Editing Testosterone (section)

===Metabolism===
{{Testosterone metabolism mini|align=right|caption=The [[metabolic pathway]]s involved in the [[metabolism]] of testosterone in humans. In addition to the [[biotransformation|transformation]]s shown in the diagram, [[conjugation (biochemistry)|conjugation]] via [[sulfation]] and [[glucuronidation]] occurs with testosterone and [[metabolite]]s that have one or more available [[hydroxyl group|hydroxyl]] (–OH) [[functional group|group]]s.}}

Both testosterone and 5α-DHT are [[metabolism|metabolized]] mainly in the [[liver]].<ref name="MelmedPolonsky2015">{{cite book | vauthors = Melmed S, Polonsky KD, Larsen PR, Kronenberg HM | title = Williams Textbook of Endocrinology | url = https://books.google.com/books?id=YZ8_CwAAQBAJ&pg=PA711 | date = 30 November 2015 | publisher = Elsevier Health Sciences|isbn=978-0-323-29738-7 | pages = 711– }}</ref><ref name="Becker2001">{{cite book | vauthors = Becker KL | title = Principles and Practice of Endocrinology and Metabolism | url = https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1116 | year = 2001 | publisher = Lippincott Williams & Wilkins | isbn = 978-0-7817-1750-2 | pages = 1116, 1119, 1183 | access-date = November 3, 2016 | archive-date = January 11, 2023 | archive-url = https://web.archive.org/web/20230111143043/https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1116 | url-status = live }}</ref> Approximately 50% of testosterone is metabolized via [[conjugation (biochemistry)|conjugation]] into [[testosterone glucuronide]] and to a lesser extent [[testosterone sulfate]] by [[glucuronosyltransferase]]s and [[sulfotransferase]]s, respectively.<ref name="MelmedPolonsky2015" /> An additional 40% of testosterone is metabolized in equal proportions into the [[17-ketosteroid]]s [[androsterone]] and [[etiocholanolone]] via the combined actions of [[5α-reductase|5α-]] and [[5β-reductase]]s, [[3α-hydroxysteroid dehydrogenase]], and 17β-HSD, in that order.<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /><ref name="WeckerWatts2009">{{cite book | vauthors = Wecker L, Watts S, Faingold C, Dunaway G, Crespo L | title = Brody's Human Pharmacology | url = https://books.google.com/books?id=kfsrz_-OrMQC&pg=PA468 | date = 1 April 2009 | publisher = Elsevier Health Sciences | isbn = 978-0-323-07575-6 | pages = 468–469 | access-date = November 3, 2016 | archive-date = January 11, 2023 | archive-url = https://web.archive.org/web/20230111143031/https://books.google.com/books?id=kfsrz_-OrMQC&pg=PA468 | url-status = live }}</ref> Androsterone and etiocholanolone are then [[glucuronidation|glucuronidated]] and to a lesser extent [[sulfation|sulfated]] similarly to testosterone.<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /> The conjugates of testosterone and its hepatic metabolites are released from the liver into [[circulatory system|circulation]] and [[excretion|excreted]] in the [[urine]] and [[bile]].<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /><ref name="WeckerWatts2009" /> Only a small fraction (2%) of testosterone is excreted unchanged in the urine.<ref name="Becker2001" />

In the hepatic 17-ketosteroid pathway of testosterone metabolism, testosterone is converted in the liver by 5α-reductase and 5β-reductase into 5α-DHT and the inactive [[5β-Dihydrotestosterone|5β-DHT]], respectively.<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /> Then, 5α-DHT and 5β-DHT are converted by 3α-HSD into [[3α-androstanediol]] and [[3α-etiocholanediol]], respectively.<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /> Subsequently, 3α-androstanediol and 3α-etiocholanediol are converted by 17β-HSD into androsterone and etiocholanolone, which is followed by their conjugation and excretion.<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /> [[3β-Androstanediol]] and [[3β-etiocholanediol]] can also be formed in this pathway when 5α-DHT and 5β-DHT are acted upon by 3β-HSD instead of 3α-HSD, respectively, and they can then be transformed into [[epiandrosterone]] and [[epietiocholanolone]], respectively.<ref name="pmid20186052">{{cite journal | vauthors = Penning TM | title = New frontiers in androgen biosynthesis and metabolism | journal = Curr Opin Endocrinol Diabetes Obes | volume = 17 | issue = 3 | pages = 233–9 | year = 2010 | pmid = 20186052 | pmc = 3206266 | doi = 10.1097/MED.0b013e3283381a31 }}</ref><ref name="HorskyPresl2012">{{cite book | vauthors = Horsky J, Presl J | title = Ovarian Function and its Disorders: Diagnosis and Therapy | url = https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA107 | date = 6 December 2012 | publisher = Springer Science & Business Media | isbn = 978-94-009-8195-9 | pages = 107– | access-date = November 5, 2016 | archive-date = January 11, 2023 | archive-url = https://web.archive.org/web/20230111143033/https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA107 | url-status = live }}</ref> A small portion of approximately 3% of testosterone is [[reversible reaction|reversibly]] converted in the liver into [[androstenedione]] by 17β-HSD.<ref name="WeckerWatts2009" />

In addition to conjugation and the 17-ketosteroid pathway, testosterone can also be [[hydroxylation|hydroxylated]] and [[oxidation|oxidized]] in the liver by [[cytochrome P450]] [[enzyme]]s, including [[CYP3A4]], [[CYP3A5]], [[CYP2C9]], [[CYP2C19]], and [[CYP2D6]].<ref name="Zhou2016">{{cite book | vauthors = Zhou S | title=Cytochrome P450 2D6: Structure, Function, Regulation and Polymorphism | url = https://books.google.com/books?id=UJqmCwAAQBAJ&pg=PA242|date=6 April 2016 | publisher = CRC Press | isbn = 978-1-4665-9788-4 | pages = 242– }}</ref> 6β-Hydroxylation and to a lesser extent 16β-hydroxylation are the major transformations.<ref name="Zhou2016" /> The 6β-hydroxylation of testosterone is catalyzed mainly by CYP3A4 and to a lesser extent CYP3A5 and is responsible for 75 to 80% of cytochrome P450-mediated testosterone metabolism.<ref name="Zhou2016" /> In addition to 6β- and 16β-hydroxytestosterone, 1β-, 2α/β-, 11β-, and 15β-hydroxytestosterone are also formed as minor metabolites.<ref name="Zhou2016" /><ref name="isbn0-3870-8012-0">{{cite book | vauthors = Trager L | title = Steroidhormone: Biosynthese, Stoffwechsel, Wirkung | language = de | publisher = Springer-Verlag  | year = 1977 | page = 349  | isbn = 978-0-387-08012-3  }}</ref> Certain cytochrome P450 enzymes such as CYP2C9 and CYP2C19 can also oxidize testosterone at the C17 position to form androstenedione.<ref name="Zhou2016" />

Two of the immediate metabolites of testosterone, 5α-DHT and [[estradiol]], are biologically important and can be formed both in the liver and in extrahepatic tissues.<ref name="Becker2001" /> Approximately 5 to 7% of testosterone is converted by 5α-reductase into 5α-DHT, with circulating levels of 5α-DHT about 10% of those of testosterone, and approximately 0.3% of testosterone is converted into estradiol by [[aromatase]].<ref name="pmid3549275"/><ref name="Becker2001" /><ref name="pmid8092979">{{cite journal | vauthors = Randall VA | title = Role of 5 alpha-reductase in health and disease | journal = Baillière's Clinical Endocrinology and Metabolism | volume = 8 | issue = 2 | pages = 405–31 | date = Apr 1994 | pmid = 8092979 | doi = 10.1016/S0950-351X(05)80259-9 }}</ref><ref name="pmid12428207">{{cite journal | vauthors = Meinhardt U, Mullis PE | title = The essential role of the aromatase/p450arom | journal = Seminars in Reproductive Medicine | volume = 20 | issue = 3 | pages = 277–84 | date = August 2002 | pmid = 12428207 | doi = 10.1055/s-2002-35374 | s2cid = 25407830 }}</ref> 5α-Reductase is highly expressed in the [[male reproductive system|male reproductive organ]]s (including the [[prostate gland]], [[seminal vesicle]]s, and [[epididymides]]),<ref name="Noakes2009">{{cite book | vauthors = Noakes DE | title=Arthur's Veterinary Reproduction and Obstetrics | url = https://books.google.com/books?id=W5TdAwAAQBAJ&pg=PA695 | date = 23 April 2009 | publisher = Elsevier Health Sciences UK | isbn = 978-0-7020-3990-4 | pages = 695– }}</ref> [[skin]], [[hair follicle]]s, and [[brain]]<ref name="NieschlagBehre2004">{{cite book | vauthors  = Nieschlag E, Behre HM | title = Testosterone: Action, Deficiency, Substitution | url = https://books.google.com/books?id=ZiZ7MWDqo5oC&pg=PA626 | date = 1 April 2004 | publisher = Cambridge University Press | isbn = 978-1-139-45221-2 | pages = 626– }}</ref> and aromatase is highly expressed in adipose tissue, [[bone]], and the brain.<ref name="Parl2000">{{cite book | vauthors = Parl FF | title = Estrogens, Estrogen Receptor and Breast Cancer | url = https://books.google.com/books?id=v7ai5Mz9TZQC&pg=PA25 | year = 2000 | publisher = IOS Press | isbn = 978-0-9673355-4-4 | pages = 25– }}</ref><ref name="NormanHenry2014">{{cite book | vauthors = Norman AW, Henry HL | title = Hormones|url=https://books.google.com/books?id=_renonjXq68C&pg=PA261 | date=30 July 2014 | publisher = Academic Press | isbn = 978-0-08-091906-5 | pages = 261– }}</ref> As much as 90% of testosterone is converted into 5α-DHT in so-called androgenic tissues with high 5α-reductase expression,<ref name="WeckerWatts2009" /> and due to the several-fold greater potency of 5α-DHT as an AR agonist relative to testosterone,<ref name="MozayaniRaymon2011">{{cite book | vauthors = Mozayani A, Raymon L | title = Handbook of Drug Interactions: A Clinical and Forensic Guide | url = https://books.google.com/books?id=NhBJ6kg_uP0C&pg=PA656 | date = 18 September 2011 | publisher = Springer Science & Business Media | isbn = 978-1-61779-222-9 | pages = 656– }}</ref> it has been estimated that the effects of testosterone are potentiated 2- to 3-fold in such tissues.<ref name="pmid7626464">{{cite journal | vauthors = Sundaram K, Kumar N, Monder C, Bardin CW | s2cid = 32619627 | title = Different patterns of metabolism determine the relative anabolic activity of 19-norandrogens | journal = J. Steroid Biochem. Mol. Biol. | volume = 53 | issue = 1–6 | pages = 253–7 | year = 1995 | pmid = 7626464 | doi = 10.1016/0960-0760(95)00056-6}}</ref>