Editing Progesterone (section)

==Biological activity==

{{See also|Pharmacodynamics of progesterone#Mechanism of action}}

Progesterone is the most important progestogen in the body. As a potent [[agonist]] of the [[progesterone receptor|nuclear progesterone receptor]] (nPR) (with an [[affinity (pharmacology)|affinity]] of K<sub>D</sub> = 1 nM) the resulting effects on ribosomal transcription plays a major role in regulation of female reproduction.<ref name="KingBrucker2010" /><ref name="Josimovich2013" /> In addition, progesterone is an agonist of the more recently discovered [[membrane progesterone receptor]]s (mPRs),<ref name="pmid22687885">{{cite journal | vauthors = Thomas P, Pang Y | title = Membrane progesterone receptors: evidence for neuroprotective, neurosteroid signaling and neuroendocrine functions in neuronal cells | journal = Neuroendocrinology | volume = 96 | issue = 2 | pages = 162–171 | year = 2012 | pmid = 22687885 | pmc = 3489003 | doi = 10.1159/000339822 }}</ref> of which the expression has regulation effects in reproduction function ([[oocyte maturation]], labor, and [[sperm motility]]) and cancer although additional research is required to further define the roles.<ref name="pmid27368976">{{cite journal | vauthors = Valadez-Cosmes P, Vázquez-Martínez ER, Cerbón M, Camacho-Arroyo I | title = Membrane progesterone receptors in reproduction and cancer | journal = Molecular and Cellular Endocrinology | volume = 434 | pages = 166–175 | date = October 2016 | pmid = 27368976 | doi = 10.1016/j.mce.2016.06.027 | s2cid = 3826650 }}</ref> It also functions as a ligand of the [[PGRMC1]] (progesterone receptor membrane component 1) which impacts [[tumor progression]], metabolic regulation, and viability control of [[nerve cells]].<ref name="pmid9516722">{{cite journal | vauthors = Meyer C, Schmid R, Schmieding K, Falkenstein E, Wehling M | title = Characterization of high affinity progesterone-binding membrane proteins by anti-peptide antiserum | journal = Steroids | volume = 63 | issue = 2 | pages = 111–116 | date = February 1998 | pmid = 9516722 | doi = 10.1016/s0039-128x(97)00143-8 | s2cid = 40096058 }}</ref><ref name="pmid30087538">{{cite journal | vauthors = Kabe Y, Handa H, Suematsu M | title = Function and structural regulation of the carbon monoxide (CO)-responsive membrane protein PGRMC1 | journal = Journal of Clinical Biochemistry and Nutrition | volume = 63 | issue = 1 | pages = 12–17 | date = July 2018 | pmid = 30087538 | pmc = 6064819 | doi = 10.3164/jcbn.17-132 }}</ref><ref name="pmid28396637">{{cite journal | vauthors = Ryu CS, Klein K, Zanger UM | title = Membrane Associated Progesterone Receptors: Promiscuous Proteins with Pleiotropic Functions - Focus on Interactions with Cytochromes P450 | journal = Frontiers in Pharmacology | volume = 8 | pages = 159 | date = 27 March 2017 | pmid = 28396637 | pmc = 5366339 | doi = 10.3389/fphar.2017.00159 | doi-access = free }}</ref> Moreover, progesterone is also known to be an antagonist of the [[sigma receptor|sigma]] [[sigma-1 receptor|σ<sub>1</sub> receptor]],<ref name="pmid11744080">{{cite journal | vauthors = Maurice T, Urani A, Phan VL, Romieu P | title = The interaction between neuroactive steroids and the sigma1 receptor function: behavioral consequences and therapeutic opportunities | journal = Brain Research. Brain Research Reviews | volume = 37 | issue = 1–3 | pages = 116–132 | date = November 2001 | pmid = 11744080 | doi = 10.1016/s0165-0173(01)00112-6 | s2cid = 44931783 }}</ref><ref name="pmid21084640">{{cite journal | vauthors = Johannessen M, Fontanilla D, Mavlyutov T, Ruoho AE, Jackson MB | title = Antagonist action of progesterone at σ-receptors in the modulation of voltage-gated sodium channels | journal = American Journal of Physiology. Cell Physiology | volume = 300 | issue = 2 | pages = C328–C337 | date = February 2011 | pmid = 21084640 | pmc = 3043630 | doi = 10.1152/ajpcell.00383.2010 }}</ref> a [[negative allosteric modulator]] of [[nicotinic acetylcholine receptor]]s,<ref name="pmid11108866" /> and a potent antagonist of the [[mineralocorticoid receptor]] (MR).<ref name="pmid8282004">{{cite journal | vauthors = Rupprecht R, Reul JM, van Steensel B, Spengler D, Söder M, Berning B, Holsboer F, Damm K | display-authors = 6 | title = Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands | journal = European Journal of Pharmacology | volume = 247 | issue = 2 | pages = 145–154 | date = October 1993 | pmid = 8282004 | doi = 10.1016/0922-4106(93)90072-H }}</ref> Progesterone prevents MR activation by binding to this receptor with an affinity exceeding even those of [[aldosterone]] and [[glucocorticoid]]s such as [[cortisol]] and [[corticosterone]],<ref name="pmid8282004" /> and produces [[antimineralocorticoid]] effects, such as [[natriuresis]], at physiological concentrations.<ref name="pmid14667981">{{cite journal | vauthors = Elger W, Beier S, Pollow K, Garfield R, Shi SQ, Hillisch A | title = Conception and pharmacodynamic profile of drospirenone | journal = Steroids | volume = 68 | issue = 10–13 | pages = 891–905 | date = November 2003 | pmid = 14667981 | doi = 10.1016/j.steroids.2003.08.008 | s2cid = 41756726 }}</ref> In addition, progesterone binds to and behaves as a [[partial agonist]] of the [[glucocorticoid receptor]] (GR), albeit with very low potency ([[EC50|EC<sub>50</sub>]] >100-fold less relative to [[cortisol]]).<ref name="pmid18060946">{{cite journal | vauthors = Attardi BJ, Zeleznik A, Simhan H, Chiao JP, Mattison DR, Caritis SN | title = Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17-alpha hydroxyprogesterone caproate, and related progestins | journal = American Journal of Obstetrics and Gynecology | volume = 197 | issue = 6 | pages = 599.e1–599.e7 | date = December 2007 | pmid = 18060946 | pmc = 2278032 | doi = 10.1016/j.ajog.2007.05.024 }}</ref><ref name="pmid23209664">{{cite journal | vauthors = Lei K, Chen L, Georgiou EX, Sooranna SR, Khanjani S, Brosens JJ, Bennett PR, Johnson MR | display-authors = 6 | title = Progesterone acts via the nuclear glucocorticoid receptor to suppress IL-1β-induced COX-2 expression in human term myometrial cells | journal = PLOS ONE | volume = 7 | issue = 11 | pages = e50167 | year = 2012 | pmid = 23209664 | pmc = 3509141 | doi = 10.1371/journal.pone.0050167 | doi-access = free | bibcode = 2012PLoSO...750167L }}</ref>

Progesterone, through its [[neurosteroid]] [[active metabolite]]s such as [[5α-dihydroprogesterone]] and [[allopregnanolone]], acts indirectly as a [[positive allosteric modulator]] of the [[GABAA receptor|GABA<sub>A</sub> receptor]].<ref name="pmid1347506">{{cite journal | vauthors = Paul SM, Purdy RH | title = Neuroactive steroids | journal = FASEB Journal | volume = 6 | issue = 6 | pages = 2311–2322 | date = March 1992 | pmid = 1347506 | doi = 10.1096/fasebj.6.6.1347506 | s2cid = 221753076 | doi-access = free }}</ref>

Progesterone and some of its metabolites, such as [[5β-dihydroprogesterone]], are agonists of the [[pregnane X receptor]] (PXR),<ref name="pmid12372848">{{cite journal | vauthors = Kliewer SA, Goodwin B, Willson TM | title = The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism | journal = Endocrine Reviews | volume = 23 | issue = 5 | pages = 687–702 | date = October 2002 | pmid = 12372848 | doi = 10.1210/er.2001-0038 | doi-access = free }}</ref> albeit weakly so ([[EC50|EC<sub>50</sub>]] >10 μM).<ref name="pmid9727070">{{cite journal | vauthors = Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA | title = The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions | journal = The Journal of Clinical Investigation | volume = 102 | issue = 5 | pages = 1016–1023 | date = September 1998 | pmid = 9727070 | pmc = 508967 | doi = 10.1172/JCI3703 }}</ref> In accordance, progesterone [[enzyme inducer|induce]]s several [[hepatic]] [[cytochrome P450]] [[enzyme]]s,<ref name="Meanwell2014">{{cite book|vauthors=Meanwell NA|title=Tactics in Contemporary Drug Design|url=https://books.google.com/books?id=j2HEBQAAQBAJ&pg=PA161|date=8 December 2014|publisher=Springer|isbn=978-3-642-55041-6|pages=161–|access-date=1 February 2016|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114024941/https://books.google.com/books?id=j2HEBQAAQBAJ&pg=PA161|url-status=live}}</ref> such as [[CYP3A4]],<ref name="LegatoBilezikian2004">{{cite book|vauthors=Legato MJ, Bilezikian JP|title=Principles of Gender-specific Medicine|url=https://books.google.com/books?id=TiLxa8nPbLkC&pg=PA146|year=2004|publisher=Gulf Professional Publishing|isbn=978-0-12-440906-4|pages=146–|access-date=1 February 2016|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114024928/https://books.google.com/books?id=TiLxa8nPbLkC&pg=PA146|url-status=live}}</ref><ref name="LemkeWilliams2012 p164">{{cite book | vauthors = Williams DA | chapter = Drug Metabolism | veditors = Lemke TL, Williams DA | title = Foye's Principles of Medicinal Chemistry | chapter-url = https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA164|date=24 January 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-345-0|page=164}}</ref> especially during [[pregnancy]] when concentrations are much higher than usual.<ref name="ScholarlyEditions2013">{{cite book|title=Estrogens—Advances in Research and Application: 2013 Edition: ScholarlyBrief|url=https://books.google.com/books?id=9WdGK_3ujQMC&pg=PA4|date=21 June 2013|publisher=ScholarlyEditions|isbn=978-1-4816-7550-5|pages=4–|access-date=1 February 2016|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114024941/https://books.google.com/books?id=9WdGK_3ujQMC&pg=PA4|url-status=live}}</ref> Perimenopausal women have been found to have greater CYP3A4 activity relative to men and postmenopausal women, and it has been inferred that this may be due to the higher progesterone levels present in perimenopausal women.<ref name="LegatoBilezikian2004" />

Progesterone modulates the activity of [[cation channels of sperm|CatSper]] (cation channels of sperm) [[voltage-gated ion channel|voltage-gated]] Ca<sup>2+</sup> channels. Since eggs release progesterone, sperm may use progesterone as a homing signal to swim toward eggs ([[chemotaxis]]). As a result, it has been suggested that substances that block the progesterone binding site on CatSper channels could potentially be used in [[male contraception]].<ref name="pmid21412338">{{cite journal | vauthors = Strünker T, Goodwin N, Brenker C, Kashikar ND, Weyand I, Seifert R, Kaupp UB | title = The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm | journal = Nature | volume = 471 | issue = 7338 | pages = 382–386 | date = March 2011 | pmid = 21412338 | doi = 10.1038/nature09769 | s2cid = 4431334 | bibcode = 2011Natur.471..382S }}</ref><ref name="pmid21412339">{{cite journal | vauthors = Lishko PV, Botchkina IL, Kirichok Y | title = Progesterone activates the principal Ca2+ channel of human sperm | journal = Nature | volume = 471 | issue = 7338 | pages = 387–391 | date = March 2011 | pmid = 21412339 | doi = 10.1038/nature09767 | s2cid = 4340309 | bibcode = 2011Natur.471..387L }}</ref>