 1980, 1981, 1986, 2005, 2008, 2052, 2062, 2070, 2091, 2105, 2114, 2168, 2177, 2213, 2225, 2246, 2264, 2306, 2329, 2348, 2354, 2367, 2385, 2426, 2434, 2442, 2446, 2460, 2489, 2506, 2511, 2520, 2523, 2525, 2554, 2558, 2572, 2581, 2593, 2602, 2603, 2621, 2623 (all at n=2K) | colspan="1" rowspan="1" |2243 (1839) 292 (1830) 194 (1767) 929 (1763) 1049 (1729) 1238 (1702) 518 (1699) 956 (1673) 2643 (1635) 214 (1622) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |194 | colspan="1" rowspan="1" |4 | colspan="1" rowspan="1" |3, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven | colspan="1" rowspan="1" |1 (4) 3 (2) 2 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |195 | colspan="1" rowspan="1" |13 | colspan="1" rowspan="1" |2, 7 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (the k=11 prime is proven prime by N-1, and [http://factordb.com/cert.php?id=1100000001575508200 primality certificate for the large prime factor of N-1]) | colspan="1" rowspan="1" |11 (239) 8 (16) 2 (6) 9 (4) 4 (3) 5 (2) 1 (2) 12 (1) 10 (1) 7 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |196 | colspan="1" rowspan="1" |16457 | colspan="1" rowspan="1" |3, 61, 211 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |84, 155, 196, 208, 335, 421, 434, 481, 497, 729, 974, 1262, 1268, 1271, 1313, 1378, 1397, 1494, 1553, 1770, 1854, 1861, 1913, 1971, 2024, 2027, 2036, 2078, 2096, 2168, 2378, 2480, 2541, 2547, 2558, 2561, 2615, 2643, 2705, 2779, 2839, 2881, 2954, 3023, 3044, 3110, 3230, 3472, 3503, 3658, 3689, 3722, 3830, 3851, 3938, 4286, 4377, 4451, 4523, 4574, 4730, 4886, 4924, 4952, 5088, 5116, 5123, 5149, 5274, 5302, 5342, 5378, 5444, 5477, 5557, 5714, 5759, 5770, 5771, 5794, 5810, 5909, 6026, 6038, 6116, 6139, 6179, 6221, 6354, 6541, 6654, 6674, 6715, 6716, 6784, 6896, 6962, 7006, 7009, 7090, 7102, 7175, 7301, 7442, 7544, 7595, 7637, 7697, 7760, 7827, 7871, 7904, 8261, 8324, 8363, 8405, 8434, 8539, 8648, 8664, 8684, 8771, 8807, 8819, 8876, 8896, 9103, 9104, 9113, 9206, 9286, 9393, 9415, 9494, 9641, 9743, 9852, 9929, 10016, 10093, 10139, 10199, 10215, 10313, 10325, 10474, 10524, 10613, 10655, 10757, 10830, 10832, 10889, 10905, 10919, 10920, 10973, 10979, 11015, 11165, 11228, 11258, 11314, 11348, 11519, 11586, 11591, 11624, 11699, 11831, 11952, 11971, 12209, 12238, 12446, 12458, 12464, 12493, 12614, 12766, 12782, 12814, 12899, 12923, 12938, 13070, 13088, 13092, 13198, 13251, 13364, 13414, 13421, 13430, 13436, 13556, 13566, 13571, 13595, 13631, 13664, 13700, 13745, 13791, 13859, 13982, 14090, 14091, 14104, 14123, 14144, 14255, 14348, 14414, 14435, 14438, 14444, 14569, 14588, 14625, 14670, 14711, 14715, 14759, 14810, 14823, 14900, 14959, 14971, 15083, 15098, 15172, 15317, 15362, 15485, 15659, 15728, 15835, 15861, 16133, 16187, 16208, 16265, 16286, 16350, 16391 (all at n=2K) | colspan="1" rowspan="1" |789 (1926) 9609 (1914) 3618 (1887) 9530 (1823) 15177 (1804) 14390 (1790) 2082 (1774) 13983 (1772) 14585 (1767) 11387 (1767) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |197 | colspan="1" rowspan="1" |7 | colspan="1" rowspan="1" |2, 3 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |1 (524K) | colspan="1" rowspan="1" |4 (6) 6 (5) 3 (4) 5 (3) 2 (3) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |198 | colspan="1" rowspan="1" |4105 | colspan="1" rowspan="1" |7, 13, 19, 2053 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |173, 311, 374, 381, 486, 714, 907, 979, 996, 1193, 1195, 1298, 1338, 1557, 1678, 1762, 1812, 1889, 1991, 2064, 2071, 2166, 2196, 2287, 2389, 2400, 2427, 2817, 2924, 3058, 3338, 3431, 3618, 3891, 3981, 4016, 4065 (k = 2166 at n=2K, other k at n=100K) | colspan="1" rowspan="1" |1074 (86150) 2976 (78439) 4014 (73851) 2864 (62462) 2084 (56478) 706 (55247) 2253 (54740) 621 (53839) 3962 (49750) 758 (47832) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |199 | colspan="1" rowspan="1" |9 | colspan="1" rowspan="1" |2, 5 | colspan="1" rowspan="1" | | colspan="1" rowspan="1" |none - proven (for the k=3 prime, factor N+1 is equivalent to factor [http://myfactorcollection.mooo.com:8090/cgi-bin/showSingleEntry?Base=199&Exp=183&c0=%2B&EN= 199^183+1]) | colspan="1" rowspan="1" |3 (183) 2 (16) 5 (6) 7 (3) 8 (2) 6 (2) 1 (2) 4 (1) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |200 | colspan="1" rowspan="1" |47 | colspan="1" rowspan="1" |3, 13, 17 | colspan="1" rowspan="1" |k = 16: odd n: factor of 3 n = = 0 mod 4: factor of 17 n = = 2 mod 4: let n = 4*q - 2 and let m = 20^q*10^(q-1); factors to: (2*m^2 + 2m + 1) * (2*m^2 - 2m + 1) | colspan="1" rowspan="1" |1, 40 (k = 1 at n=16.77M, k = 40 at n=1M) | colspan="1" rowspan="1" |25 (21874) 10 (6036) 13 (1858) 38 (1669) 26 (1011) 5 (767) 34 (710) 19 (528) 46 (226) 43 (124) | colspan="1" rowspan="1" | |- | colspan="1" rowspan="1" |256 | colspan="1" rowspan="1" |38 | colspan="1" rowspan="1" |3, 7, 13 | colspan="1" rowspan="1" |All k=4*q^4 for all n: let k=4*q^4 and let m=q*4^n; factors to: (2*m^2 + 2m + 1) * (2*m^2 - 2m + 1) | colspan="1" rowspan="1" |none - proven ([http://factordb.com/cert.php?id=1100000000317528486 primality certificate for k=11], [http://factordb.com/cert.php?id=1100000000001707231 primality certificate for k=23]) | colspan="1" rowspan="1" |11 (5702) 23 (537) 20 (20) 7 (15) 22 (10) 25 (8) 15 (6) 36 (5) 6 (5) 28 (3) | colspan="1" rowspan="1" |k = 4 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |512 | colspan="1" rowspan="1" |18 | colspan="1" rowspan="1" |5, 13, 19 | colspan="1" rowspan="1" |All k = m^3 for all n; factors to: (m*8^n + 1) * (m^2*64^n - m*8^n + 1) | colspan="1" rowspan="1" |2, 4, 5, 16 (k = 2 at n=2.001P, k = 4 at n=62.54T, k = 5 at n=1M, k = 16 at n=1.954T) | colspan="1" rowspan="1" |12 (23) 14 (21) 7 (20) 11 (9) 9 (7) 10 (6) 17 (3) 13 (2) 3 (2) 15 (1) | colspan="1" rowspan="1" |k = 1 and 8 proven composite by full algebraic factors. |- | colspan="1" rowspan="1" |1024 | colspan="1" rowspan="1" |81 | colspan="1" rowspan="1" |5, 41 | colspan="1" rowspan="1" |All k = m^5 for all n; factors to: (m*4^n + 1) * (m^4*256^n - m^3*64^n + m^2*16^n - m*4^n + 1) | colspan="1" rowspan="1" |4, 16, 29, 38, 56 (k = 4 at n=858.9M, k = 16 at n=1.717G, other k at n=3K) | colspan="1" rowspan="1" |44 (1933) 41 (350) 9 (323) 51 (266) 14 (221) 33 (142) 48 (53) 11 (46) 54 (37) 10 (36) | colspan="1" rowspan="1" |k = 1 and 32 proven composite by full algebraic factors. |} a7wx2kf08iffjw2mqucwgjd20r1oc9n 2 285290 2408094 2407263 2022-07-20T03:20:50Z Jtwsaddress42 234843 /* Wächtershäuser, Günter (1938 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:G%C3%BCnter_W%C3%A4chtersh%C3%A4user|Wächtershäuser, Günter (1938 - )]] === [[File:Drwachteshauser1-signed.jpg|thumb|Günter Wächtershäuser (1938 - )]] '''Notable Accomplishments''' * The Iron-Sulfur World theory of Chemoautotrophic Origins <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Wächtershäuser,_Günter}} <br /><hr /> {{User:Jtwsaddress42/Bibliography/Wächtershäuser et al.}} <br /><hr /> '''Articles about Günter Wächtershäuser''' {{User:Jtwsaddress42/Bibliography/Hagmann, Michael}} {{RoundBoxBottom}} <hr /> trqc9c4hbqb58yg4ee7lylel25m73sd 2 285325 2408062 2406594 2022-07-20T01:25:42Z Jtwsaddress42 234843 /* Krishnamurti, Jiddu (1895-1986) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Jiddu Krishnamurti|Krishnamurti, Jiddu (1895-1986)]] === [[File:Jiddu Krishnamurti 01.jpg|thumb|Jiddu Krishnamurti (1895-1986)]] '''Notable Accomplishments''' * Dissolved Theosophical "Order of the Star in the East" and renounced his role as a prophetic vehicle for the World Teacher. * Krishnamurti-Bohm Dialogs <br /> <hr /> {{User:Jtwsaddress42/Quotes/Krishnamurti, Jiddu 1969a}} {{User:Jtwsaddress42/Gallery/Jiddu Krishnamurti}} <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Krishnamurti, Jiddu}} {{RoundBoxBottom}} <hr /> r68d6359arvoieji29a2r5r97qhdrxu 2 285343 2408061 2406619 2022-07-20T01:18:24Z Jtwsaddress42 234843 /* Kandel, Eric R. (1929-) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Eric Kandel|Kandel, Eric R. (1929-)]] === [[File:Eric Kandel 1978.jpg|thumb|Eric Kandel 1978]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/2000/kandel/facts/ The Nobel Prize in Physiology or Medicine 2000 ] - shared with Arvid Carlsson and Paul Greengard “for their discoveries concerning signal transduction in the nervous system.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Kandel, Eric R.}} <br /><hr /> {{User:Jtwsaddress42/Bibliography/Kandel et al.}} {{RoundBoxBottom}} <hr /> p2zh1qoq7meh1vl7yo1hj2bci3was45 4 285346 2408144 2407968 2022-07-20T10:01:54Z Bert Niehaus 2387134 /* Voting */ wikitext text/x-wiki === {{User|Eyoungstrom}} === [[User:Eyoungstrom|Eyoungstrom]] is being nominated by users [[User:Ncharamut|Ncharamut]] and [[User:Cody naccarato|Cody naccarato]]. He has been editing for over 7 years with a good track record of good-faith edits related to psychological information. He is associated with the non-profit HGAPS, and would help to monitor pages created by the group. He has successfully appealed to consensus, and has positive history with [[User:OhanaUnited|OhanaUnited]], [[User:Dave Braunschweig|Dave Braunschweig]], and [[User:Evolution and evolvability|Evolution and evolvability]]. Other Wiki affiliations include good editing history and civil discussions on Wikipedia. Eyoungstrom is also a member of the [[WikiJournal User Group]]. In this group, he has served as an editor for the [[WikiJournal of Medicine]], and is working to establish the [[WikiJournal of Psychology, Psychiatry and Behavioral Sciences]]. He is also a member of the [https://meta.wikimedia.org/wiki/North_Carolina_Wikipedians North Carolina Wikipedians user group] and the [https://meta.wikimedia.org/wiki/H-GAPS_User_Group HGAPS user group]. In all, we think his endorsement for curatorship will be a great asset to Wikiversity, which is supported by his suburb editing history and willingness to collaborate openly and fairly. This nomination comes as a suggestion from [[User:Dave Braunschweig|Dave Braunschweig]] to [[User:Ncharamut|Ncharamut]] as a result of recent vandalism across a few of HGAPS' wiki pages containing sensitive information. ==== Questions ==== ==== Comments ==== As I am completely out of my depth to make any judgement calls on anyone's nomination I can only say that what little I've read about the nomination and the candidate that he would be a worthy addition. [[User:Hamish84|Hamish84]] ([[User talk:Hamish84|discuss]] • [[Special:Contributions/Hamish84|contribs]]) 06:42, 19 July 2022 (UTC) Hamish84 James Brines. ==== Voting ==== * {{support}} [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 02:05, 16 July 2022 (UTC) * {{support}} --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 02:21, 16 July 2022 (UTC) * {{support}} [[User:Bobbyshabangu|Bobbyshabangu]] ([[User talk:Bobbyshabangu|discuss]] • [[Special:Contributions/Bobbyshabangu|contribs]]) 13:49, 16 July 2022 (UTC) *{{support}} --[[User:Lbeaumont|Lbeaumont]] ([[User talk:Lbeaumont|discuss]] • [[Special:Contributions/Lbeaumont|contribs]]) 14:28, 17 July 2022 (UTC) *{{support}} --[[User:Bert Niehaus|Bert Niehaus]] ([[User talk:Bert Niehaus|discuss]] • [[Special:Contributions/Bert Niehaus|contribs]]) 10:01, 20 July 2022 (UTC) gy7s5aazl7v08nmnb1oivfqxlyu1yrv 0 285380 2408005 2407834 2022-07-19T14:39:09Z Young1lim 21186 /* Applications */ wikitext text/x-wiki === Introduction === * Overview ([[Media:C01.Intro1.Overview.1.A.20170925.pdf |A.pdf]], [[Media:C01.Intro1.Overview.1.B.20170901.pdf |B.pdf]], [[Media:C01.Intro1.Overview.1.C.20170904.pdf |C.pdf]]) * Number System ([[Media:C01.Intro2.Number.1.A.20171023.pdf |A.pdf]], [[Media:C01.Intro2.Number.1.B.20170909.pdf |B.pdf]], [[Media:C01.Intro2.Number.1.C.20170914.pdf |C.pdf]]) * Memory System ([[Media:C01.Intro2.Memory.1.A.20170907.pdf |A.pdf]], [[Media:C01.Intro3.Memory.1.B.20170909.pdf |B.pdf]], [[Media:C01.Intro3.Memory.1.C.20170914.pdf |C.pdf]]) === Handling Repetition === * Control ([[Media:C02.Repeat1.Control.1.A.20170925.pdf |A.pdf]], [[Media:C02.Repeat1.Control.1.B.20170918.pdf |B.pdf]], [[Media:C02.Repeat1.Control.1.C.20170926.pdf |C.pdf]]) * Loop ([[Media:C02.Repeat2.Loop.1.A.20170925.pdf |A.pdf]], [[Media:C02.Repeat2.Loop.1.B.20170918.pdf |B.pdf]]) === Handling a Big Work === * Function Overview ([[Media:C03.Func1.Overview.1.A.20171030.pdf |A.pdf]], [[Media:C03.Func1.Oerview.1.B.20161022.pdf |B.pdf]]) * Functions & Variables ([[Media:C03.Func2.Variable.1.A.20161222.pdf |A.pdf]], [[Media:C03.Func2.Variable.1.B.20161222.pdf |B.pdf]]) * Functions & Pointers ([[Media:C03.Func3.Pointer.1.A.20161122.pdf |A.pdf]], [[Media:C03.Func3.Pointer.1.B.20161122.pdf |B.pdf]]) * Functions & Recursions ([[Media:C03.Func4.Recursion.1.A.20161214.pdf |A.pdf]], [[Media:C03.Func4.Recursion.1.B.20161214.pdf |B.pdf]]) === Handling Series of Data === ==== Background ==== * Background ([[Media:C04.Series0.Background.1.A.20180727.pdf |A.pdf]]) ==== Basics ==== * Arrays ([[Media:C04.Series1.Array.1.A.20220718.pdf |A.pdf]], [[Media:C04.Series1.Array.1.B.20161115.pdf |B.pdf]]) * Pointers ([[Media:C04.Series2.Pointer.1.A.20180726.pdf |A.pdf]], [[Media:C04.Series2.Pointer.1.B.20161115.pdf |B.pdf]]) * Array Pointers ([[Media:C04.Series3.ArrayPointer.1.A.20220718.pdf |A.pdf]], [[Media:C04.Series3.ArrayPointer.1.B.20181203.pdf |B.pdf]]) * Multi-dimensional Arrays ([[Media:C04.Series4.MultiDim.1.A.20220418.pdf |A.pdf]], [[Media:C04.Series4.MultiDim.1.B.11.pdf |B.pdf]]) * Array Access Methods ([[Media:C04.Series4.ArrayAccess.1.A.20190511.pdf |A.pdf]], [[Media:C04.Series3.ArrayPointer.1.B.20181203.pdf |B.pdf]]) * Structures ([[Media:C04.Series3.Structure.1.A.20171204.pdf |A.pdf]], [[Media:C04.Series2.Structure.1.B.20161130.pdf |B.pdf]]) ==== Applications ==== * Applications of Arrays ([[Media:C04.Series1App.Array.1.A.20220718.pdf |A.pdf]]) * Applications of Pointers ([[Media:C04.Series7.AppPoint.1.A.20200424.pdf |A.pdf]]) * Applications of Array Pointers ([[Media:C04.Series3App.ArrayPointer.1.A.2022024.pdf |A.pdf]]) * Applications of Multi-dimensional Arrays ([[Media:C04.Series4App.MultiDim.1.A.20210719.pdf |A.pdf]]) * Applications of Array Access Methods ([[Media:C04.Series9.AppArrAcess.1.A.20190511.pdf |A.pdf]]) * Applications of Structures ([[Media:C04.Series6.AppStruct.1.A.20190423.pdf |A.pdf]]) ==== Examples ==== * Spreadsheet Example Programs :: Example 1 ([[Media:C04.Series7.Example.1.A.20171213.pdf |A.pdf]], [[Media:C04.Series7.Example.1.C.20171213.pdf |C.pdf]]) :: Example 2 ([[Media:C04.Series7.Example.2.A.20171213.pdf |A.pdf]], [[Media:C04.Series7.Example.2.C.20171213.pdf |C.pdf]]) :: Example 3 ([[Media:C04.Series7.Example.3.A.20171213.pdf |A.pdf]], [[Media:C04.Series7.Example.3.C.20171213.pdf |C.pdf]]) :: Bubble Sort ([[Media:C04.Series7.BubbleSort.1.A.20171211.pdf |A.pdf]]) === Handling Various Kinds of Data === * Types ([[Media:C05.Data1.Type.1.A.20180217.pdf |A.pdf]], [[Media:C05.Data1.Type.1.B.20161212.pdf |B.pdf]]) * Typecasts ([[Media:C05.Data2.TypeCast.1.A.20180217.pdf |A.pdf]], [[Media:C05.Data2.TypeCast.1.B.20161216.pdf |A.pdf]]) * Operators ([[Media:C05.Data3.Operators.1.A.20161219.pdf |A.pdf]], [[Media:C05.Data3.Operators.1.B.20161216.pdf |B.pdf]]) * Files ([[Media:C05.Data4.File.1.A.20161124.pdf |A.pdf]], [[Media:C05.Data4.File.1.B.20161212.pdf |B.pdf]]) === Handling Low Level Operations === * Bitwise Operations ([[Media:BitOp.1.B.20161214.pdf |A.pdf]], [[Media:BitOp.1.B.20161203.pdf |B.pdf]]) * Bit Field ([[Media:BitField.1.A.20161214.pdf |A.pdf]], [[Media:BitField.1.B.20161202.pdf |B.pdf]]) * Union ([[Media:Union.1.A.20161221.pdf |A.pdf]], [[Media:Union.1.B.20161111.pdf |B.pdf]]) * Accessing IO Registers ([[Media:IO.1.A.20141215.pdf |A.pdf]], [[Media:IO.1.B.20161217.pdf |B.pdf]]) === Declarations === * Type Specifiers and Qualifiers ([[Media:C07.Spec1.Type.1.A.20171004.pdf |pdf]]) * Storage Class Specifiers ([[Media:C07.Spec2.Storage.1.A.20171009.pdf |pdf]]) * Scope === Class Notes === * TOC ([[Media:TOC.20171007.pdf |TOC.pdf]]) * Day01 ([[Media:Day01.A.20171007.pdf |A.pdf]], [[Media:Day01.B.20171209.pdf |B.pdf]], [[Media:Day01.C.20171211.pdf |C.pdf]]) ...... Introduction (1) Standard Library * Day02 ([[Media:Day02.A.20171007.pdf |A.pdf]], [[Media:Day02.B.20171209.pdf |B.pdf]], [[Media:Day02.C.20171209.pdf |C.pdf]]) ...... Introduction (2) Basic Elements * Day03 ([[Media:Day03.A.20171007.pdf |A.pdf]], [[Media:Day03.B.20170908.pdf |B.pdf]], [[Media:Day03.C.20171209.pdf |C.pdf]]) ...... Introduction (3) Numbers * Day04 ([[Media:Day04.A.20171007.pdf |A.pdf]], [[Media:Day04.B.20170915.pdf |B.pdf]], [[Media:Day04.C.20171209.pdf |C.pdf]]) ...... Structured Programming (1) Flowcharts * Day05 ([[Media:Day05.A.20171007.pdf |A.pdf]], [[Media:Day05.B.20170915.pdf |B.pdf]], [[Media:Day05.C.20171209.pdf |C.pdf]]) ...... Structured Programming (2) Conditions and Loops * Day06 ([[Media:Day06.A.20171007.pdf |A.pdf]], [[Media:Day06.B.20170923.pdf |B.pdf]], [[Media:Day06.C.20171209.pdf |C.pdf]]) ...... Program Control * Day07 ([[Media:Day07.A.20171007.pdf |A.pdf]], [[Media:Day07.B.20170926.pdf |B.pdf]], [[Media:Day07.C.20171209.pdf |C.pdf]]) ...... Function (1) Definitions * Day08 ([[Media:Day08.A.20171028.pdf |A.pdf]], [[Media:Day08.B.20171016.pdf |B.pdf]], [[Media:Day08.C.20171209.pdf |C.pdf]]) ...... Function (2) Storage Class and Scope * Day09 ([[Media:Day09.A.20171007.pdf |A.pdf]], [[Media:Day09.B.20171017.pdf |B.pdf]], [[Media:Day09.C.20171209.pdf |C.pdf]]) ...... Function (3) Recursion * Day10 ([[Media:Day10.A.20171209.pdf |A.pdf]], [[Media:Day10.B.20171017.pdf |B.pdf]], [[Media:Day10.C.20171209.pdf |C.pdf]]) ...... Arrays (1) Definitions * Day11 ([[Media:Day11.A.20171024.pdf |A.pdf]], [[Media:Day11.B.20171017.pdf |B.pdf]], [[Media:Day11.C.20171212.pdf |C.pdf]]) ...... Arrays (2) Applications * Day12 ([[Media:Day12.A.20171024.pdf |A.pdf]], [[Media:Day12.B.20171020.pdf |B.pdf]], [[Media:Day12.C.20171209.pdf |C.pdf]]) ...... Pointers (1) Definitions * Day13 ([[Media:Day13.A.20171025.pdf |A.pdf]], [[Media:Day13.B.20171024.pdf |B.pdf]], [[Media:Day13.C.20171209.pdf |C.pdf]]) ...... Pointers (2) Applications * Day14 ([[Media:Day14.A.20171226.pdf |A.pdf]], [[Media:Day14.B.20171101.pdf |B.pdf]], [[Media:Day14.C.20171209.pdf |C.pdf]]) ...... C String (1) * Day15 ([[Media:Day15.A.20171209.pdf |A.pdf]], [[Media:Day15.B.20171124.pdf |B.pdf]], [[Media:Day15.C.20171209.pdf |C.pdf]]) ...... C String (2) * Day16 ([[Media:Day16.A.20171208.pdf |A.pdf]], [[Media:Day16.B.20171114.pdf |B.pdf]], [[Media:Day16.C.20171209.pdf |C.pdf]]) ...... C Formatted IO * Day17 ([[Media:Day17.A.20171031.pdf |A.pdf]], [[Media:Day17.B.20171111.pdf |B.pdf]], [[Media:Day17.C.20171209.pdf |C.pdf]]) ...... Structure (1) Definitions * Day18 ([[Media:Day18.A.20171206.pdf |A.pdf]], [[Media:Day18.B.20171128.pdf |B.pdf]], [[Media:Day18.C.20171212.pdf |C.pdf]]) ...... Structure (2) Applications * Day19 ([[Media:Day19.A.20171205.pdf |A.pdf]], [[Media:Day19.B.20171121.pdf |B.pdf]], [[Media:Day19.C.20171209.pdf |C.pdf]]) ...... Union, Bitwise Operators, Enum * Day20 ([[Media:Day20.A.20171205.pdf |A.pdf]], [[Media:Day20.B.20171201.pdf |B.pdf]], [[Media:Day20.C.20171212.pdf |C.pdf]]) ...... Linked List * Day21 ([[Media:Day21.A.20171206.pdf |A.pdf]], [[Media:Day21.B.20171208.pdf |B.pdf]], [[Media:Day21.C.20171212.pdf |C.pdf]]) ...... File Processing * Day22 ([[Media:Day22.A.20171212.pdf |A.pdf]], [[Media:Day22.B.20171213.pdf |B.pdf]], [[Media:Day22.C.20171212.pdf |C.pdf]]) ...... Preprocessing <!----------------------------------------------------------------------> </br> See also https://cprogramex.wordpress.com/ == '''Old Materials '''== until 201201 * Intro.Overview.1.A ([[Media:C.Intro.Overview.1.A.20120107.pdf |pdf]]) * Intro.Memory.1.A ([[Media:C.Intro.Memory.1.A.20120107.pdf |pdf]]) * Intro.Number.1.A ([[Media:C.Intro.Number.1.A.20120107.pdf |pdf]]) * Repeat.Control.1.A ([[Media:C.Repeat.Control.1.A.20120109.pdf |pdf]]) * Repeat.Loop.1.A ([[Media:C.Repeat.Loop.1.A.20120113.pdf |pdf]]) * Work.Function.1.A ([[Media:C.Work.Function.1.A.20120117.pdf |pdf]]) * Work.Scope.1.A ([[Media:C.Work.Scope.1.A.20120117.pdf |pdf]]) * Series.Array.1.A ([[Media:Series.Array.1.A.20110718.pdf |pdf]]) * Series.Pointer.1.A ([[Media:Series.Pointer.1.A.20110719.pdf |pdf]]) * Series.Structure.1.A ([[Media:Series.Structure.1.A.20110805.pdf |pdf]]) * Data.Type.1.A ([[Media:C05.Data2.TypeCast.1.A.20130813.pdf |pdf]]) * Data.TypeCast.1.A ([[Media:Data.TypeCast.1.A.pdf |pdf]]) * Data.Operators.1.A ([[Media:Data.Operators.1.A.20110712.pdf |pdf]]) <br> until 201107 * Intro.1.A ([[Media:Intro.1.A.pdf |pdf]]) * Control.1.A ([[Media:Control.1.A.20110706.pdf |pdf]]) * Iteration.1.A ([[Media:Iteration.1.A.pdf |pdf]]) * Function.1.A ([[Media:Function.1.A.20110705.pdf |pdf]]) * Variable.1.A ([[Media:Variable.1.A.20110708.pdf |pdf]]) * Operators.1.A ([[Media:Operators.1.A.20110712.pdf |pdf]]) * Pointer.1.A ([[Media:Pointer.1.A.pdf |pdf]]) * Pointer.2.A ([[Media:Pointer.2.A.pdf |pdf]]) * Array.1.A ([[Media:Array.1.A.pdf |pdf]]) * Type.1.A ([[Media:Type.1.A.pdf |pdf]]) * Structure.1.A ([[Media:Structure.1.A.pdf |pdf]]) go to [ [[C programming in plain view]] ] [[Category:C programming]] </br> tgdiq2qlt3jyaqi24uu2a8va03jwj6u 2408011 2408005 2022-07-19T14:42:11Z Young1lim 21186 /* Applications */ wikitext text/x-wiki === Introduction === * Overview ([[Media:C01.Intro1.Overview.1.A.20170925.pdf |A.pdf]], [[Media:C01.Intro1.Overview.1.B.20170901.pdf |B.pdf]], [[Media:C01.Intro1.Overview.1.C.20170904.pdf |C.pdf]]) * Number System ([[Media:C01.Intro2.Number.1.A.20171023.pdf |A.pdf]], [[Media:C01.Intro2.Number.1.B.20170909.pdf |B.pdf]], [[Media:C01.Intro2.Number.1.C.20170914.pdf |C.pdf]]) * Memory System ([[Media:C01.Intro2.Memory.1.A.20170907.pdf |A.pdf]], [[Media:C01.Intro3.Memory.1.B.20170909.pdf |B.pdf]], [[Media:C01.Intro3.Memory.1.C.20170914.pdf |C.pdf]]) === Handling Repetition === * Control ([[Media:C02.Repeat1.Control.1.A.20170925.pdf |A.pdf]], [[Media:C02.Repeat1.Control.1.B.20170918.pdf |B.pdf]], [[Media:C02.Repeat1.Control.1.C.20170926.pdf |C.pdf]]) * Loop ([[Media:C02.Repeat2.Loop.1.A.20170925.pdf |A.pdf]], [[Media:C02.Repeat2.Loop.1.B.20170918.pdf |B.pdf]]) === Handling a Big Work === * Function Overview ([[Media:C03.Func1.Overview.1.A.20171030.pdf |A.pdf]], [[Media:C03.Func1.Oerview.1.B.20161022.pdf |B.pdf]]) * Functions & Variables ([[Media:C03.Func2.Variable.1.A.20161222.pdf |A.pdf]], [[Media:C03.Func2.Variable.1.B.20161222.pdf |B.pdf]]) * Functions & Pointers ([[Media:C03.Func3.Pointer.1.A.20161122.pdf |A.pdf]], [[Media:C03.Func3.Pointer.1.B.20161122.pdf |B.pdf]]) * Functions & Recursions ([[Media:C03.Func4.Recursion.1.A.20161214.pdf |A.pdf]], [[Media:C03.Func4.Recursion.1.B.20161214.pdf |B.pdf]]) === Handling Series of Data === ==== Background ==== * Background ([[Media:C04.Series0.Background.1.A.20180727.pdf |A.pdf]]) ==== Basics ==== * Arrays ([[Media:C04.Series1.Array.1.A.20220718.pdf |A.pdf]], [[Media:C04.Series1.Array.1.B.20161115.pdf |B.pdf]]) * Pointers ([[Media:C04.Series2.Pointer.1.A.20180726.pdf |A.pdf]], [[Media:C04.Series2.Pointer.1.B.20161115.pdf |B.pdf]]) * Array Pointers ([[Media:C04.Series3.ArrayPointer.1.A.20220718.pdf |A.pdf]], [[Media:C04.Series3.ArrayPointer.1.B.20181203.pdf |B.pdf]]) * Multi-dimensional Arrays ([[Media:C04.Series4.MultiDim.1.A.20220418.pdf |A.pdf]], [[Media:C04.Series4.MultiDim.1.B.11.pdf |B.pdf]]) * Array Access Methods ([[Media:C04.Series4.ArrayAccess.1.A.20190511.pdf |A.pdf]], [[Media:C04.Series3.ArrayPointer.1.B.20181203.pdf |B.pdf]]) * Structures ([[Media:C04.Series3.Structure.1.A.20171204.pdf |A.pdf]], [[Media:C04.Series2.Structure.1.B.20161130.pdf |B.pdf]]) ==== Applications ==== * Applications of Arrays ([[Media:C04.Series1App.Array.1.A.20220719.pdf |A.pdf]]) * Applications of Pointers ([[Media:C04.Series7.AppPoint.1.A.20200424.pdf |A.pdf]]) * Applications of Array Pointers ([[Media:C04.Series3App.ArrayPointer.1.A.2022024.pdf |A.pdf]]) * Applications of Multi-dimensional Arrays ([[Media:C04.Series4App.MultiDim.1.A.20210719.pdf |A.pdf]]) * Applications of Array Access Methods ([[Media:C04.Series9.AppArrAcess.1.A.20190511.pdf |A.pdf]]) * Applications of Structures ([[Media:C04.Series6.AppStruct.1.A.20190423.pdf |A.pdf]]) ==== Examples ==== * Spreadsheet Example Programs :: Example 1 ([[Media:C04.Series7.Example.1.A.20171213.pdf |A.pdf]], [[Media:C04.Series7.Example.1.C.20171213.pdf |C.pdf]]) :: Example 2 ([[Media:C04.Series7.Example.2.A.20171213.pdf |A.pdf]], [[Media:C04.Series7.Example.2.C.20171213.pdf |C.pdf]]) :: Example 3 ([[Media:C04.Series7.Example.3.A.20171213.pdf |A.pdf]], [[Media:C04.Series7.Example.3.C.20171213.pdf |C.pdf]]) :: Bubble Sort ([[Media:C04.Series7.BubbleSort.1.A.20171211.pdf |A.pdf]]) === Handling Various Kinds of Data === * Types ([[Media:C05.Data1.Type.1.A.20180217.pdf |A.pdf]], [[Media:C05.Data1.Type.1.B.20161212.pdf |B.pdf]]) * Typecasts ([[Media:C05.Data2.TypeCast.1.A.20180217.pdf |A.pdf]], [[Media:C05.Data2.TypeCast.1.B.20161216.pdf |A.pdf]]) * Operators ([[Media:C05.Data3.Operators.1.A.20161219.pdf |A.pdf]], [[Media:C05.Data3.Operators.1.B.20161216.pdf |B.pdf]]) * Files ([[Media:C05.Data4.File.1.A.20161124.pdf |A.pdf]], [[Media:C05.Data4.File.1.B.20161212.pdf |B.pdf]]) === Handling Low Level Operations === * Bitwise Operations ([[Media:BitOp.1.B.20161214.pdf |A.pdf]], [[Media:BitOp.1.B.20161203.pdf |B.pdf]]) * Bit Field ([[Media:BitField.1.A.20161214.pdf |A.pdf]], [[Media:BitField.1.B.20161202.pdf |B.pdf]]) * Union ([[Media:Union.1.A.20161221.pdf |A.pdf]], [[Media:Union.1.B.20161111.pdf |B.pdf]]) * Accessing IO Registers ([[Media:IO.1.A.20141215.pdf |A.pdf]], [[Media:IO.1.B.20161217.pdf |B.pdf]]) === Declarations === * Type Specifiers and Qualifiers ([[Media:C07.Spec1.Type.1.A.20171004.pdf |pdf]]) * Storage Class Specifiers ([[Media:C07.Spec2.Storage.1.A.20171009.pdf |pdf]]) * Scope === Class Notes === * TOC ([[Media:TOC.20171007.pdf |TOC.pdf]]) * Day01 ([[Media:Day01.A.20171007.pdf |A.pdf]], [[Media:Day01.B.20171209.pdf |B.pdf]], [[Media:Day01.C.20171211.pdf |C.pdf]]) ...... Introduction (1) Standard Library * Day02 ([[Media:Day02.A.20171007.pdf |A.pdf]], [[Media:Day02.B.20171209.pdf |B.pdf]], [[Media:Day02.C.20171209.pdf |C.pdf]]) ...... Introduction (2) Basic Elements * Day03 ([[Media:Day03.A.20171007.pdf |A.pdf]], [[Media:Day03.B.20170908.pdf |B.pdf]], [[Media:Day03.C.20171209.pdf |C.pdf]]) ...... Introduction (3) Numbers * Day04 ([[Media:Day04.A.20171007.pdf |A.pdf]], [[Media:Day04.B.20170915.pdf |B.pdf]], [[Media:Day04.C.20171209.pdf |C.pdf]]) ...... Structured Programming (1) Flowcharts * Day05 ([[Media:Day05.A.20171007.pdf |A.pdf]], [[Media:Day05.B.20170915.pdf |B.pdf]], [[Media:Day05.C.20171209.pdf |C.pdf]]) ...... Structured Programming (2) Conditions and Loops * Day06 ([[Media:Day06.A.20171007.pdf |A.pdf]], [[Media:Day06.B.20170923.pdf |B.pdf]], [[Media:Day06.C.20171209.pdf |C.pdf]]) ...... Program Control * Day07 ([[Media:Day07.A.20171007.pdf |A.pdf]], [[Media:Day07.B.20170926.pdf |B.pdf]], [[Media:Day07.C.20171209.pdf |C.pdf]]) ...... Function (1) Definitions * Day08 ([[Media:Day08.A.20171028.pdf |A.pdf]], [[Media:Day08.B.20171016.pdf |B.pdf]], [[Media:Day08.C.20171209.pdf |C.pdf]]) ...... Function (2) Storage Class and Scope * Day09 ([[Media:Day09.A.20171007.pdf |A.pdf]], [[Media:Day09.B.20171017.pdf |B.pdf]], [[Media:Day09.C.20171209.pdf |C.pdf]]) ...... Function (3) Recursion * Day10 ([[Media:Day10.A.20171209.pdf |A.pdf]], [[Media:Day10.B.20171017.pdf |B.pdf]], [[Media:Day10.C.20171209.pdf |C.pdf]]) ...... Arrays (1) Definitions * Day11 ([[Media:Day11.A.20171024.pdf |A.pdf]], [[Media:Day11.B.20171017.pdf |B.pdf]], [[Media:Day11.C.20171212.pdf |C.pdf]]) ...... Arrays (2) Applications * Day12 ([[Media:Day12.A.20171024.pdf |A.pdf]], [[Media:Day12.B.20171020.pdf |B.pdf]], [[Media:Day12.C.20171209.pdf |C.pdf]]) ...... Pointers (1) Definitions * Day13 ([[Media:Day13.A.20171025.pdf |A.pdf]], [[Media:Day13.B.20171024.pdf |B.pdf]], [[Media:Day13.C.20171209.pdf |C.pdf]]) ...... Pointers (2) Applications * Day14 ([[Media:Day14.A.20171226.pdf |A.pdf]], [[Media:Day14.B.20171101.pdf |B.pdf]], [[Media:Day14.C.20171209.pdf |C.pdf]]) ...... C String (1) * Day15 ([[Media:Day15.A.20171209.pdf |A.pdf]], [[Media:Day15.B.20171124.pdf |B.pdf]], [[Media:Day15.C.20171209.pdf |C.pdf]]) ...... C String (2) * Day16 ([[Media:Day16.A.20171208.pdf |A.pdf]], [[Media:Day16.B.20171114.pdf |B.pdf]], [[Media:Day16.C.20171209.pdf |C.pdf]]) ...... C Formatted IO * Day17 ([[Media:Day17.A.20171031.pdf |A.pdf]], [[Media:Day17.B.20171111.pdf |B.pdf]], [[Media:Day17.C.20171209.pdf |C.pdf]]) ...... Structure (1) Definitions * Day18 ([[Media:Day18.A.20171206.pdf |A.pdf]], [[Media:Day18.B.20171128.pdf |B.pdf]], [[Media:Day18.C.20171212.pdf |C.pdf]]) ...... Structure (2) Applications * Day19 ([[Media:Day19.A.20171205.pdf |A.pdf]], [[Media:Day19.B.20171121.pdf |B.pdf]], [[Media:Day19.C.20171209.pdf |C.pdf]]) ...... Union, Bitwise Operators, Enum * Day20 ([[Media:Day20.A.20171205.pdf |A.pdf]], [[Media:Day20.B.20171201.pdf |B.pdf]], [[Media:Day20.C.20171212.pdf |C.pdf]]) ...... Linked List * Day21 ([[Media:Day21.A.20171206.pdf |A.pdf]], [[Media:Day21.B.20171208.pdf |B.pdf]], [[Media:Day21.C.20171212.pdf |C.pdf]]) ...... File Processing * Day22 ([[Media:Day22.A.20171212.pdf |A.pdf]], [[Media:Day22.B.20171213.pdf |B.pdf]], [[Media:Day22.C.20171212.pdf |C.pdf]]) ...... Preprocessing <!----------------------------------------------------------------------> </br> See also https://cprogramex.wordpress.com/ == '''Old Materials '''== until 201201 * Intro.Overview.1.A ([[Media:C.Intro.Overview.1.A.20120107.pdf |pdf]]) * Intro.Memory.1.A ([[Media:C.Intro.Memory.1.A.20120107.pdf |pdf]]) * Intro.Number.1.A ([[Media:C.Intro.Number.1.A.20120107.pdf |pdf]]) * Repeat.Control.1.A ([[Media:C.Repeat.Control.1.A.20120109.pdf |pdf]]) * Repeat.Loop.1.A ([[Media:C.Repeat.Loop.1.A.20120113.pdf |pdf]]) * Work.Function.1.A ([[Media:C.Work.Function.1.A.20120117.pdf |pdf]]) * Work.Scope.1.A ([[Media:C.Work.Scope.1.A.20120117.pdf |pdf]]) * Series.Array.1.A ([[Media:Series.Array.1.A.20110718.pdf |pdf]]) * Series.Pointer.1.A ([[Media:Series.Pointer.1.A.20110719.pdf |pdf]]) * Series.Structure.1.A ([[Media:Series.Structure.1.A.20110805.pdf |pdf]]) * Data.Type.1.A ([[Media:C05.Data2.TypeCast.1.A.20130813.pdf |pdf]]) * Data.TypeCast.1.A ([[Media:Data.TypeCast.1.A.pdf |pdf]]) * Data.Operators.1.A ([[Media:Data.Operators.1.A.20110712.pdf |pdf]]) <br> until 201107 * Intro.1.A ([[Media:Intro.1.A.pdf |pdf]]) * Control.1.A ([[Media:Control.1.A.20110706.pdf |pdf]]) * Iteration.1.A ([[Media:Iteration.1.A.pdf |pdf]]) * Function.1.A ([[Media:Function.1.A.20110705.pdf |pdf]]) * Variable.1.A ([[Media:Variable.1.A.20110708.pdf |pdf]]) * Operators.1.A ([[Media:Operators.1.A.20110712.pdf |pdf]]) * Pointer.1.A ([[Media:Pointer.1.A.pdf |pdf]]) * Pointer.2.A ([[Media:Pointer.2.A.pdf |pdf]]) * Array.1.A ([[Media:Array.1.A.pdf |pdf]]) * Type.1.A ([[Media:Type.1.A.pdf |pdf]]) * Structure.1.A ([[Media:Structure.1.A.pdf |pdf]]) go to [ [[C programming in plain view]] ] [[Category:C programming]] </br> 3ox8iedqqoq3mld9ahd2aup7u5qbo8n 2408012 2408011 2022-07-19T14:42:36Z Young1lim 21186 /* Basics */ wikitext text/x-wiki === Introduction === * Overview ([[Media:C01.Intro1.Overview.1.A.20170925.pdf |A.pdf]], [[Media:C01.Intro1.Overview.1.B.20170901.pdf |B.pdf]], [[Media:C01.Intro1.Overview.1.C.20170904.pdf |C.pdf]]) * Number System ([[Media:C01.Intro2.Number.1.A.20171023.pdf |A.pdf]], [[Media:C01.Intro2.Number.1.B.20170909.pdf |B.pdf]], [[Media:C01.Intro2.Number.1.C.20170914.pdf |C.pdf]]) * Memory System ([[Media:C01.Intro2.Memory.1.A.20170907.pdf |A.pdf]], [[Media:C01.Intro3.Memory.1.B.20170909.pdf |B.pdf]], [[Media:C01.Intro3.Memory.1.C.20170914.pdf |C.pdf]]) === Handling Repetition === * Control ([[Media:C02.Repeat1.Control.1.A.20170925.pdf |A.pdf]], [[Media:C02.Repeat1.Control.1.B.20170918.pdf |B.pdf]], [[Media:C02.Repeat1.Control.1.C.20170926.pdf |C.pdf]]) * Loop ([[Media:C02.Repeat2.Loop.1.A.20170925.pdf |A.pdf]], [[Media:C02.Repeat2.Loop.1.B.20170918.pdf |B.pdf]]) === Handling a Big Work === * Function Overview ([[Media:C03.Func1.Overview.1.A.20171030.pdf |A.pdf]], [[Media:C03.Func1.Oerview.1.B.20161022.pdf |B.pdf]]) * Functions & Variables ([[Media:C03.Func2.Variable.1.A.20161222.pdf |A.pdf]], [[Media:C03.Func2.Variable.1.B.20161222.pdf |B.pdf]]) * Functions & Pointers ([[Media:C03.Func3.Pointer.1.A.20161122.pdf |A.pdf]], [[Media:C03.Func3.Pointer.1.B.20161122.pdf |B.pdf]]) * Functions & Recursions ([[Media:C03.Func4.Recursion.1.A.20161214.pdf |A.pdf]], [[Media:C03.Func4.Recursion.1.B.20161214.pdf |B.pdf]]) === Handling Series of Data === ==== Background ==== * Background ([[Media:C04.Series0.Background.1.A.20180727.pdf |A.pdf]]) ==== Basics ==== * Arrays ([[Media:C04.Series1.Array.1.A.20220719.pdf |A.pdf]], [[Media:C04.Series1.Array.1.B.20161115.pdf |B.pdf]]) * Pointers ([[Media:C04.Series2.Pointer.1.A.20180726.pdf |A.pdf]], [[Media:C04.Series2.Pointer.1.B.20161115.pdf |B.pdf]]) * Array Pointers ([[Media:C04.Series3.ArrayPointer.1.A.20220719.pdf |A.pdf]], [[Media:C04.Series3.ArrayPointer.1.B.20181203.pdf |B.pdf]]) * Multi-dimensional Arrays ([[Media:C04.Series4.MultiDim.1.A.20220418.pdf |A.pdf]], [[Media:C04.Series4.MultiDim.1.B.11.pdf |B.pdf]]) * Array Access Methods ([[Media:C04.Series4.ArrayAccess.1.A.20190511.pdf |A.pdf]], [[Media:C04.Series3.ArrayPointer.1.B.20181203.pdf |B.pdf]]) * Structures ([[Media:C04.Series3.Structure.1.A.20171204.pdf |A.pdf]], [[Media:C04.Series2.Structure.1.B.20161130.pdf |B.pdf]]) ==== Applications ==== * Applications of Arrays ([[Media:C04.Series1App.Array.1.A.20220719.pdf |A.pdf]]) * Applications of Pointers ([[Media:C04.Series7.AppPoint.1.A.20200424.pdf |A.pdf]]) * Applications of Array Pointers ([[Media:C04.Series3App.ArrayPointer.1.A.2022024.pdf |A.pdf]]) * Applications of Multi-dimensional Arrays ([[Media:C04.Series4App.MultiDim.1.A.20210719.pdf |A.pdf]]) * Applications of Array Access Methods ([[Media:C04.Series9.AppArrAcess.1.A.20190511.pdf |A.pdf]]) * Applications of Structures ([[Media:C04.Series6.AppStruct.1.A.20190423.pdf |A.pdf]]) ==== Examples ==== * Spreadsheet Example Programs :: Example 1 ([[Media:C04.Series7.Example.1.A.20171213.pdf |A.pdf]], [[Media:C04.Series7.Example.1.C.20171213.pdf |C.pdf]]) :: Example 2 ([[Media:C04.Series7.Example.2.A.20171213.pdf |A.pdf]], [[Media:C04.Series7.Example.2.C.20171213.pdf |C.pdf]]) :: Example 3 ([[Media:C04.Series7.Example.3.A.20171213.pdf |A.pdf]], [[Media:C04.Series7.Example.3.C.20171213.pdf |C.pdf]]) :: Bubble Sort ([[Media:C04.Series7.BubbleSort.1.A.20171211.pdf |A.pdf]]) === Handling Various Kinds of Data === * Types ([[Media:C05.Data1.Type.1.A.20180217.pdf |A.pdf]], [[Media:C05.Data1.Type.1.B.20161212.pdf |B.pdf]]) * Typecasts ([[Media:C05.Data2.TypeCast.1.A.20180217.pdf |A.pdf]], [[Media:C05.Data2.TypeCast.1.B.20161216.pdf |A.pdf]]) * Operators ([[Media:C05.Data3.Operators.1.A.20161219.pdf |A.pdf]], [[Media:C05.Data3.Operators.1.B.20161216.pdf |B.pdf]]) * Files ([[Media:C05.Data4.File.1.A.20161124.pdf |A.pdf]], [[Media:C05.Data4.File.1.B.20161212.pdf |B.pdf]]) === Handling Low Level Operations === * Bitwise Operations ([[Media:BitOp.1.B.20161214.pdf |A.pdf]], [[Media:BitOp.1.B.20161203.pdf |B.pdf]]) * Bit Field ([[Media:BitField.1.A.20161214.pdf |A.pdf]], [[Media:BitField.1.B.20161202.pdf |B.pdf]]) * Union ([[Media:Union.1.A.20161221.pdf |A.pdf]], [[Media:Union.1.B.20161111.pdf |B.pdf]]) * Accessing IO Registers ([[Media:IO.1.A.20141215.pdf |A.pdf]], [[Media:IO.1.B.20161217.pdf |B.pdf]]) === Declarations === * Type Specifiers and Qualifiers ([[Media:C07.Spec1.Type.1.A.20171004.pdf |pdf]]) * Storage Class Specifiers ([[Media:C07.Spec2.Storage.1.A.20171009.pdf |pdf]]) * Scope === Class Notes === * TOC ([[Media:TOC.20171007.pdf |TOC.pdf]]) * Day01 ([[Media:Day01.A.20171007.pdf |A.pdf]], [[Media:Day01.B.20171209.pdf |B.pdf]], [[Media:Day01.C.20171211.pdf |C.pdf]]) ...... Introduction (1) Standard Library * Day02 ([[Media:Day02.A.20171007.pdf |A.pdf]], [[Media:Day02.B.20171209.pdf |B.pdf]], [[Media:Day02.C.20171209.pdf |C.pdf]]) ...... Introduction (2) Basic Elements * Day03 ([[Media:Day03.A.20171007.pdf |A.pdf]], [[Media:Day03.B.20170908.pdf |B.pdf]], [[Media:Day03.C.20171209.pdf |C.pdf]]) ...... Introduction (3) Numbers * Day04 ([[Media:Day04.A.20171007.pdf |A.pdf]], [[Media:Day04.B.20170915.pdf |B.pdf]], [[Media:Day04.C.20171209.pdf |C.pdf]]) ...... Structured Programming (1) Flowcharts * Day05 ([[Media:Day05.A.20171007.pdf |A.pdf]], [[Media:Day05.B.20170915.pdf |B.pdf]], [[Media:Day05.C.20171209.pdf |C.pdf]]) ...... Structured Programming (2) Conditions and Loops * Day06 ([[Media:Day06.A.20171007.pdf |A.pdf]], [[Media:Day06.B.20170923.pdf |B.pdf]], [[Media:Day06.C.20171209.pdf |C.pdf]]) ...... Program Control * Day07 ([[Media:Day07.A.20171007.pdf |A.pdf]], [[Media:Day07.B.20170926.pdf |B.pdf]], [[Media:Day07.C.20171209.pdf |C.pdf]]) ...... Function (1) Definitions * Day08 ([[Media:Day08.A.20171028.pdf |A.pdf]], [[Media:Day08.B.20171016.pdf |B.pdf]], [[Media:Day08.C.20171209.pdf |C.pdf]]) ...... Function (2) Storage Class and Scope * Day09 ([[Media:Day09.A.20171007.pdf |A.pdf]], [[Media:Day09.B.20171017.pdf |B.pdf]], [[Media:Day09.C.20171209.pdf |C.pdf]]) ...... Function (3) Recursion * Day10 ([[Media:Day10.A.20171209.pdf |A.pdf]], [[Media:Day10.B.20171017.pdf |B.pdf]], [[Media:Day10.C.20171209.pdf |C.pdf]]) ...... Arrays (1) Definitions * Day11 ([[Media:Day11.A.20171024.pdf |A.pdf]], [[Media:Day11.B.20171017.pdf |B.pdf]], [[Media:Day11.C.20171212.pdf |C.pdf]]) ...... Arrays (2) Applications * Day12 ([[Media:Day12.A.20171024.pdf |A.pdf]], [[Media:Day12.B.20171020.pdf |B.pdf]], [[Media:Day12.C.20171209.pdf |C.pdf]]) ...... Pointers (1) Definitions * Day13 ([[Media:Day13.A.20171025.pdf |A.pdf]], [[Media:Day13.B.20171024.pdf |B.pdf]], [[Media:Day13.C.20171209.pdf |C.pdf]]) ...... Pointers (2) Applications * Day14 ([[Media:Day14.A.20171226.pdf |A.pdf]], [[Media:Day14.B.20171101.pdf |B.pdf]], [[Media:Day14.C.20171209.pdf |C.pdf]]) ...... C String (1) * Day15 ([[Media:Day15.A.20171209.pdf |A.pdf]], [[Media:Day15.B.20171124.pdf |B.pdf]], [[Media:Day15.C.20171209.pdf |C.pdf]]) ...... C String (2) * Day16 ([[Media:Day16.A.20171208.pdf |A.pdf]], [[Media:Day16.B.20171114.pdf |B.pdf]], [[Media:Day16.C.20171209.pdf |C.pdf]]) ...... C Formatted IO * Day17 ([[Media:Day17.A.20171031.pdf |A.pdf]], [[Media:Day17.B.20171111.pdf |B.pdf]], [[Media:Day17.C.20171209.pdf |C.pdf]]) ...... Structure (1) Definitions * Day18 ([[Media:Day18.A.20171206.pdf |A.pdf]], [[Media:Day18.B.20171128.pdf |B.pdf]], [[Media:Day18.C.20171212.pdf |C.pdf]]) ...... Structure (2) Applications * Day19 ([[Media:Day19.A.20171205.pdf |A.pdf]], [[Media:Day19.B.20171121.pdf |B.pdf]], [[Media:Day19.C.20171209.pdf |C.pdf]]) ...... Union, Bitwise Operators, Enum * Day20 ([[Media:Day20.A.20171205.pdf |A.pdf]], [[Media:Day20.B.20171201.pdf |B.pdf]], [[Media:Day20.C.20171212.pdf |C.pdf]]) ...... Linked List * Day21 ([[Media:Day21.A.20171206.pdf |A.pdf]], [[Media:Day21.B.20171208.pdf |B.pdf]], [[Media:Day21.C.20171212.pdf |C.pdf]]) ...... File Processing * Day22 ([[Media:Day22.A.20171212.pdf |A.pdf]], [[Media:Day22.B.20171213.pdf |B.pdf]], [[Media:Day22.C.20171212.pdf |C.pdf]]) ...... Preprocessing <!----------------------------------------------------------------------> </br> See also https://cprogramex.wordpress.com/ == '''Old Materials '''== until 201201 * Intro.Overview.1.A ([[Media:C.Intro.Overview.1.A.20120107.pdf |pdf]]) * Intro.Memory.1.A ([[Media:C.Intro.Memory.1.A.20120107.pdf |pdf]]) * Intro.Number.1.A ([[Media:C.Intro.Number.1.A.20120107.pdf |pdf]]) * Repeat.Control.1.A ([[Media:C.Repeat.Control.1.A.20120109.pdf |pdf]]) * Repeat.Loop.1.A ([[Media:C.Repeat.Loop.1.A.20120113.pdf |pdf]]) * Work.Function.1.A ([[Media:C.Work.Function.1.A.20120117.pdf |pdf]]) * Work.Scope.1.A ([[Media:C.Work.Scope.1.A.20120117.pdf |pdf]]) * Series.Array.1.A ([[Media:Series.Array.1.A.20110718.pdf |pdf]]) * Series.Pointer.1.A ([[Media:Series.Pointer.1.A.20110719.pdf |pdf]]) * Series.Structure.1.A ([[Media:Series.Structure.1.A.20110805.pdf |pdf]]) * Data.Type.1.A ([[Media:C05.Data2.TypeCast.1.A.20130813.pdf |pdf]]) * Data.TypeCast.1.A ([[Media:Data.TypeCast.1.A.pdf |pdf]]) * Data.Operators.1.A ([[Media:Data.Operators.1.A.20110712.pdf |pdf]]) <br> until 201107 * Intro.1.A ([[Media:Intro.1.A.pdf |pdf]]) * Control.1.A ([[Media:Control.1.A.20110706.pdf |pdf]]) * Iteration.1.A ([[Media:Iteration.1.A.pdf |pdf]]) * Function.1.A ([[Media:Function.1.A.20110705.pdf |pdf]]) * Variable.1.A ([[Media:Variable.1.A.20110708.pdf |pdf]]) * Operators.1.A ([[Media:Operators.1.A.20110712.pdf |pdf]]) * Pointer.1.A ([[Media:Pointer.1.A.pdf |pdf]]) * Pointer.2.A ([[Media:Pointer.2.A.pdf |pdf]]) * Array.1.A ([[Media:Array.1.A.pdf |pdf]]) * Type.1.A ([[Media:Type.1.A.pdf |pdf]]) * Structure.1.A ([[Media:Structure.1.A.pdf |pdf]]) go to [ [[C programming in plain view]] ] [[Category:C programming]] </br> rivh8ofeyd251prtt9hcrqxd9nsxeur 2 285382 2408064 2406958 2022-07-20T01:33:29Z Jtwsaddress42 234843 /* Lovelock, James E. (1919 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:James Lovelock|Lovelock, James E. (1919 - )]] === [[File:James Lovelock in 2005.jpg|thumb|James_Lovelock]] [[File:James Lovelocks Electron capture detector for a gas chromatograph, 1960. (9660569973).jpg|thumb|James Lovelocks Electron capture detector for a gas chromatograph, 1960.]] '''Notable Accomplishments''' * Electron Capture Detector * Gaia Hypothesis <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Lovelock, James E.}} {{RoundBoxBottom}} <hr /> 61p4txaz8v5lmzs8cggm7vobzce12pl 0 285384 2408072 2406988 2022-07-20T02:23:27Z Young1lim 21186 /* Workings of the GNU Compiler */ wikitext text/x-wiki === Workings of the GNU Compiler === * Overview ([[Media:Overview.20200211.pdf |pdf]]) * Access ([[Media:Access.20200409.pdf |pdf]]) * Operators ([[Media:Operator.20200427.pdf |pdf]]) * Conditions ([[Media:Condition.20220718.pdf |pdf]]) * Control ([[Media:Control.20220616.pdf |pdf]]) * Procedure ([[Media:Procedure.20220412.pdf |pdf]]) * Recursion ([[Media:Recursion.20210824-2.pdf |pdf]]) * Arrays ([[Media:Array.20211018.pdf |pdf]]) * Structures ([[Media:Structure.20220101.pdf |pdf]]) * Alignment ([[Media:Alignment.20201117.pdf |pdf]]) * Pointers ([[Media:Pointer.20201106.pdf |pdf]]) </br> === Workings of the GNU Linker === ==== Overview ==== * Static Linking Overview ([[Media:Link.1.StaticOverview.20181120.pdf |pdf]]) * Dynamic Linking Overview ([[Media:Link.2.DynamicOverview.20181120.pdf |pdf]]) ==== Linking Process ==== * Object Files ([[Media:Link.3.A.Object.20190121.pdf |A.pdf]], [[Media:Link.3.B.Object.20190405.pdf |B.pdf]]) * Symbols ([[Media:Link.4.A.Symbol.20190312.pdf |A.pdf]], [[Media:Link.4.B.Symbol.20190312.pdf |B.pdf]]) * Relocation ([[Media:Link.5.A.Relocation.20190320.pdf |A.pdf]], [[Media:Link.5.B.Relocation.20190322.pdf |B.pdf]]) * Loading ([[Media:Link.6.A.Loading.20190501.pdf |A.pdf]], [[Media:Link.6.B.Loading.20190126.pdf |B.pdf]]) * Static Linking ([[Media:Link.7.A.StaticLink.20190122.pdf |A.pdf]], [[Media:Link.7.B.StaticLink.20190128.pdf |B.pdf]]) * Dynamic Linking ([[Media:Link.8.A.DynamicLink.20190207.pdf |A.pdf]], [[Media:Link.8.B.DynamicLink.20190209.pdf |B.pdf]]) * Position Independent Code ([[Media:Link.9.A.PIC.20190304.pdf |A.pdf]], [[Media:Link.9.B.PIC.20190309.pdf |B.pdf]]) ==== Example I ==== * Vector addition ([[Media:Eg1.1A.Vector.20190121.pdf |A.pdf]], [[Media:Eg1.1B.Vector.20190121.pdf |B.pdf]]) * Swapping array elements ([[Media:Eg1.2A.Swap.20190302.pdf |A.pdf]], [[Media:Eg1.2B.Swap.20190121.pdf |B.pdf]]) * Nested functions ([[Media:Eg1.3A.Nest.20190121.pdf |A.pdf]], [[Media:Eg1.3B.Nest.20190121.pdf |B.pdf]]) ==== Examples II ==== * analysis of static linking ([[Media:Ex1.A.StaticLinkEx.20190121.pdf |A.pdf]], [[Media:Ex2.B.StaticLinkEx.20190121.pdf |B.pdf]]) * analysis of dynamic linking ([[Media:Ex2.A.DynamicLinkEx.20190121.pdf |A.pdf]]) * analysis of PIC ([[Media:Ex3.A.PICEx.20190121.pdf |A.pdf]]) </br> go to [ [[C programming in plain view]] ] [[Category:C programming]] mdblk6o97naahhieoc38c8l0xtw16y5 2408074 2408072 2022-07-20T02:25:15Z Young1lim 21186 /* Workings of the GNU Compiler */ wikitext text/x-wiki === Workings of the GNU Compiler === * Overview ([[Media:Overview.20200211.pdf |pdf]]) * Access ([[Media:Access.20200409.pdf |pdf]]) * Operators ([[Media:Operator.20200427.pdf |pdf]]) * Conditions ([[Media:Condition.20220719.pdf |pdf]]) * Control ([[Media:Control.20220616.pdf |pdf]]) * Procedure ([[Media:Procedure.20220412.pdf |pdf]]) * Recursion ([[Media:Recursion.20210824-2.pdf |pdf]]) * Arrays ([[Media:Array.20211018.pdf |pdf]]) * Structures ([[Media:Structure.20220101.pdf |pdf]]) * Alignment ([[Media:Alignment.20201117.pdf |pdf]]) * Pointers ([[Media:Pointer.20201106.pdf |pdf]]) </br> === Workings of the GNU Linker === ==== Overview ==== * Static Linking Overview ([[Media:Link.1.StaticOverview.20181120.pdf |pdf]]) * Dynamic Linking Overview ([[Media:Link.2.DynamicOverview.20181120.pdf |pdf]]) ==== Linking Process ==== * Object Files ([[Media:Link.3.A.Object.20190121.pdf |A.pdf]], [[Media:Link.3.B.Object.20190405.pdf |B.pdf]]) * Symbols ([[Media:Link.4.A.Symbol.20190312.pdf |A.pdf]], [[Media:Link.4.B.Symbol.20190312.pdf |B.pdf]]) * Relocation ([[Media:Link.5.A.Relocation.20190320.pdf |A.pdf]], [[Media:Link.5.B.Relocation.20190322.pdf |B.pdf]]) * Loading ([[Media:Link.6.A.Loading.20190501.pdf |A.pdf]], [[Media:Link.6.B.Loading.20190126.pdf |B.pdf]]) * Static Linking ([[Media:Link.7.A.StaticLink.20190122.pdf |A.pdf]], [[Media:Link.7.B.StaticLink.20190128.pdf |B.pdf]]) * Dynamic Linking ([[Media:Link.8.A.DynamicLink.20190207.pdf |A.pdf]], [[Media:Link.8.B.DynamicLink.20190209.pdf |B.pdf]]) * Position Independent Code ([[Media:Link.9.A.PIC.20190304.pdf |A.pdf]], [[Media:Link.9.B.PIC.20190309.pdf |B.pdf]]) ==== Example I ==== * Vector addition ([[Media:Eg1.1A.Vector.20190121.pdf |A.pdf]], [[Media:Eg1.1B.Vector.20190121.pdf |B.pdf]]) * Swapping array elements ([[Media:Eg1.2A.Swap.20190302.pdf |A.pdf]], [[Media:Eg1.2B.Swap.20190121.pdf |B.pdf]]) * Nested functions ([[Media:Eg1.3A.Nest.20190121.pdf |A.pdf]], [[Media:Eg1.3B.Nest.20190121.pdf |B.pdf]]) ==== Examples II ==== * analysis of static linking ([[Media:Ex1.A.StaticLinkEx.20190121.pdf |A.pdf]], [[Media:Ex2.B.StaticLinkEx.20190121.pdf |B.pdf]]) * analysis of dynamic linking ([[Media:Ex2.A.DynamicLinkEx.20190121.pdf |A.pdf]]) * analysis of PIC ([[Media:Ex3.A.PICEx.20190121.pdf |A.pdf]]) </br> go to [ [[C programming in plain view]] ] [[Category:C programming]] 2g2r4r32huwse59l2huotvv62mnz44x 2 285413 2408116 2407150 2022-07-20T04:34:42Z Jtwsaddress42 234843 /* Mircéa Éliade (1907 - 1986) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Mircea_Eliade|Mircéa Éliade (1907 - 1986)]] === [[File:Mircea Eliade young.jpg|thumb|Éliade, Mircéa (1907 - 1986)]] '''Notable Accomplishments''' * The History of Alchemy <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Éliade, Mircéa}} <br /><hr /> {{User:Jtwsaddress42/Gallery/Mircéa Éliade}} {{RoundBoxBottom}} <hr /> juiayhg0rjdpltg03iu1n149s9s0ibt 2408117 2408116 2022-07-20T04:35:40Z Jtwsaddress42 234843 /* Mircéa Éliade (1907 - 1986) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Mircea_Eliade|Mircéa Éliade (1907 - 1986)]] === [[File:Mircea Eliade young.jpg|thumb|Éliade, Mircéa (1907 - 1986)]] '''Notable Accomplishments''' * The History of Alchemy, Shamanism, and other Religious Modes <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Éliade, Mircéa}} <br /><hr /> {{User:Jtwsaddress42/Gallery/Mircéa Éliade}} {{RoundBoxBottom}} <hr /> jm7oxcg0t51i9bn4atwlfiqvgu6ckka 4 285424 2408103 2407196 2022-07-20T04:01:59Z JackBot 238563 Bot: Fixing double redirect to [[Helping Give Away Psychological Science/Standard Operating Procedures/Speaker Series and Continuing Education]] wikitext text/x-wiki #REDIRECT [[Helping Give Away Psychological Science/Standard Operating Procedures/Speaker Series and Continuing Education]] c8h0rqchoim8lv8cwpm657bty38ma1f 2 285429 2408092 2407213 2022-07-20T03:14:16Z Jtwsaddress42 234843 /* Tonegawa, Susumu (1939 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Susumu Tonegawa|Tonegawa, Susumu (1939 - )]] === [[File:Susumu Tonegawa Photo.jpg|thumb|Susumu Tonegawa]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/1987/tonegawa/facts/ The Nobel Prize in Physiology or Medicine 1987] - “for his discovery of the genetic principle for generation of antibody diversity.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Tonegawa, Susumu}} {{RoundBoxBottom}} <hr /> e4q5gyo9scs4jpzzly1o3r2dhxjqc1k 2408104 2408092 2022-07-20T04:03:12Z Jtwsaddress42 234843 /* Tonegawa, Susumu (1939 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Susumu Tonegawa|Tonegawa, Susumu (1939 - )]] === [[File:Susumu Tonegawa Photo.jpg|thumb|Susumu Tonegawa]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/1987/tonegawa/facts/ The Nobel Prize in Physiology or Medicine 1987] - “for his discovery of the genetic principle for generation of antibody diversity.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Tonegawa, Susumu}} <br /><hr /> {| align= center |'''V(D)J Recombination''' [[File:VDJ recombination.png|640px|VDJ recombination]] <br /> |} {{RoundBoxBottom}} <hr /> ti0zuq2izg6w3k50x0d2fpcum6dud5p 2 285430 2408060 2407230 2022-07-20T01:11:50Z Jtwsaddress42 234843 /* Jerne, Niels K. (1911 - 1994) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Niels K. Jerne|Jerne, Niels K. (1911 - 1994)]] === [[File:Niels Kaj Jerne 1950 crop.jpg|thumb|Niels Kaj Jerne]] [[File:Niels Kaj Jerne 1950.jpg|thumb|Maaløe, Jerne, & Watson 1950{{efn|Niels K. Jerne was assistant to Ole Maaløe at Statens Seruminstitut. This photo of 1950, taken from Jernes' private collection, shows Maaløe in the middle with a pipe and Jerne at the window; the DNA discoverer James Watson sits in front of him.}}]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/1984/jerne/facts/ The Nobel Prize in Physiology or Medicine 1984] - shared with Georges J.F. Köhler and César Milstein “for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Jerne, Niels K.}} {{RoundBoxBottom}} <hr /> 4jze95hxn146pxrj3pe6rfwg03a5fkh 0 285439 2408041 2407351 2022-07-19T19:24:39Z KlayLay 2946787 Grammar wikitext text/x-wiki '''Socialism''' is a [[wikipedia:Left-wing_politics|left-wing]] to [[wikipedia:Far-left_politics|far-left]] [[wikipedia:Economic_ideology|economic philosophy]] and [[wikipedia:Political_movement|movement]] encompassing a range of [[wikipedia:Economic_system|economic systems]] characterized by the dominance of [[wikipedia:Social_ownership|social ownership]] of the [[wikipedia:Means_of_production|means of production]] within the economy and [[wikipedia:Workers'_control|worker participation]] in the management of [[wikipedia:Production_(economics)|productive enterprises]] as opposed to [[wikipedia:Private_property|private ownership]].<ref>[[Wikipedia: Socialism]]</ref> == Resources == == Socialism categories == <categorytree mode="categories" showcount="on">Socialism</categorytree> == See also == == References == {{Reflist}} [[Category:Socialism| ]] a79jeojpkztamtdpobrqhbneizrc4ee 2 285466 2408059 2407482 2022-07-20T00:30:13Z Jtwsaddress42 234843 /* Suzuki, Akira (1930 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Akira Suzuki (chemist)|Suzuki, Akira (1930 - )]] === [[File:Nobel Prize 2010-Press Conference KVA-DSC 7383.jpg|thumb|Akira Suzuki{{efn|Nobel Prize 2010-Press Conference KVA-DSC 7383}}]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/2010/suzuki/facts/ The Nobel Prize in Chemistry 2010] - shared with Richard Heck and Ei-ichi Negishi “for palladium-catalyzed cross couplings in organic synthesis.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Suzuki, Akira}} <br /><hr /> {| align= center | border=0 cellspacing=0 cellpadding=0 | style="vertical-align:top; |'''Mechanism of Suzuki coupling reaction'''<br /> [[File:Mechanism of Suzuki coupling reaction.png|640px|Mechanism of Suzuki coupling reaction]] |} <br /><hr /> Miyaura et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Miyaura, Norio}} <br /><hr /> {| align= center | border=0 cellspacing=0 cellpadding=0 | style="vertical-align:top; |'''Mechanism of Suzuki-Miyaura coupling reaction'''<br /> [[File:Suzuki-Miyaura reaction generalized mechanism.png|640px|Suzuki-Miyaura reaction generalized mechanism]] |} <br /> {{RoundBoxBottom}} <hr /> o7vn21q67ett0mf2za7wzj3czbuf20a 2408087 2408059 2022-07-20T02:58:37Z Jtwsaddress42 234843 /* Suzuki, Akira (1930 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Akira Suzuki (chemist)|Suzuki, Akira (1930 - )]] === [[File:Nobel Prize 2010-Press Conference KVA-DSC 7383.jpg|thumb|Akira Suzuki{{efn|Nobel Prize 2010-Press Conference KVA-DSC 7383}}]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/2010/suzuki/facts/ The Nobel Prize in Chemistry 2010] - shared with Richard Heck and Ei-ichi Negishi “for palladium-catalyzed cross couplings in organic synthesis.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Suzuki, Akira}} <br /><hr /> {| align= center | border=0 cellspacing=0 cellpadding=0 | style="vertical-align:top; |'''Mechanism of Suzuki coupling reaction'''<br /> [[File:Mechanism of Suzuki coupling reaction.png|640px|Suzuki coupling reaction]] |} <br /><hr /> Miyaura et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Miyaura, Norio}} <br /><hr /> {| align= center | border=0 cellspacing=0 cellpadding=0 | style="vertical-align:top; |'''Mechanism of Suzuki-Miyaura coupling reaction'''<br /> [[File:Suzuki-Miyaura reaction generalized mechanism.png|640px|Suzuki-Miyaura reaction]] |} <br /> {{RoundBoxBottom}} <hr /> icxwt69bgjwxhn7auv2mqjcqb1kniba 2408088 2408087 2022-07-20T02:59:24Z Jtwsaddress42 234843 /* Suzuki, Akira (1930 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Akira Suzuki (chemist)|Suzuki, Akira (1930 - )]] === [[File:Nobel Prize 2010-Press Conference KVA-DSC 7383.jpg|thumb|Akira Suzuki{{efn|Nobel Prize 2010-Press Conference KVA-DSC 7383}}]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/2010/suzuki/facts/ The Nobel Prize in Chemistry 2010] - shared with Richard Heck and Ei-ichi Negishi “for palladium-catalyzed cross couplings in organic synthesis.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Suzuki, Akira}} <br /><hr /> {| align= center | border=0 cellspacing=0 cellpadding=0 | style="vertical-align:top; |'''Suzuki coupling reaction'''<br /> [[File:Mechanism of Suzuki coupling reaction.png|640px|Suzuki coupling reaction]] |} <br /><hr /> Miyaura et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Miyaura, Norio}} <br /><hr /> {| align= center | border=0 cellspacing=0 cellpadding=0 | style="vertical-align:top; |'''Suzuki-Miyaura coupling reaction'''<br /> [[File:Suzuki-Miyaura reaction generalized mechanism.png|640px|Suzuki-Miyaura reaction]] |} <br /> {{RoundBoxBottom}} <hr /> rwujre1srvssjigbsvowjkjsyopq9qa 2 285469 2408058 2407504 2022-07-20T00:28:05Z Jtwsaddress42 234843 /* Negishi, Ei-ichi (1935 - 2021) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Ei-ichi Negishi|Negishi, Ei-ichi (1935 - 2021)]] === [[File:Nobel Prize 2010-Press Conference KVA-DSC 7398.jpg|thumb|Ei-ichi Negishi (1935 - 2021){{efn|Nobel Prize 2010-Press Conference KVA-DSC 7398}}]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/2010/negishi/facts/ The Nobel Prize in Chemistry 2010] - shared with Richard Heck and Akira Suzuki “for palladium-catalyzed cross couplings in organic synthesis.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Negishi, Ei-ichi}} <hr /> {| align= center |'''Pd & Ni Catalytic Cycles for Negishi Reaction'''<br /> [[File:NegishiScheme1.png]]<br /> |- |''Palladium Mechanism'' [[File:Scheme2Catcycle.png|640px|Scheme2Catcycle]] <br /><br /> |- |''Nickel Mechanism'' [[File:NickelMechanism.png|NickelMechanism]] |} {{RoundBoxBottom}} <hr /> n66giy7e92rss95yl92aximwsib2vvy 2 285471 2408102 2407544 2022-07-20T03:56:30Z Jtwsaddress42 234843 /* Brown, Herbert C. (1912 - 2004) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Herbert C. Brown|Brown, Herbert C. (1912 - 2004)]] === [[File:Structural formula of (+)-Diisopinocampheylborane.svg|thumb|(+)-Diisopinocampheylborane]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/1979/brown/facts/ The Nobel Prize in Chemistry 1979] - shared with [[w:George Wittig|George Wittig]], "for their development of the use of boron- and phosphorus-containing compounds, respectively, into important reagents in organic synthesis." <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Brown, Herbert C.}} {{RoundBoxBottom}} <hr /> 8xgv10sxnzpuuqv0kjdqix279gd9uzu 2 285472 2408057 2407483 2022-07-20T00:26:32Z Jtwsaddress42 234843 /* Heck, Richard F. (1931 - 2015) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Richard F. Heck|Heck, Richard F. (1931 - 2015)]] === [[File:Richard F. Heck2010.jpg|thumb|Richard F. Heck (1931 - 2015)]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/2010/heck/facts/ The Nobel Prize in Chemistry 2010] - shared with Ei-ichi Negishi and Akira Suzuki “for palladium-catalyzed cross couplings in organic synthesis.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Heck, Richard F.}} <br /><hr /> {| align = center |'''Heck Mechanism'''<br /> [[File:Heck mechanism.png|640px|Heck mechanism]] <br /><br /> |- |'''Reductive Heck vs. Classical Mizoroki–Heck Mechanism'''<br /> [[File:Reductive Heck vs. Classical Mizoroki–Heck Mechanism.png|640px|Reductive_Heck_vs._Classical_Mizoroki–Heck_Mechanism]] <br /> |} {{RoundBoxBottom}} <hr /> rz243lt2krmpyg5vrw4t7il9cvezlr9 2 285475 2408063 2407477 2022-07-20T01:31:18Z Jtwsaddress42 234843 /* Lefkowitz, Robert J. (1943 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Robert J. Lefkowitz|Lefkowitz, Robert J. (1943 - )]] === [[File:Robert Lefkowitz 2 2012.jpg|thumb|Robert Lefkowitz]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/2012/lefkowitz/facts/ The Nobel Prize in Chemistry 2012] - shared with Brian K. Kobilka “for studies of G-protein-coupled receptors.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Lefkowitz, Robert J.}} {{RoundBoxBottom}} <hr /> f0rqikshgr55d304o0da4p37fe1x0d7 4 285491 2408039 2407961 2022-07-19T18:35:53Z Alexis Jazz 791434 Updating gadget usage statistics from [[Special:GadgetUsage]] ([[phab:T121049]]) wikitext text/x-wiki {{#ifexist:Project:GUS2Wiki/top|{{/top}}}} The following data is cached, and was last updated 2022-07-16T21:38:21Z. A maximum of {{PLURAL:$4|one result is|$4 results are}} available in the cache. {| class="sortable wikitable" ! Gadget !! data-sort-type="number" | Number of users |- |EnhancedTalk || 1303 |- |Round Corners || 1107 |- |HotCat || 815 |- |popups || 788 |- |HideFundraisingNotice || 747 |- |purge || 663 |- |sidebartranslate || 495 |- |edittop || 457 |- |contribsrange || 347 |- |jquery || 213 |- |gadget-EnhancedUndelete || 146 |- |gadget-usurper-count || 75 |- |gadget-CleanDeletions || 75 |- |LintHint || 71 |- |dark-mode-toggle || 26 |- |dark-mode || 14 |- |gadget-Wikidebate || 4 |- |gadget-ReferenceTooltips || 0 |- |gadget-mySandbox || 0 |} * [[Special:GadgetUsage]] * [[w:en:User:Alexis Jazz/GUS2Wiki|GUS2Wiki]] q26bgeyh9obd9wclj2b984hs73se7dk 2408042 2408039 2022-07-19T19:26:35Z Alexis Jazz 791434 Updating gadget usage statistics from [[Special:GadgetUsage]] ([[phab:T121049]]) wikitext text/x-wiki {{#ifexist:Project:GUS2Wiki/top|{{/top}}}} The following data is cached, and was last updated 2022-07-16T21:38:21Z. A maximum of {{PLURAL:5000|one result is|5000 results are}} available in the cache. {| class="sortable wikitable" ! Gadget !! data-sort-type="number" | Number of users !! data-sort-type="number" | Active users |- |EnhancedTalk || 1303 || 4 |- |Round Corners || 1107 || 4 |- |HotCat || 815 || 12 |- |popups || 788 || 4 |- |HideFundraisingNotice || 747 || 8 |- |purge || 663 || 9 |- |sidebartranslate || 495 || 2 |- |edittop || 457 || 9 |- |contribsrange || 347 || 2 |- |jquery || 213 || 1 |- |gadget-EnhancedUndelete || 146 || 0 |- |gadget-usurper-count || 75 || 0 |- |gadget-CleanDeletions || 75 || 0 |- |LintHint || 71 || 1 |- |dark-mode-toggle || 26 || 5 |- |dark-mode || 14 || 2 |- |gadget-Wikidebate || 4 || 0 |- |gadget-ReferenceTooltips || 0 || 0 |- |gadget-mySandbox || 0 || 0 |} * [[Special:GadgetUsage]] * [[w:en:User:Alexis Jazz/GUS2Wiki|GUS2Wiki]] pzj0ox6o0z1igqxvbv2pxbond9peovz 1 285494 2407994 2022-07-19T12:20:35Z Eyoungstrom 1933979 /* Articles related to translation */ new section wikitext text/x-wiki == Articles related to translation == Here are some links to articles about translation, generally. [https://www.theatlantic.com/technology/archive/2018/01/the-shallowness-of-google-translate/551570/ This article] in ''The Atlantic'' argues that translation requires understanding, not just mechanical substitution. It's an interesting read. [https://www.economist.com/technology-quarterly/2017-05-01/language This article] in ''The Economist'' is more enthusiastic about the advances made in the technology and is well done. There's [https://www.nytimes.com/2016/12/14/magazine/the-great-ai-awakening.html one] in the ''New York Times Magazine'' ("The Great A.I. Awakening") that also looks promising, but is paywalled. [https://www.thegear.kr/news/articleView.html?idxno=13372 This article] from 5 years ago introduces some of the principals in the Korea Wikimedia User Group (in Hanguel). Let's add other "general reading" articles and links to pages as we find them interesting, and start grouping into "chunks" when we have 3+ that fit a theme. [[User:Eyoungstrom|Eyoungstrom]] ([[User talk:Eyoungstrom|discuss]] • [[Special:Contributions/Eyoungstrom|contribs]]) 12:20, 19 July 2022 (UTC) 1o1lqzmzu7hddkzcq48e0jrk3zkp1dy 6 285495 2408003 2022-07-19T14:37:36Z Young1lim 21186 {{Information |Description=Laurent.5: Double Pole Examples 7A (20220718 - 20220716) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. Lim |Permission={{cc-by-sa-3.0,2.5,2.0,1.0}} }} wikitext text/x-wiki == Summary == {{Information |Description=Laurent.5: Double Pole Examples 7A (20220718 - 20220716) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. Lim |Permission={{cc-by-sa-3.0,2.5,2.0,1.0}} }} == Licensing == {{self|GFDL|cc-by-sa-4.0,3.0,2.5,2.0,1.0}} dhz8v4aze0vnt9t6heo7unyg15yve9y 6 285496 2408004 2022-07-19T14:38:23Z Young1lim 21186 {{Information |Description=Laurent.5: Double Pole Examples 7B (20220718 - 20220716) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. Lim |Permission={{cc-by-sa-3.0,2.5,2.0,1.0}} }} wikitext text/x-wiki == Summary == {{Information |Description=Laurent.5: Double Pole Examples 7B (20220718 - 20220716) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. Lim |Permission={{cc-by-sa-3.0,2.5,2.0,1.0}} }} == Licensing == {{self|GFDL|cc-by-sa-4.0,3.0,2.5,2.0,1.0}} 5u3gm0x7hon0skw5hgnsfxc4hdjr3fs 6 285497 2408006 2022-07-19T14:40:02Z Young1lim 21186 {{Information |Description=C04.Series.1App: Applications of Arrays 1A (20220718 - 20220716) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. Lim |Permission={{GFDL}} }} wikitext text/x-wiki == Summary == {{Information |Description=C04.Series.1App: Applications of Arrays 1A (20220718 - 20220716) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. Lim |Permission={{GFDL}} }} == Licensing == {{self|GFDL|cc-by-sa-4.0,3.0,2.5,2.0,1.0}} bfxhjnvwx5kv32axyptnok1yg63n51z 6 285498 2408009 2022-07-19T14:41:15Z Young1lim 21186 {{Information |Description=VLSI.Arith.1.A: Variable Block Adders (20220718 - 20220716) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. Lim |Permission={{GFDL}} }} wikitext text/x-wiki == Summary == {{Information |Description=VLSI.Arith.1.A: Variable Block Adders (20220718 - 20220716) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. Lim |Permission={{GFDL}} }} == Licensing == {{self|GFDL|cc-by-sa-4.0,3.0,2.5,2.0,1.0}} jfubid2gac9glen7mgxkvf3tgct0v2n 6 285499 2408015 2022-07-19T14:43:40Z Young1lim 21186 {{Information |Description=Laurent.5: Double Pole Examples 7A (20220719 - 20220718) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. Lim |Permission={{cc-by-sa-3.0,2.5,2.0,1.0}} }} wikitext text/x-wiki == Summary == {{Information |Description=Laurent.5: Double Pole Examples 7A (20220719 - 20220718) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. Lim |Permission={{cc-by-sa-3.0,2.5,2.0,1.0}} }} == Licensing == {{self|GFDL|cc-by-sa-4.0,3.0,2.5,2.0,1.0}} h0bw8zj5it1anucpgz0s7hm3290v8p0 6 285500 2408016 2022-07-19T14:44:21Z Young1lim 21186 {{Information |Description=Laurent.5: Double Pole Examples 7B (20220719 - 20220718) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. Lim |Permission={{cc-by-sa-3.0,2.5,2.0,1.0}} }} wikitext text/x-wiki == Summary == {{Information |Description=Laurent.5: Double Pole Examples 7B (20220719 - 20220718) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. Lim |Permission={{cc-by-sa-3.0,2.5,2.0,1.0}} }} == Licensing == {{self|GFDL|cc-by-sa-4.0,3.0,2.5,2.0,1.0}} hunjt50kspilz32lukelr2kk0zqgis6 6 285501 2408017 2022-07-19T14:45:51Z Young1lim 21186 {{Information |Description=C04.Series.1: Arrays 1A (20220719 - 20220719) |Source={{own|Young1lim}} |Date=2022-07-18 |Author=Young W. Lim |Permission={{GFDL}} }} wikitext text/x-wiki == Summary == {{Information |Description=C04.Series.1: Arrays 1A (20220719 - 20220719) |Source={{own|Young1lim}} |Date=2022-07-18 |Author=Young W. Lim |Permission={{GFDL}} }} == Licensing == {{self|GFDL|cc-by-sa-4.0,3.0,2.5,2.0,1.0}} b85fqka85oyuynvqkl8v89nmnpxmfv3 2408020 2408017 2022-07-19T14:47:59Z Young1lim 21186 /* Summary */ wikitext text/x-wiki == Summary == {{Information |Description=C04.Series.1: Arrays 1A (20220719 - 20220718) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. 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Lim |Permission={{GFDL}} }} == Licensing == {{self|GFDL|cc-by-sa-4.0,3.0,2.5,2.0,1.0}} nzqbv823h301f3c2tvl8z0wil0l8aqc 6 285505 2408033 2022-07-19T16:48:49Z Young1lim 21186 {{Information |Description=MP3.1F: Mutability - Lambda Calculus (20220718 - 20220716) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. Lim |Permission={{GFDL}} }} wikitext text/x-wiki == Summary == {{Information |Description=MP3.1F: Mutability - Lambda Calculus (20220718 - 20220716) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. Lim |Permission={{GFDL}} }} == Licensing == {{self|GFDL|cc-by-sa-4.0,3.0,2.5,2.0,1.0}} qmuhettp9liucp45u7a642m94j2npou 6 285506 2408035 2022-07-19T16:50:04Z Young1lim 21186 {{Information |Description=MP3.1F: Mutability - Lambda Calculus (20220719 - 20220718) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. Lim |Permission={{GFDL}} }} wikitext text/x-wiki == Summary == {{Information |Description=MP3.1F: Mutability - Lambda Calculus (20220719 - 20220718) |Source={{own|Young1lim}} |Date=2022-07-19 |Author=Young W. Lim |Permission={{GFDL}} }} == Licensing == {{self|GFDL|cc-by-sa-4.0,3.0,2.5,2.0,1.0}} butgvx20pxb3m0iyjzeef9ocn01rkfz 0 285507 2408040 2022-07-19T18:43:53Z NikhilJNimbalkar 2946780 Refrences have been added wikitext text/x-wiki {{Article info | first1 = Nikhil | last1 = Nimbalkar | orcid1 = 0000-0002-5882-186X | affiliation1 = Department of Mechanical Engineering, MIT School of Engineering, Pune | correspondence1 = niksnimbalkar2000@gmail.com | affiliations = University | first2 = Ashwinkumar | last2 = Mahindrakar | affiliation2 = Department of Mechanical Engineering, MIT School of Engineering, Pune | correspondence = niksnimbalkar2000@gmail.com | journal = WikiJournal of Science <!-- WikiJournal of Medicine, Science, or Humanities --> | license = <!-- default is CC-BY --> | abstract = As the world is looking toward automation and efficient techniques in every possible situation to create user facile life. In every industry, there is a huge demand, and implementation of automation is done or going on to increase the efficiency and production rate. Increasing the product rate gives a greater output from the same amount of input, increasing the power of the economy while satisfying more human needs from the same resources. Studying and implementing increasing efficiency techniques on production lines would help the plant and engineering society acquire in the field. By implementing more efficient techniques on the production line, a difference in product rate and the valuation and supply rate of the product can be seen. Kaizen is a Japanese productivity philosophy that focuses on making tiny adjustments and improvements to the production plant. Eliminating any kinds of waste in a facility will assist to increase production, and the Kaizen methodology encourages a clean and organized workspace to keep workers moving around the facility more effectively. While the minor improvements may not have a big impact on productivity right away, Kaizen creates an environment where continuous improvement is achievable. Kaizen is a philosophy that encourages small, incremental process improvements to achieve a high level of efficiency. The plant will be significantly more productive in weeks, months, and years than it was before Kaizen was applied. Studying this field can improve the command of your engineering skills. | keywords = Automation, Product rate, Efficiency, Kaizen. }} == Introduction == The usage of polythene baggage for packaging is growing by the day. Polythene baggage is extensively utilized in everyday lifestyles with each family the usage of it for numerous functions of packaging and storage. They are taken into consideration being greater handy in packing merchandise. There is an ever-increasing call for polythene baggage within the market. Nowadays, all store storekeeper sealers of any merchandise use polythene baggage for packing purposes. The device for generating polythene film/roll that is used to make polythene baggage produces 45-50 kg of polythene film consistent with the hour. This film might be then used for making polythene baggage. So, as we are focusing on studying the Polypack industry parameters should be considered as the basics of necessity''.'' Although productivity isn't everything, it is virtually everything in the long term. The ability of a country to gain momentum in its way of life over time is almost entirely dependent on its ability to increase its yield per specialist. Paul Krugman, The Age of Decreased Desires (1994) Productivity is commonly defined as the ratio of yield volume to the volume of information sources. In other words, it assesses how an economy's productively generated inputs, like labor and capital, are used to achieve a specific amount of yield. Efficiency data, for example, is used to investigate the impact of item and labor market restrictions on financial execution. It enables examiners to determine capacity utilization, allowing them to assess the role of economies in the economic cycle and forecast financial growth. Efficiency improvement is a crucial component in exhibiting an economy's productive capacity. Extrusion is a technique in which metal or another material is forced through a sequence of dies to produce the required shape. Expulsion is used to make a lot of ceramics because the cycle allows for efficient, constant production. A screw drill continuously drives the plastic feed material through a hole or passes on in a business screw-type extruder, resulting in simple shapes like barrel-shaped bars and lines, rectangular strong and empty bars, and long plates. Kaizen focuses on reducing waste by removing overproduction, enhancing quality, increasing efficiency, eliminating the idle time, and eliminating needless tasks. All of this adds up to cost savings and the ability to turn losses into profits (Kataria,2018). Kaizen has two aspects: flow Kaizen and process Kaizen, each addressing a distinct aspect of the organizational structure. Kaizen for continual improvement necessitates efforts in both flow and process. == '''''Literature Review''''' == As we have seen this poly pack industry has only a countable number of raw products using the most appropriate contents of bitumen (with the aid of using the weight of aggregates) and Low- Density-Polyethylene (LDPE) plastic (with the aid of using the weight of bitumen) to make sure the long-time period overall performance of HMA mixtures by Asphalt-Technology & Infrastructure (Amin,2020). By referring to the Manufacturing unit we can get knowledgeable about the Bag making generally has sure principal features which make up of material feeding, sealing, creasing, gluing, drying, slicing, stacking, etc. In the Feeding section, a roll-fed flexible packaging movie is unwound from a feeder roll (Kashif,2016). The film bubble is constantly cooled by chilled air as it rises upwards from the die. To maintain the blown film aligned with the machine, it is usually directed upward through a few helper rolls. When the cylinder passes through nip rollers, it is flattened to create a 'lay-level' container of film. According to a paper by A. Moreno-Muoz et al., the pivoting tempo of the nip rolls is a crucial device for managing the rate with which the air pocket is sucked (Moreno,2009). Another extrusion procedure used to make film objects is blown film. In this case, the dust is expelled in the shape of a circle, and pneumatic force is also used to expand the film. It is cooled once it has been extended to the proper dimensions to cement the polymer (Laurence,2017). Different methodologies are being used in this poly pack industry for the production of polythene bag rolls. Some old module-based industries still use the manual process on the mechanical setup. Nowadays semi-automated industries are also working more efficiently. Besides, completely fully automated ventures have enormous productivity rates and proficiency. Plastic expulsion is a regularly high-volume manufacturing process where a polymer material, enhanced with the ideal added substances, is liquefied and formed in a ceaseless interaction (Almahadi,2021). The approach is to be momentarily examined in the production and examination part. The main parameters of this industry to be taken under observation would be the manufacturing unit, the wastage of raw materials as well as the output, and its production rate (Rahman,2019). Above all, Kaizen is a mindset, a manner of approaching work that enables engineers who practice it to Eliminate waste, Improve process flow, Boost productivity. The parameters like raw material, chemicals, every single machinery part, and its working are considered. == Methods and Findings == * As from this literature we have seen the actual implementation in industry and the various reviews on the different types of techniques being used. * Kaizen can help most to solve the issue of wastage so implementation of kaizen with process procedure is necessary. * Eliminating any form of waste in a facility will assist to increase production, and the Kaizen methodology encourages a clean and tidy workspace to keep workers moving around the facility more effectively. * The gaps from referring to this literature can be considered as more as the implementation of automation and decreasing the labor work. * Scope of work in the actual field is also a part of our project which is to be found out with the help of this literature. === '''Kaizen Phase I''' === The first obstacle is determining an acceptable target region for quick plant improvement. A small Kaizen event for the team was arranged. The task of identifying the wastage of raw product parts in the initial operation of mixing LDPE and LLDPE was completed in the production area where substantial delays occur (Flores,2009). A more particular "waste elimination" concern within that area is picked for the focus of the kaizen event once a suitable manufacturing process or location in a facility has been determined (i.e., the specific problem of mixing raw materials needs improvement, such as lead time reduction, quality improvement, and production yield improvement). After deciding on a problem area, study suitable alternatives and automation. === '''Kaizen Phase II''' === At the individual/team level, Process Kaizen entails taking tiny, targeted measures to increase efficiency, productivity, communication, and transparency. Practice Kaizen is available to everyone trying to improve their performance, regardless of whether their firm is through a Lean initiative because it is just the process of creating incremental improvements (Gupta,2014). Wastage reduction was not the only important factor in increasing production in this project; automating the manual setup was also crucial. Kaizen, or continuous improvement, is at the heart of lean production. Small, incremental changes made regularly and sustained over time result in big benefits, according to this viewpoint. The kaizen strategy tries to bring together all important changes required. === '''Objectives''' === * Implementation of Kaizen to Improve Productivity. * Kaizen strategy or plan that is to be implemented should go through the Plan > Do > Check > Act (PDCA) Cycle. * Improvement in the rate of productivity using Automation wherever required and by a collection of data from step to step. * Improvement in speed w.r.t gauge adjustment * Atomization in Winder for Reducing the Wastages with Kaizen Lean Production. * Adding a mixing machine from Kaizen for less labor work and time utilization with hygiene mixing (ISO Purpose). * Increase in productivity rate by using Automated Air shafts instead of trim winders for rolling the blown film. ==== '''Installation of Polymer Mixing Machine''' ==== As a part of the improvement in productivity rate with eliminating wastage and for hygiene mixing to follow the norms of ISO Mixing machine needs to be installed. Initially, we were mixing granules with our hands and appropriate mixing may not be done as dust particles can be mixed up while mixing with our hands (Laurence,2017). Mixing machines minimized the time required for the input of granules, eliminated raw material wastage, and did not need to stop the machine in an extra load of work or continuous work. The vertical mixing machine's functioning concept is that the barrel surrounds the mixer drum screw. For smooth rotation, the screw shaft is connected to the motor on top and placed in a bearing on the bottom. The Screw revolves, lifting and dropping the material from the top. Inside the drum is a Heater Chamber that is connected to the Heater and Blower to eliminate moisture from the material. The quantity of moisture inside the material determines the cycle time. Fig 4. Newley Installed Polymer Mixing Machine The material lifts off both the tray and the interior barrel, allowing for more efficient mixing. The material will also pass through the shutter above the tray, which will be elevated by the screw once more. Shutter with a hinge at the bottom of the screw to make it easier to clean the material with air. The height of the tray makes loading the material a breeze. The mixer includes an output shutter from which the drum may be readily filled. ==== '''Replacing Trim Winders with Pneumatic Winders (Air hafts) for Automation''' ==== As earlier we were using a trim winder to roll the films which used to take more time and skilled laborers are needed for that fitting purpose. Fig 5. Newly Installed Blown Film Winder Now Trim winders need to be fitted on a rolling panel with Allen Key and the core needs to be adjusted manually every time. Replacement of the pneumatic winder the automation is done as we already have a compressor unit we just require to choose and implement the Pneumatic winder which fits the core accordingly and much easier to carry the rolls of film. * Blown Film Winder Description: Plastic Film Blowing Machine's Extrusion Blown Film Winder is the final step in the production of plastic film products. The job of the Extrusion Winder in a Plastic Blown Film Line is critical for maintaining film tension and making it easy to utilize for post-processing. Ensure that the film that came from the Take-Up Unit is of the flat type and that the final step keeps the film stable and free of unevenness. Winder for the film. Additionally, the line speed (take-up speed) is the key control device for film thickness and stability. *  Functions and Working: The film become incredibly flat after processing in the Take-Up Unit, and it reaches the first phase of the Extrusion Blown Film Winder. The main purpose is to gather the film perfectly on the collecting roll without any uneven edges. The purpose of a high-precision blown film winder is to keep the average air content value between each layer of film constant to avoid uneven and irregular locations. The film initially travels through Surface Winding, which is constructed of rubber and steel bars, in the Blown Film Winder process. The film is stretched to retain its tension by the interaction of these two bars. The film then adheres to a spinning roll known as the online Roller, which collects it. To wind the plastic sheet, you must lead it in the right direction. The Shifting Forks then take up the position of the Standby Roller for the next winding when the online roller reaches the required meters or wound-up diameters. Knives are frequently used to cut the well-wrapped roll down at this point. In addition, the Extrusion Film Winder will be equipped with a Slitting Knife and a Side Open Knife to cut film for various applications. For items like cling wrap and shrink film, the Side Open Knife divides the film into two sections. The Slitting Knife, on the other hand, cuts the film into strips according to the size requirements. Furthermore, the possibility of an automatic system boosts the Winding Unit's efficacy. == '''Numerical Methodology''' == As part of the production line, the numerical methodology plays the most important role. Numerical methodology decides the actual status of a company. In this chapter, we will see the data collected from the industry while accrual working''.'' In this methodology part, we have taken readings of the number of experiments and production of different products on an actual basis. As shown below in tabular form we can see the actual production rate of the company for different products of different microns. We have considered actual readings from several attempts while experimenting and on industrial production time. Graph 1. Actual vs Expected Output === '''Output of the Extruder before Kaizen''' === The output below is taken before the implementation of the kaizen method in the plant. The investigation part was done before it and testing were taken of the output at normal conditions''.''    Table I. Actual Output of Extruder {| class="wikitable" |'''Product''' |'''Hourly Production (Average till date)''' |'''Microns''' |'''Gauge (microns*4)''' |- |'''Shrink Film''' |65 kg |85-90 |340-360 |- |'''Dairy Film''' |67kg |75-80 |300-320 |- |'''  LD Film''' |70kg |Above 50 |   200+ |- |'''Anti-Static''' |63kg |Around 100 |Around 400 |} The above Table I. shows the actual output of the extruder on an hourly basis. The different products Shrink Film, Dairy Film, Normal LD Film, and Anti-Static take different times to produce as per the microns . Graph 2. Actual Output of the Extruder before Kaizen Average Output = 65+67+70+63 / 4    =66.25 Kg/Hr. === '''Output of the Extruder after Kaizen''' === Below is Table II. shows the output of the extruder after Kaizen on an hourly basis. The different products Shrink Film, Dairy Film, Normal LD Film, and Anti-Static take different times to produce as per the microns. Table II. Actual Output of Extruder {| class="wikitable" |'''Product''' |'''Hourly Production (Average till date)''' |'''Microns''' |'''Gauge (microns*4)''' |- |'''Shrink Film''' |70 kg |85-90 |340-360 |- |'''Dairy Film''' |72kg |75-80 |300-320 |- |'''Normal LD Film''' |75kg |Above 50 |200+ |- |'''Anti-Static''' |68kg |Around 100 |Around 400 |} Graph 3. Actual Output of the Extruder after Kaizen Average Output= 72+73+77+68 / 4 =72.5 Kg/Hr.  == '''Result and Discussion''' == Plastic ejection is a high-volume fabricating procedure in which a polymer material is dissolved and shaped. A continuous process after being advanced with the appropriate additional chemicals. So, with the use of automation, we must deliberately identify areas for Productivity Improvement and other enhancements to be one for the good of the industry. Studying in this field can improve the Automation and PLC knowledge as well as help in the improvement of productivity rate. So, the expected outcome is to be knowledgeable in this industry and help the Polypack production plant to improve the Productivity Rate. Graph 4. Comparison Output of the Extruder before and after Kaizen === '''Percentage Increment in Production Rate''' === Productivity Rate (% Increment) = Avg. before Kaizen x 100   Avg. before Kaizen = 62.25 x 100    77.5 = 8.62% The Overall Improvement in Productivity Rate is 8.62% more than the previous output. == '''Conclusion ''' == From this project, we conquered that Kaizen is a way of thinking about continuous improvement that is founded on the premise that little, consistent positive adjustments can add up to big results. Implementing Kaizen to any industrial non-industrial issues can make a huge improvement. Studying in this field has improved the Automation and PLC knowledge as well as helped in the improvement of productivity rate.                           We got a chance to analyze, research, and implement the procedure in the poly pack industry has given us an 8.62% of increment in productivity rate which was more than expectations also the wastage of raw material and output is reduced almost totally. Significant results in reducing Production time, lowering Production cost, decreasing Labor cost and efficient system has been done through this project.     === Acknowledgements === Words cannot express my gratitude to my professor Ashwinkumar Mahindrakar and for his invaluable patience and feedback. I also could not have undertaken this journey without my chair committee, who generously provided knowledge and expertise. Additionally, this endeavor would not have been possible without the generous support from the Department of Mechanical Engineering, MIT Art Design and Technology University towards my research. I am also grateful to my industrial mentors for keeping faith in me. Thanks, should also go to the librarians, research assistants, and study participants from the university, who impacted and inspired me. Lastly, I would be remiss in not mentioning my family, especially my parents. Their belief in me has kept my spirits and motivation high during this process. === Competing interests === The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. == References == 1. Almahdi B.*, “Feasibility of Utilising Waste Polyethylene Terephthalate as Replacement in Asphalt binder Mixture”, Knowledge-Based Engineering and Science (2021) vol.2 no.1 January-April. 2. Amin S. * “Impacts of Low-Density Polyethylene (Plastic Shopping Bags) on Structural Performance and Permeability of HMA Mixtures”, Conference Paper, (2020). 3. Flores-Arias J.M, Pallarés V. and de la Rosa J. J. G., “Extrusion of blown Film”, IEEE Xplore, (2009). 4. Gupta S.*, “The 5S and kaizen concept for overall improvement of the organisation: a case study”, Int. J. Lean Enterprise Research, (2014), vol. 1, no. 1. 5. Kashif F.“Design and Fabrication of Low-Cost Paper Bag Manufacturing Unit”, (2016). 6. Kataria R.*, “Quality and Productivity Improvement in Industry Using Kaizen: A Review”, JETIR (2018) vol. 5, issue 12. 7. Laurence W. McKeen* “Production of Films, Containers, and Membranes”, in Permeability Properties of Plastics and Elastomers (Fourth Edition),(2017) 8. Moreno-Muñoz, J.M Flores-Arias, V. Pallarés and J. J. G. de la Rosa “Power Quality Immunity in Factory Automation”, IEEE Xplore, (2009). 9. Rahman L., “The Concept and Implementation of Kaizen in an Organization”, Global Journals, (2019) ISSN 2249-4588. jt88sqgvbi9ti37dbrww9cm2g2nruss 2408044 2408040 2022-07-19T20:09:50Z OhanaUnited 18921 same affiliation wikitext text/x-wiki {{Article info | first1 = Nikhil | last1 = Nimbalkar | orcid1 = 0000-0002-5882-186X | affiliation1 = Department of Mechanical Engineering, MIT School of Engineering, Pune | correspondence1 = niksnimbalkar2000@gmail.com | affiliations = University | first2 = Ashwinkumar | last2 = Mahindrakar{{affiliation|name=Nimbalkar}} | journal = WikiJournal of Science <!-- WikiJournal of Medicine, Science, or Humanities --> | license = <!-- default is CC-BY --> | abstract = As the world is looking toward automation and efficient techniques in every possible situation to create user facile life. In every industry, there is a huge demand, and implementation of automation is done or going on to increase the efficiency and production rate. Increasing the product rate gives a greater output from the same amount of input, increasing the power of the economy while satisfying more human needs from the same resources. Studying and implementing increasing efficiency techniques on production lines would help the plant and engineering society acquire in the field. By implementing more efficient techniques on the production line, a difference in product rate and the valuation and supply rate of the product can be seen. Kaizen is a Japanese productivity philosophy that focuses on making tiny adjustments and improvements to the production plant. Eliminating any kinds of waste in a facility will assist to increase production, and the Kaizen methodology encourages a clean and organized workspace to keep workers moving around the facility more effectively. While the minor improvements may not have a big impact on productivity right away, Kaizen creates an environment where continuous improvement is achievable. Kaizen is a philosophy that encourages small, incremental process improvements to achieve a high level of efficiency. The plant will be significantly more productive in weeks, months, and years than it was before Kaizen was applied. Studying this field can improve the command of your engineering skills. | keywords = Automation, Product rate, Efficiency, Kaizen. }} == Introduction == The usage of polythene baggage for packaging is growing by the day. Polythene baggage is extensively utilized in everyday lifestyles with each family the usage of it for numerous functions of packaging and storage. They are taken into consideration being greater handy in packing merchandise. There is an ever-increasing call for polythene baggage within the market. Nowadays, all store storekeeper sealers of any merchandise use polythene baggage for packing purposes. The device for generating polythene film/roll that is used to make polythene baggage produces 45-50 kg of polythene film consistent with the hour. This film might be then used for making polythene baggage. So, as we are focusing on studying the Polypack industry parameters should be considered as the basics of necessity''.'' Although productivity isn't everything, it is virtually everything in the long term. The ability of a country to gain momentum in its way of life over time is almost entirely dependent on its ability to increase its yield per specialist. Paul Krugman, The Age of Decreased Desires (1994) Productivity is commonly defined as the ratio of yield volume to the volume of information sources. In other words, it assesses how an economy's productively generated inputs, like labor and capital, are used to achieve a specific amount of yield. Efficiency data, for example, is used to investigate the impact of item and labor market restrictions on financial execution. It enables examiners to determine capacity utilization, allowing them to assess the role of economies in the economic cycle and forecast financial growth. Efficiency improvement is a crucial component in exhibiting an economy's productive capacity. Extrusion is a technique in which metal or another material is forced through a sequence of dies to produce the required shape. Expulsion is used to make a lot of ceramics because the cycle allows for efficient, constant production. A screw drill continuously drives the plastic feed material through a hole or passes on in a business screw-type extruder, resulting in simple shapes like barrel-shaped bars and lines, rectangular strong and empty bars, and long plates. Kaizen focuses on reducing waste by removing overproduction, enhancing quality, increasing efficiency, eliminating the idle time, and eliminating needless tasks. All of this adds up to cost savings and the ability to turn losses into profits (Kataria,2018). Kaizen has two aspects: flow Kaizen and process Kaizen, each addressing a distinct aspect of the organizational structure. Kaizen for continual improvement necessitates efforts in both flow and process. == '''''Literature Review''''' == As we have seen this poly pack industry has only a countable number of raw products using the most appropriate contents of bitumen (with the aid of using the weight of aggregates) and Low- Density-Polyethylene (LDPE) plastic (with the aid of using the weight of bitumen) to make sure the long-time period overall performance of HMA mixtures by Asphalt-Technology & Infrastructure (Amin,2020). By referring to the Manufacturing unit we can get knowledgeable about the Bag making generally has sure principal features which make up of material feeding, sealing, creasing, gluing, drying, slicing, stacking, etc. In the Feeding section, a roll-fed flexible packaging movie is unwound from a feeder roll (Kashif,2016). The film bubble is constantly cooled by chilled air as it rises upwards from the die. To maintain the blown film aligned with the machine, it is usually directed upward through a few helper rolls. When the cylinder passes through nip rollers, it is flattened to create a 'lay-level' container of film. According to a paper by A. Moreno-Muoz et al., the pivoting tempo of the nip rolls is a crucial device for managing the rate with which the air pocket is sucked (Moreno,2009). Another extrusion procedure used to make film objects is blown film. In this case, the dust is expelled in the shape of a circle, and pneumatic force is also used to expand the film. It is cooled once it has been extended to the proper dimensions to cement the polymer (Laurence,2017). Different methodologies are being used in this poly pack industry for the production of polythene bag rolls. Some old module-based industries still use the manual process on the mechanical setup. Nowadays semi-automated industries are also working more efficiently. Besides, completely fully automated ventures have enormous productivity rates and proficiency. Plastic expulsion is a regularly high-volume manufacturing process where a polymer material, enhanced with the ideal added substances, is liquefied and formed in a ceaseless interaction (Almahadi,2021). The approach is to be momentarily examined in the production and examination part. The main parameters of this industry to be taken under observation would be the manufacturing unit, the wastage of raw materials as well as the output, and its production rate (Rahman,2019). Above all, Kaizen is a mindset, a manner of approaching work that enables engineers who practice it to Eliminate waste, Improve process flow, Boost productivity. The parameters like raw material, chemicals, every single machinery part, and its working are considered. == Methods and Findings == * As from this literature we have seen the actual implementation in industry and the various reviews on the different types of techniques being used. * Kaizen can help most to solve the issue of wastage so implementation of kaizen with process procedure is necessary. * Eliminating any form of waste in a facility will assist to increase production, and the Kaizen methodology encourages a clean and tidy workspace to keep workers moving around the facility more effectively. * The gaps from referring to this literature can be considered as more as the implementation of automation and decreasing the labor work. * Scope of work in the actual field is also a part of our project which is to be found out with the help of this literature. === '''Kaizen Phase I''' === The first obstacle is determining an acceptable target region for quick plant improvement. A small Kaizen event for the team was arranged. The task of identifying the wastage of raw product parts in the initial operation of mixing LDPE and LLDPE was completed in the production area where substantial delays occur (Flores,2009). A more particular "waste elimination" concern within that area is picked for the focus of the kaizen event once a suitable manufacturing process or location in a facility has been determined (i.e., the specific problem of mixing raw materials needs improvement, such as lead time reduction, quality improvement, and production yield improvement). After deciding on a problem area, study suitable alternatives and automation. === '''Kaizen Phase II''' === At the individual/team level, Process Kaizen entails taking tiny, targeted measures to increase efficiency, productivity, communication, and transparency. Practice Kaizen is available to everyone trying to improve their performance, regardless of whether their firm is through a Lean initiative because it is just the process of creating incremental improvements (Gupta,2014). Wastage reduction was not the only important factor in increasing production in this project; automating the manual setup was also crucial. Kaizen, or continuous improvement, is at the heart of lean production. Small, incremental changes made regularly and sustained over time result in big benefits, according to this viewpoint. The kaizen strategy tries to bring together all important changes required. === '''Objectives''' === * Implementation of Kaizen to Improve Productivity. * Kaizen strategy or plan that is to be implemented should go through the Plan > Do > Check > Act (PDCA) Cycle. * Improvement in the rate of productivity using Automation wherever required and by a collection of data from step to step. * Improvement in speed w.r.t gauge adjustment * Atomization in Winder for Reducing the Wastages with Kaizen Lean Production. * Adding a mixing machine from Kaizen for less labor work and time utilization with hygiene mixing (ISO Purpose). * Increase in productivity rate by using Automated Air shafts instead of trim winders for rolling the blown film. ==== '''Installation of Polymer Mixing Machine''' ==== As a part of the improvement in productivity rate with eliminating wastage and for hygiene mixing to follow the norms of ISO Mixing machine needs to be installed. Initially, we were mixing granules with our hands and appropriate mixing may not be done as dust particles can be mixed up while mixing with our hands (Laurence,2017). Mixing machines minimized the time required for the input of granules, eliminated raw material wastage, and did not need to stop the machine in an extra load of work or continuous work. The vertical mixing machine's functioning concept is that the barrel surrounds the mixer drum screw. For smooth rotation, the screw shaft is connected to the motor on top and placed in a bearing on the bottom. The Screw revolves, lifting and dropping the material from the top. Inside the drum is a Heater Chamber that is connected to the Heater and Blower to eliminate moisture from the material. The quantity of moisture inside the material determines the cycle time. Fig 4. Newley Installed Polymer Mixing Machine The material lifts off both the tray and the interior barrel, allowing for more efficient mixing. The material will also pass through the shutter above the tray, which will be elevated by the screw once more. Shutter with a hinge at the bottom of the screw to make it easier to clean the material with air. The height of the tray makes loading the material a breeze. The mixer includes an output shutter from which the drum may be readily filled. ==== '''Replacing Trim Winders with Pneumatic Winders (Air hafts) for Automation''' ==== As earlier we were using a trim winder to roll the films which used to take more time and skilled laborers are needed for that fitting purpose. Fig 5. Newly Installed Blown Film Winder Now Trim winders need to be fitted on a rolling panel with Allen Key and the core needs to be adjusted manually every time. Replacement of the pneumatic winder the automation is done as we already have a compressor unit we just require to choose and implement the Pneumatic winder which fits the core accordingly and much easier to carry the rolls of film. * Blown Film Winder Description: Plastic Film Blowing Machine's Extrusion Blown Film Winder is the final step in the production of plastic film products. The job of the Extrusion Winder in a Plastic Blown Film Line is critical for maintaining film tension and making it easy to utilize for post-processing. Ensure that the film that came from the Take-Up Unit is of the flat type and that the final step keeps the film stable and free of unevenness. Winder for the film. Additionally, the line speed (take-up speed) is the key control device for film thickness and stability. *  Functions and Working: The film become incredibly flat after processing in the Take-Up Unit, and it reaches the first phase of the Extrusion Blown Film Winder. The main purpose is to gather the film perfectly on the collecting roll without any uneven edges. The purpose of a high-precision blown film winder is to keep the average air content value between each layer of film constant to avoid uneven and irregular locations. The film initially travels through Surface Winding, which is constructed of rubber and steel bars, in the Blown Film Winder process. The film is stretched to retain its tension by the interaction of these two bars. The film then adheres to a spinning roll known as the online Roller, which collects it. To wind the plastic sheet, you must lead it in the right direction. The Shifting Forks then take up the position of the Standby Roller for the next winding when the online roller reaches the required meters or wound-up diameters. Knives are frequently used to cut the well-wrapped roll down at this point. In addition, the Extrusion Film Winder will be equipped with a Slitting Knife and a Side Open Knife to cut film for various applications. For items like cling wrap and shrink film, the Side Open Knife divides the film into two sections. The Slitting Knife, on the other hand, cuts the film into strips according to the size requirements. Furthermore, the possibility of an automatic system boosts the Winding Unit's efficacy. == '''Numerical Methodology''' == As part of the production line, the numerical methodology plays the most important role. Numerical methodology decides the actual status of a company. In this chapter, we will see the data collected from the industry while accrual working''.'' In this methodology part, we have taken readings of the number of experiments and production of different products on an actual basis. As shown below in tabular form we can see the actual production rate of the company for different products of different microns. We have considered actual readings from several attempts while experimenting and on industrial production time. Graph 1. Actual vs Expected Output === '''Output of the Extruder before Kaizen''' === The output below is taken before the implementation of the kaizen method in the plant. The investigation part was done before it and testing were taken of the output at normal conditions''.''    Table I. Actual Output of Extruder {| class="wikitable" |'''Product''' |'''Hourly Production (Average till date)''' |'''Microns''' |'''Gauge (microns*4)''' |- |'''Shrink Film''' |65 kg |85-90 |340-360 |- |'''Dairy Film''' |67kg |75-80 |300-320 |- |'''  LD Film''' |70kg |Above 50 |   200+ |- |'''Anti-Static''' |63kg |Around 100 |Around 400 |} The above Table I. shows the actual output of the extruder on an hourly basis. The different products Shrink Film, Dairy Film, Normal LD Film, and Anti-Static take different times to produce as per the microns . Graph 2. Actual Output of the Extruder before Kaizen Average Output = 65+67+70+63 / 4    =66.25 Kg/Hr. === '''Output of the Extruder after Kaizen''' === Below is Table II. shows the output of the extruder after Kaizen on an hourly basis. The different products Shrink Film, Dairy Film, Normal LD Film, and Anti-Static take different times to produce as per the microns. Table II. Actual Output of Extruder {| class="wikitable" |'''Product''' |'''Hourly Production (Average till date)''' |'''Microns''' |'''Gauge (microns*4)''' |- |'''Shrink Film''' |70 kg |85-90 |340-360 |- |'''Dairy Film''' |72kg |75-80 |300-320 |- |'''Normal LD Film''' |75kg |Above 50 |200+ |- |'''Anti-Static''' |68kg |Around 100 |Around 400 |} Graph 3. Actual Output of the Extruder after Kaizen Average Output= 72+73+77+68 / 4 =72.5 Kg/Hr.  == '''Result and Discussion''' == Plastic ejection is a high-volume fabricating procedure in which a polymer material is dissolved and shaped. A continuous process after being advanced with the appropriate additional chemicals. So, with the use of automation, we must deliberately identify areas for Productivity Improvement and other enhancements to be one for the good of the industry. Studying in this field can improve the Automation and PLC knowledge as well as help in the improvement of productivity rate. So, the expected outcome is to be knowledgeable in this industry and help the Polypack production plant to improve the Productivity Rate. Graph 4. Comparison Output of the Extruder before and after Kaizen === '''Percentage Increment in Production Rate''' === Productivity Rate (% Increment) = Avg. before Kaizen x 100   Avg. before Kaizen = 62.25 x 100    77.5 = 8.62% The Overall Improvement in Productivity Rate is 8.62% more than the previous output. == '''Conclusion ''' == From this project, we conquered that Kaizen is a way of thinking about continuous improvement that is founded on the premise that little, consistent positive adjustments can add up to big results. Implementing Kaizen to any industrial non-industrial issues can make a huge improvement. Studying in this field has improved the Automation and PLC knowledge as well as helped in the improvement of productivity rate.                           We got a chance to analyze, research, and implement the procedure in the poly pack industry has given us an 8.62% of increment in productivity rate which was more than expectations also the wastage of raw material and output is reduced almost totally. Significant results in reducing Production time, lowering Production cost, decreasing Labor cost and efficient system has been done through this project.     === Acknowledgements === Words cannot express my gratitude to my professor Ashwinkumar Mahindrakar and for his invaluable patience and feedback. I also could not have undertaken this journey without my chair committee, who generously provided knowledge and expertise. Additionally, this endeavor would not have been possible without the generous support from the Department of Mechanical Engineering, MIT Art Design and Technology University towards my research. I am also grateful to my industrial mentors for keeping faith in me. Thanks, should also go to the librarians, research assistants, and study participants from the university, who impacted and inspired me. Lastly, I would be remiss in not mentioning my family, especially my parents. Their belief in me has kept my spirits and motivation high during this process. === Competing interests === The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. == References == 1. Almahdi B.*, “Feasibility of Utilising Waste Polyethylene Terephthalate as Replacement in Asphalt binder Mixture”, Knowledge-Based Engineering and Science (2021) vol.2 no.1 January-April. 2. Amin S. * “Impacts of Low-Density Polyethylene (Plastic Shopping Bags) on Structural Performance and Permeability of HMA Mixtures”, Conference Paper, (2020). 3. Flores-Arias J.M, Pallarés V. and de la Rosa J. J. G., “Extrusion of blown Film”, IEEE Xplore, (2009). 4. Gupta S.*, “The 5S and kaizen concept for overall improvement of the organisation: a case study”, Int. J. Lean Enterprise Research, (2014), vol. 1, no. 1. 5. Kashif F.“Design and Fabrication of Low-Cost Paper Bag Manufacturing Unit”, (2016). 6. Kataria R.*, “Quality and Productivity Improvement in Industry Using Kaizen: A Review”, JETIR (2018) vol. 5, issue 12. 7. Laurence W. McKeen* “Production of Films, Containers, and Membranes”, in Permeability Properties of Plastics and Elastomers (Fourth Edition),(2017) 8. Moreno-Muñoz, J.M Flores-Arias, V. Pallarés and J. J. G. de la Rosa “Power Quality Immunity in Factory Automation”, IEEE Xplore, (2009). 9. Rahman L., “The Concept and Implementation of Kaizen in an Organization”, Global Journals, (2019) ISSN 2249-4588. dzw84bmhz6plxokkcytpnr9rli3bhcn 0 285508 2408052 2022-07-19T23:24:04Z 2601:40B:8503:4060:8042:8DD4:BE89:E9DB New resource with "====== Descripiton ====== ===== These spiders have legs and eyes. Their species often includes the desert, garden, european, striped, giant and brown wolf spider. Females are also unqiue of any spider. Threats of this spider often include crows, scorpions, ants, tarantulas, and sometimes other wolf spiders. Humans are bitten when they step on the spider or pick it up to take a closer look. ===== ===== Reproduction ===== Female wolf spiders often giv..." wikitext text/x-wiki ====== Descripiton ====== ===== These spiders have legs and eyes. Their species often includes the desert, garden, european, striped, giant and brown wolf spider. Females are also unqiue of any spider. Threats of this spider often include crows, scorpions, ants, tarantulas, and sometimes other wolf spiders. Humans are bitten when they step on the spider or pick it up to take a closer look. ===== ===== Reproduction ===== Female wolf spiders often give birth while hanging eggs. The babies remain on their mother's back, until they get off of her. ==== Appearance on Monster Bug Wars ==== However, on the tv show, Mr. Stozier states that " The spider tries to run. But the scorpion attacks first, and grabs with his pincers. He swings his tail forward and lands a direct hit. Then, he stabs again, but this time, the spider is not avoiding it.<nowiki>''</nowiki> === Links === [[File:Wolf spider&egg sac.jpg|thumb|A wolf spider with her egg ]] Wolf Spider ( Wiki books ) Top ten spider species in the world ( Wikiverstiy ) Aranha Lobo ( Espanol Latino ) tct154x9tpreytt88elybso09t91pqx 2408053 2408052 2022-07-19T23:58:52Z Dave Braunschweig 426084 Advise wikitext text/x-wiki {{Advise|Spider}} m6b7oqtv0yeken4sca69a546n3vbba2 3 285509 2408054 2022-07-20T00:02:54Z Dave Braunschweig 426084 Welcome wikitext text/x-wiki {{Robelbox|theme=9|title=Welcome!|width=100%}} <div style="{{Robelbox/pad}}"> '''Hello and [[Wikiversity:Welcome|Welcome]] to [[Wikiversity:What is Wikiversity|Wikiversity]] KlayLay!''' You can [[Wikiversity:Contact|contact us]] with [[Wikiversity:Questions|questions]] at the [[Wikiversity:Colloquium|colloquium]] or [[User talk:Dave Braunschweig|me personally]] when you need [[Help:Contents|help]]. 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Lim |Permission={{cc-by-sa-3.0,2.5,2.0,1.0}} }} wikitext text/x-wiki == Summary == {{Information |Description=Condition (20220718 - 20220716) |Source={{own|Young1lim}} |Date=2022-07-20 |Author=Young W. Lim |Permission={{cc-by-sa-3.0,2.5,2.0,1.0}} }} == Licensing == {{self|GFDL|cc-by-sa-4.0,3.0,2.5,2.0,1.0}} nv7nma7ffsrzd5gl15esuw0znan9qn1 6 285513 2408075 2022-07-20T02:26:08Z Young1lim 21186 {{Information |Description=Condition (20220719 - 20220718) |Source={{own|Young1lim}} |Date=2022-07-20 |Author=Young W. Lim |Permission={{cc-by-sa-3.0,2.5,2.0,1.0}} }} wikitext text/x-wiki == Summary == {{Information |Description=Condition (20220719 - 20220718) |Source={{own|Young1lim}} |Date=2022-07-20 |Author=Young W. Lim |Permission={{cc-by-sa-3.0,2.5,2.0,1.0}} }} == Licensing == {{self|GFDL|cc-by-sa-4.0,3.0,2.5,2.0,1.0}} 2ke46d24jwnxnvk5wozf9fsnustmwxe 2 285514 2408078 2022-07-20T02:37:10Z Jtwsaddress42 234843 New resource with "* {{cite AV media | last= Dunning | first= Brian | year= 2022 | title= The Dark Side of Polyvagal Theory - A controversial mental health framework is also being peddled by unqualified coaches. | series= Skeptoid Podcast | number= 816 | publisher= Skeptoid Media | publication-date= January 25, 2022 | url= https://dts.podtrac.com/redirect.mp3/dovetail.prxu.org/_/819/c0152ca0-e392-43d6-8fc4-36b72cc7736a/Skeptoid_Polyvagal_Ep816_Seg1.mp3 }} [https://skeptoid.com/episode..." wikitext text/x-wiki * {{cite AV media | last= Dunning | first= Brian | year= 2022 | title= The Dark Side of Polyvagal Theory - A controversial mental health framework is also being peddled by unqualified coaches. | series= Skeptoid Podcast | number= 816 | publisher= Skeptoid Media | publication-date= January 25, 2022 | url= https://dts.podtrac.com/redirect.mp3/dovetail.prxu.org/_/819/c0152ca0-e392-43d6-8fc4-36b72cc7736a/Skeptoid_Polyvagal_Ep816_Seg1.mp3 }} [https://skeptoid.com/episodes/4816 transcript] (0:20:46) diimtck64drn96bqnl49vretrrzjxzj 2 285515 2408081 2022-07-20T02:47:58Z Jtwsaddress42 234843 New resource with "* {{cite journal | last1= Love | first1= Alan C. | last2= Raff | first2= Rudolf A. | year= 2003 | title= Knowing Your Ancestors: Themes in the History of Evo-Devo | journal= Evolution & Development | volume= 5 | number= 4 | pages= 327-330 | publication-date= July-August 2003 | pmid= 12823449 | doi= 10.1046/j.1525-142x.2003.03040.x | url= https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1525-142X.2003.03040.x }}" wikitext text/x-wiki * {{cite journal | last1= Love | first1= Alan C. | last2= Raff | first2= Rudolf A. | year= 2003 | title= Knowing Your Ancestors: Themes in the History of Evo-Devo | journal= Evolution & Development | volume= 5 | number= 4 | pages= 327-330 | publication-date= July-August 2003 | pmid= 12823449 | doi= 10.1046/j.1525-142x.2003.03040.x | url= https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1525-142X.2003.03040.x }} n9ytrkxjzo8akay5ramqhptc4nra68k 6 285516 2408107 2022-07-20T04:21:47Z Young1lim 21186 {{Information |Description=ARM.2ASM: Exceptions (20220718 - 20220716) |Source={{own|Young1lim}} |Date=2022-07-20 |Author=Young W. Lim |Permission={{GFDL}} }} wikitext text/x-wiki == Summary == {{Information |Description=ARM.2ASM: Exceptions (20220718 - 20220716) |Source={{own|Young1lim}} |Date=2022-07-20 |Author=Young W. Lim |Permission={{GFDL}} }} == Licensing == {{self|GFDL|cc-by-sa-4.0,3.0,2.5,2.0,1.0}} lkgk6h95fmk49clzf6eck0e4qnv1p28 6 285517 2408109 2022-07-20T04:22:41Z Young1lim 21186 {{Information |Description=ARM.2ASM: Exceptions (20220719 - 20220718) |Source={{own|Young1lim}} |Date=2022-07-20 |Author=Young W. Lim |Permission={{GFDL}} }} wikitext text/x-wiki == Summary == {{Information |Description=ARM.2ASM: Exceptions (20220719 - 20220718) |Source={{own|Young1lim}} |Date=2022-07-20 |Author=Young W. Lim |Permission={{GFDL}} }} == Licensing == {{self|GFDL|cc-by-sa-4.0,3.0,2.5,2.0,1.0}} muflb1kd3yeys33thhi2jmpjy4xyr7b 2 285518 2408143 2022-07-20T09:35:39Z Bert Niehaus 2387134 New resource with "== First Quizelement == The following quiz tag contains two questions. <quiz> {Sample Question 1 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. {Sample Question 2 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. </quiz>" wikitext text/x-wiki == First Quizelement == The following quiz tag contains two questions. <quiz> {Sample Question 1 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. {Sample Question 2 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. </quiz> sglt62zss3yc28hcgqgi3ntm28d61kc 2408146 2408143 2022-07-20T10:10:54Z Bert Niehaus 2387134 /* First Quizelement */ wikitext text/x-wiki == First Quizelement == The following quiz tag contains two questions. <quiz> {Sample Question 1 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. {Sample Question 2 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. </quiz> == Second Quiz Element == Answers that require a text input. {Location |type="{}"} Where was Aristotle born? { Stageira } {Mentor |type="{}"} Name Aristotle's famous mentor. { Plato } {Pupil |type="{}"} { Alexander } was Aristotle's most famous pupil. 4g0qt1kq6j5u9wrs2ffpw4j4t9q8j3e 2408147 2408146 2022-07-20T10:11:14Z Bert Niehaus 2387134 /* Second Quiz Element */ wikitext text/x-wiki == First Quizelement == The following quiz tag contains two questions. <quiz> {Sample Question 1 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. {Sample Question 2 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. </quiz> == Second Quiz Element == Answers that require a text input. <quiz> {Location |type="{}"} Where was Aristotle born? { Stageira } {Mentor |type="{}"} Name Aristotle's famous mentor. { Plato } {Pupil |type="{}"} { Alexander } was Aristotle's most famous pupil. </quiz> liwwbhrw45ofoeppk5be4g02pkfo2h0 2408148 2408147 2022-07-20T10:12:16Z Bert Niehaus 2387134 /* Second Quiz Element */ wikitext text/x-wiki == First Quizelement == The following quiz tag contains two questions. <quiz> {Sample Question 1 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. {Sample Question 2 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. </quiz> == Second Quiz Element == Answers that require a text input. As learning resource see [[Wikipedia:Aristotle]] <quiz> {Location |type="{}"} Where was Aristotle born? { Stageira } {Mentor |type="{}"} Name Aristotle's famous mentor. { Plato } {Pupil |type="{}"} { Alexander } was Aristotle's most famous pupil. </quiz> 8h1j8sx6fr1xvmsjbnx9gx46qwnj21l 2408149 2408148 2022-07-20T10:13:10Z Bert Niehaus 2387134 /* Second Quiz Element */ wikitext text/x-wiki == First Quizelement == The following quiz tag contains two questions. <quiz> {Sample Question 1 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. {Sample Question 2 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. </quiz> == Second Quiz Element == Answers that require a text input. As learning resource see [[Wikipedia:Aristotle]] [[File:Aristotle Altemps Inv8575.jpg|thumb|Aristotle]] <quiz> {Location |type="{}"} Where was Aristotle born? { Stageira } {Mentor |type="{}"} Name Aristotle's famous mentor. { Plato } {Pupil |type="{}"} { Alexander } was Aristotle's most famous pupil. </quiz> 2loscs264yw70wbi3zli0c4thp4ss8v 2408150 2408149 2022-07-20T10:13:42Z Bert Niehaus 2387134 /* Second Quiz Element */ wikitext text/x-wiki == First Quizelement == The following quiz tag contains two questions. <quiz> {Sample Question 1 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. {Sample Question 2 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. </quiz> == Second Quiz Element == Answers that require a text input. As learning resource see [[Wikipedia:Aristotle]] [[File:Aristotle Altemps Inv8575.jpg|thumb|Aristotle]] <quiz> {'''Location''' |type="{}"} Where was Aristotle born? { Stageira } {'''Mentor''' |type="{}"} Name Aristotle's famous mentor. { Plato } {'''Pupil''' |type="{}"} { Alexander } was Aristotle's most famous pupil. </quiz> 91yhrgi9l2ix1m2yq7fgk7n6ek2z37e 2408151 2408150 2022-07-20T10:15:50Z Bert Niehaus 2387134 /* First Quizelement */ wikitext text/x-wiki == First Quizelement == The following quiz tag contains two questions. <quiz> {Sample Question 1 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. [[[[File:BBH_gravitational_lensing_of_gw150914.webm|400px]]|450px|center|Gravitational Lens]] {Sample Question 2 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. </quiz> == Second Quiz Element == Answers that require a text input. As learning resource see [[Wikipedia:Aristotle]] [[File:Aristotle Altemps Inv8575.jpg|thumb|Aristotle]] <quiz> {'''Location''' |type="{}"} Where was Aristotle born? { Stageira } {'''Mentor''' |type="{}"} Name Aristotle's famous mentor. { Plato } {'''Pupil''' |type="{}"} { Alexander } was Aristotle's most famous pupil. </quiz> ihen5yg7xh93iiqq7f29fj3yjhe3tw4 2408152 2408151 2022-07-20T10:16:29Z Bert Niehaus 2387134 /* First Quizelement */ wikitext text/x-wiki == First Quizelement == The following quiz tag contains two questions. <quiz> {Sample Question 1 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. {Sample Question 2 [[File:BBH_gravitational_lensing_of_gw150914.webm|400px]]|450px|center|Gravitational Lens]] |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. </quiz> == Second Quiz Element == Answers that require a text input. As learning resource see [[Wikipedia:Aristotle]] [[File:Aristotle Altemps Inv8575.jpg|thumb|Aristotle]] <quiz> {'''Location''' |type="{}"} Where was Aristotle born? { Stageira } {'''Mentor''' |type="{}"} Name Aristotle's famous mentor. { Plato } {'''Pupil''' |type="{}"} { Alexander } was Aristotle's most famous pupil. </quiz> py2srdft7io94afesdf7etrh426l617 2408153 2408152 2022-07-20T10:17:10Z Bert Niehaus 2387134 /* First Quizelement */ wikitext text/x-wiki == First Quizelement == The following quiz tag contains two questions. <quiz> {Sample Question 1 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. {Sample Question 2 [[File:BBH_gravitational_lensing_of_gw150914.webm|400px]] |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. </quiz> == Second Quiz Element == Answers that require a text input. As learning resource see [[Wikipedia:Aristotle]] [[File:Aristotle Altemps Inv8575.jpg|thumb|Aristotle]] <quiz> {'''Location''' |type="{}"} Where was Aristotle born? { Stageira } {'''Mentor''' |type="{}"} Name Aristotle's famous mentor. { Plato } {'''Pupil''' |type="{}"} { Alexander } was Aristotle's most famous pupil. </quiz> cv46mmeo4jd15yy6ebi5qplyrajaand 2408154 2408153 2022-07-20T10:20:03Z Bert Niehaus 2387134 /* First Quizelement */ wikitext text/x-wiki == First Quizelement == The following quiz tag contains two questions. <quiz> {Sample Question 1 |type="()"} + The correct answer. - Distractor. - Distractor. - Distractor. {Sample Question 2 [[File:BBH_gravitational_lensing_of_gw150914.webm|400px]] |type="()"} - optical property of the vacuum. + gravitational lens. - impact of convex lens over a snapshot of the sky. - impact of concav lens over a snapshot of the sky. </quiz> == Second Quiz Element == Answers that require a text input. As learning resource see [[Wikipedia:Aristotle]] [[File:Aristotle Altemps Inv8575.jpg|thumb|Aristotle]] <quiz> {'''Location''' |type="{}"} Where was Aristotle born? { Stageira } {'''Mentor''' |type="{}"} Name Aristotle's famous mentor. { Plato } {'''Pupil''' |type="{}"} { Alexander } was Aristotle's most famous pupil. </quiz> g4cx84t03atkwuanbpgcaf07oezucup