Editing Progesterone (section)

===Metabolism===
The [[metabolism]] of progesterone is rapid and extensive and occurs mainly in the [[liver]],<ref name="FalconeHurd2007">{{cite book|vauthors=Falcone T, Hurd WW|title=Clinical Reproductive Medicine and Surgery|url=https://books.google.com/books?id=fOPtaEIKvcIC&pg=PA22|year=2007|publisher=Elsevier Health Sciences|isbn=978-0-323-03309-1|pages=22–|access-date=6 November 2016|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110014156/https://books.google.com/books?id=fOPtaEIKvcIC&pg=PA22|url-status=live}}</ref><ref name="Cupps1991">{{cite book | vauthors = Cupps PT |title=Reproduction in Domestic Animals|url=https://books.google.com/books?id=bbb-ow0N7K4C&pg=PA101|date=20 February 1991|publisher=Elsevier|isbn=978-0-08-057109-6|pages=101–}}</ref><ref name="pmid14667980" /> though [[enzyme]]s that metabolize progesterone are also expressed widely in the [[brain]], [[skin]], and various other [[wikt:extrahepatic|extrahepatic]] [[tissue (biology)|tissue]]s.<ref name="pmid558037" /><ref name="DowdJohnson2016">{{cite book | vauthors = Dowd FJ, Johnson B, Mariotti A | title = Pharmacology and Therapeutics for Dentistry|url=https://books.google.com/books?id=6xT7DAAAQBAJ&pg=PA448|date=3 September 2016|publisher=Elsevier Health Sciences|isbn=978-0-323-44595-5|pages=448–}}</ref> Progesterone has an [[elimination half-life]] of only approximately 5&nbsp;minutes in [[circulatory system|circulation]].<ref name="FalconeHurd2007" /> The metabolism of progesterone is complex, and it may form as many as 35 different [[conjugation (biochemistry)|unconjugated]] [[metabolite]]s when it is ingested orally.<ref name="pmid14667980" /><ref name="pmid16112947" /> Progesterone is highly susceptible to enzymatic [[redox|reduction]] via [[reductase]]s and [[hydroxysteroid dehydrogenase]]s due to its [[double bond]] (between the C4 and C5 positions) and its two [[ketone]]s (at the C3 and C20 positions).<ref name="pmid14667980" />

The major [[metabolic pathway]] of progesterone is reduction by [[5α-reductase]]<ref name="pmid558037" /> and [[5β-reductase]] into the dihydrogenated [[5α-dihydroprogesterone]] and [[5β-dihydroprogesterone]], respectively.<ref name="Cupps1991" /><ref name="pmid14667980">{{cite journal | vauthors = Stanczyk FZ | title = All progestins are not created equal | journal = Steroids | volume = 68 | issue = 10–13 | pages = 879–890 | date = November 2003 | pmid = 14667980 | doi = 10.1016/j.steroids.2003.08.003 | s2cid = 44601264 }}</ref><ref name="PlantZeleznik2014">{{cite book| vauthors = Plant TM, Zeleznik AJ |title=Knobil and Neill's Physiology of Reproduction|url=https://books.google.com/books?id=I1ACBAAAQBAJ&pg=PA304|date=15 November 2014|publisher=Academic Press|isbn=978-0-12-397769-4|pages=304–}}</ref><ref name="SantoroNeal-Perry2010">{{cite book|vauthors=Santoro NF, Neal-Perry G|title=Amenorrhea: A Case-Based, Clinical Guide|url=https://books.google.com/books?id=4836MLkPoIYC&pg=PA13|date=11 September 2010|publisher=Springer Science & Business Media|isbn=978-1-60327-864-5|pages=13–|access-date=6 November 2016|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114025033/https://books.google.com/books?id=4836MLkPoIYC&pg=PA13|url-status=live}}</ref> This is followed by the further reduction of these metabolites via [[3α-hydroxysteroid dehydrogenase]] and [[3β-hydroxysteroid dehydrogenase]] into the tetrahydrogenated [[allopregnanolone]], [[pregnanolone]], [[isopregnanolone]], and [[epipregnanolone]].<ref name="pmid21094889">{{cite book | vauthors = Reddy DS | title = Sex Differences in the Human Brain, their Underpinnings and Implications | chapter = Neurosteroids | series = Progress in Brain Research | volume = 186 | pages = 113–37 | year = 2010 | publisher = Elsevier | pmid = 21094889 | pmc = 3139029 | doi = 10.1016/B978-0-444-53630-3.00008-7 | isbn = 9780444536303 }}</ref><ref name="Cupps1991" /><ref name="pmid14667980" /><ref name="PlantZeleznik2014" /> Subsequently, [[20α-hydroxysteroid dehydrogenase]] and [[20β-hydroxysteroid dehydrogenase]] reduce these metabolites to form the corresponding hexahydrogenated [[pregnanediol]]s (eight different [[isomer]]s in total),<ref name="Cupps1991" /><ref name="SantoroNeal-Perry2010" /> which are then conjugated via [[glucuronidation]] and/or [[sulfation]], released from the liver into circulation, and [[excretion|excreted]] by the [[kidney]]s into the [[urine]].<ref name="FalconeHurd2007" /><ref name="pmid14667980" /> The major metabolite of progesterone in the urine is the 3α,5β,20α isomer of [[pregnanediol glucuronide]], which has been found to constitute 15 to 30% of an injection of progesterone.<ref name="Josimovich2013" /><ref name="BaulieuKelly1990">{{cite book| vauthors = Baulieu E, Kelly PA |title=Hormones: From Molecules to Disease|url=https://books.google.com/books?id=Seddp4-dulIC&pg=PA401|date=30 November 1990|publisher=Springer Science & Business Media|isbn=978-0-412-02791-8|pages=401–}}</ref> Other metabolites of progesterone formed by the enzymes in this pathway include [[3α-dihydroprogesterone]], [[3β-dihydroprogesterone]], [[20α-dihydroprogesterone]], and [[20β-dihydroprogesterone]], as well as various combination products of the enzymes aside from those already mentioned.<ref name="Josimovich2013" /><ref name="pmid14667980" /><ref name="BaulieuKelly1990" /><ref name="pmid21182831">{{cite journal | vauthors = Beranič N, Gobec S, Rižner TL | title = Progestins as inhibitors of the human 20-ketosteroid reductases, AKR1C1 and AKR1C3 | journal = Chemico-Biological Interactions | volume = 191 | issue = 1–3 | pages = 227–233 | date = May 2011 | pmid = 21182831 | doi = 10.1016/j.cbi.2010.12.012 | bibcode = 2011CBI...191..227B }}</ref> Progesterone can also first be [[hydroxylation|hydroxylated]] (see below) and then reduced.<ref name="pmid14667980" /> Endogenous progesterone is metabolized approximately 50% into 5α-dihydroprogesterone in the [[corpus luteum]], 35% into 3β-dihydroprogesterone in the liver, and 10% into 20α-dihydroprogesterone.<ref name="pmid15492972">{{cite journal | vauthors = Anderson GD, Odegard PS | title = Pharmacokinetics of estrogen and progesterone in chronic kidney disease | journal = Advances in Chronic Kidney Disease | volume = 11 | issue = 4 | pages = 357–360 | date = October 2004 | pmid = 15492972 | doi = 10.1053/j.ackd.2004.07.001 }}</ref>

Relatively small portions of progesterone are [[hydroxylation|hydroxylated]] via [[17α-hydroxylase]] (CYP17A1) and [[21-hydroxylase]] (CYP21A2) into [[17α-hydroxyprogesterone]] and [[11-deoxycorticosterone]] (21-hydroxyprogesterone), respectively,<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }}</ref> and [[pregnanetriol]]s are formed secondarily to 17α-hydroxylation.<ref name="GreenblattBrogan2016">{{cite book| vauthors = Greenblatt JM, Brogan K |title=Integrative Therapies for Depression: Redefining Models for Assessment, Treatment and Prevention|url=https://books.google.com/books?id=GpHwCgAAQBAJ&pg=PA201|date=27 April 2016|publisher=CRC Press|isbn=978-1-4987-0230-0|pages=201–}}</ref><ref name="Graham2012">{{cite book|vauthors=Graham C|title=Reproductive Biology of the Great Apes: Comparative and Biomedical Perspectives|url=https://books.google.com/books?id=iUA0CdGhYksC&pg=PA179|date=2 December 2012|publisher=Elsevier|isbn=978-0-323-14971-6|pages=179–|access-date=6 November 2016|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114024936/https://books.google.com/books?id=iUA0CdGhYksC&pg=PA179|url-status=live}}</ref> Even smaller amounts of progesterone may be also hydroxylated via [[11β-hydroxylase]] (CYP11B1) and to a lesser extent via [[aldosterone synthase]] (CYP11B2) into [[11β-hydroxyprogesterone]].<ref name="pmid23322723">{{cite journal | vauthors = Strushkevich N, Gilep AA, Shen L, Arrowsmith CH, Edwards AM, Usanov SA, Park HW | title = Structural insights into aldosterone synthase substrate specificity and targeted inhibition | journal = Molecular Endocrinology | volume = 27 | issue = 2 | pages = 315–324 | date = February 2013 | pmid = 23322723 | pmc = 5417327 | doi = 10.1210/me.2012-1287 }}</ref><ref name="pmid29277707">{{cite journal | vauthors = van Rooyen D, Gent R, Barnard L, Swart AC | 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 | date = April 2018 | pmid = 29277707 | doi = 10.1016/j.jsbmb.2017.12.014 | s2cid = 3700135 }}</ref><ref name=wj/> In addition, progesterone can be hydroxylated in the liver by other [[cytochrome P450]] enzymes which are not steroid-specific.<ref name="Piccinato2008">{{cite book| vauthors = de Azevedo Piccinato C |title=Regulation of Steroid Metabolism and the Hepatic Transcriptome by Estradiol and Progesterone|url=https://books.google.com/books?id=2nlbQ12QrSsC&pg=PA24|year=2008|isbn=978-1-109-04632-8|pages=24–25}}{{Dead link|date=February 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> 6β-Hydroxylation, which is catalyzed mainly by [[CYP3A4]], is the major transformation, and is responsible for approximately 70% of cytochrome P450-mediated progesterone metabolism.<ref name="Piccinato2008" /> Other routes include 6α-, 16α-, and 16β-hydroxylation.<ref name="pmid14667980" /> However, treatment of women with [[ketoconazole]], a strong CYP3A4 inhibitor, had minimal effects on progesterone levels, producing only a slight and non-significant increase, and this suggests that cytochrome P450 enzymes play only a small role in progesterone metabolism.<ref name="pmid1825737">{{cite journal | vauthors = Akalin S | title = Effects of ketoconazole in hirsute women | journal = Acta Endocrinologica | volume = 124 | issue = 1 | pages = 19–22 | date = January 1991 | pmid = 1825737 | doi = 10.1530/acta.0.1240019 | s2cid = 9831739 }}</ref>
{{Progesterone metabolism||align=center|caption=This diagram illustrates the [[metabolic pathway]]s involved in the [[metabolism]] of progesterone in humans. In addition to the [[biotransformation|transformation]]s shown in the diagram, [[conjugation (biochemistry)|conjugation]], specifically [[glucuronidation]] and [[sulfation]], occurs with [[metabolite]]s of progesterone that have one or more available [[hydroxyl group|hydroxyl]] (–OH) [[functional group|group]]s.}}