View source for Pharmacodynamics of progesterone

The '''[[pharmacology]] of [[progesterone (medication)|progesterone]]''', a [[progestogen (medication)|progestogen]] medication and [[natural product|naturally occurring]] [[steroid hormone]], concerns its [[pharmacodynamics]], [[pharmacokinetics]], and various [[routes of administration]].<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | pages = 3–63 | year = 2005 | issue = Suppl 1 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}</ref><ref name="UnferdiRenzo2006">{{cite journal|last1=Unfer|first1=Vittorio|last2=di Renzo|first2=Gian|last3=Gerli|first3=Sandro|last4=Casini|first4=Maria|title=The Use of Progesterone in Clinical Practice: Evaluation of its Efficacy in Diverse Indications Using Different Routes of Administration|journal=Current Drug Therapy|volume=1|issue=2|year=2006|pages=211–219|issn=1574-8855|doi=10.2174/157488506776930923}}</ref>

Progesterone is a [[natural product|naturally occurring]] and [[bioidentical hormone therapy|bioidentical]] progestogen, or an [[agonist]] of the [[progesterone receptor]], the [[biological target]] of [[progestogen]]s like [[endogenous]] [[progesterone]].<ref name="pmid16112947" /> Progesterone also has [[antimineralocorticoid]] and [[inhibitory postsynaptic potential|inhibitory]] [[neurosteroid]] activity, whereas it appears to have little or no [[glucocorticoid]] or [[antiandrogen]]ic activity and has no [[androgen]]ic activity.<ref name="pmid16112947" /> Because of its progestogenic activity, progesterone has functional [[antiestrogen]]ic effects in certain [[tissue (biology)|tissue]]s such as the [[uterus]], [[cervix]], and [[vagina]].<ref name="pmid16112947" /> In addition, progesterone has [[antigonadotropic]] effects due to its progestogenic activity and can inhibit [[fertility]] and suppress [[sex hormone]] [[biosynthesis|production]].<ref name="pmid16112947" /> Progesterone differs from [[progestin]]s ([[synthetic compound|synthetic]] [[progestogen (medication)|progestogen]]s) like [[medroxyprogesterone acetate]] and [[norethisterone]], with implications for [[pharmacodynamics]] and [[pharmacokinetics]] as well as [[efficacy]], [[tolerability]], and [[drug safety|safety]].<ref name="pmid16112947" />

Progesterone can be taken [[oral administration|by mouth]], [[intravaginal administration|in through the vagina]], and by [[injection (medicine)|injection]] into [[muscle]] or [[fat]], among other routes.<ref name="pmid16112947" /> A [[progesterone vaginal ring]] and progesterone [[intrauterine device]] are also available as pharmaceutical products.<ref name=Whit2014>{{cite book|last1=Whitaker|first1=Amy|last2=Gilliam|first2=Melissa|title=Contraception for Adolescent and Young Adult Women|date=2014|publisher=Springer|isbn=9781461465799|page=98|url=https://books.google.com/books?id=vMQkBAAAQBAJ&pg=PA98}}</ref><ref name="Chaudhuri2007">{{cite book|author=Chaudhuri|title=Practice Of Fertility Control: A Comprehensive Manual|url=https://books.google.com/books?id=pzanxKlcU74C&pg=PA153|year=2007|publisher=Elsevier India|isbn=978-81-312-1150-2|pages=153–|edition=7Th}}</ref>

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==Mechanism of action==
{{See also|Progesterone#Biological activity|Progestin#Pharmacology}}

Progesterone is a [[progestogen (medication)|progestogen]], or an [[agonist]] of the [[nuclear receptor|nuclear]] [[progesterone receptor]]s (PRs), the [[Progesterone receptor A|PR-A]], [[Progesterone receptor B|PR-B]], and [[Progesterone receptor C|PR-C]].<ref name="pmid16112947" /> In one study, progesterone showed {{abbrlink|EC<sub>50</sub>|half-maximal effective concentration}} values of 7.7&nbsp;nM for the human PR-A and 8.0&nbsp;nM for the human PR-B.<ref name="pmid15120421">{{cite journal | vauthors = Attardi BJ, Burgenson J, Hild SA, Reel JR | title = In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone | journal = J. Steroid Biochem. Mol. Biol. | volume = 88 | issue = 3 | pages = 277–88 | date = March 2004 | pmid = 15120421 | doi = 10.1016/j.jsbmb.2003.12.004 | s2cid = 23958876 }}</ref> In addition to the PRs, progesterone is an agonist of the [[membrane progesterone receptor]]s (mPRs), including the [[PAQR7|mPRα]], [[PAQR8|mPRβ]], [[PAQR5|mPRγ]], [[PAQR6|mPRδ]], and [[PAQR9|mPRϵ]].<ref name="pmid23756388">{{cite journal | author = Soltysik K, Czekaj P | title = Membrane estrogen receptors - is it an alternative way of estrogen action? | journal = J. Physiol. Pharmacol. | volume = 64 | issue = 2 | pages = 129–42 | date=April 2013 | pmid = 23756388 }}</ref><ref name="pmid24530924">{{cite journal |vauthors=Prossnitz ER, Barton M | title = Estrogen biology: New insights into GPER function and clinical opportunities | journal = Mol. Cell. Endocrinol. | volume = 389 | issue = 1–2 | pages = 71–83 |date=May 2014 | pmid = 24530924 | pmc = 4040308 | doi = 10.1016/j.mce.2014.02.002 }}</ref> It is also a potent [[antimineralocorticoid]] ([[receptor antagonist|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 | title = Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands | journal = European Journal of Pharmacology | volume = 247 | issue = 2 | pages = 145–54 | date = October 1993 | pmid = 8282004 | doi = 10.1016/0922-4106(93)90072-H }}</ref><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 | year = 2003 | pmid = 14667981 | doi = 10.1016/j.steroids.2003.08.008| s2cid = 41756726 }}</ref> as well as a very weak [[glucocorticoid]] (agonist of the [[glucocorticoid receptor]]).<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 = Am. J. Obstet. Gynecol. | volume = 197 | issue = 6 | pages = 599.e1–7 | year = 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 | 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 | doi = 10.1371/journal.pone.0050167 | bibcode = 2012PLoSO...750167L | pmc = 3509141 | doi-access = free }}</ref> Progesterone does not interact significantly with the [[androgen receptor]] (AR) or with the [[estrogen receptor]] (ER).<ref name="pmid16112947" /> In addition to its activity as a steroid hormone, progesterone is a [[neurosteroid]].<ref name="pmid11108866">{{cite journal | vauthors = Baulieu E, Schumacher M | title = Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination | journal = Steroids | volume = 65 | issue = 10–11 | pages = 605–12 | year = 2000 | pmid = 11108866 | doi = 10.1016/s0039-128x(00)00173-2 | s2cid = 14952168 }}</ref> Specifically, it is 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 = 116–32 | 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 = C328-37 | 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, via its [[active metabolite]]s [[allopregnanolone]] and [[pregnanolone]], a potent [[positive allosteric modulator]] of the [[GABAA receptor|GABA<sub>A</sub> receptor]], the major signaling receptor of the [[inhibitory postsynaptic potential|inhibitory]] [[neurotransmitter]] [[γ-aminobutyric acid]] (GABA).<ref name="pmid1347506">{{cite journal | vauthors = Paul SM, Purdy RH | title = Neuroactive steroids | journal = FASEB Journal | volume = 6 | issue = 6 | pages = 2311–22 | date = March 1992 | pmid = 1347506 | doi = 10.1096/fasebj.6.6.1347506| s2cid = 221753076 | doi-access = free }}</ref>

{| class="wikitable mw-collapsible mw-collapsed" style="width:550px; text-align:left; margin-left:auto; margin-right:auto; border:none;"
|+ class="nowrap" | Relative affinities (%) of progesterone
|-
! Compound || {{abbrlink|PR|Progesterone receptor}} || {{abbrlink|AR|Androgen receptor}} || {{abbrlink|ER|Estrogen receptor}} || {{abbrlink|GR|Glucocorticoid receptor}} || {{abbrlink|MR|Mineralocorticoid receptor}} || {{abbrlink|SHBG|Sex hormone-binding globulin}} || {{abbrlink|CBG|Corticosteroid binding globulin}}
|-
| Progesterone || 50 || 0 || 0 || 10 || 100 || 0 || 36
|- class="sortbottom"
| colspan="8" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' Values are percentages (%). Reference [[ligand (biochemistry)|ligand]]s (100%) were [[promegestone]] for the {{abbrlink|PR|progesterone receptor}}, [[metribolone]] for the {{abbrlink|AR|androgen receptor}}, {{abbrlink|E2|estradiol}} for the {{abbrlink|ER|estrogen receptor}}, {{abbrlink|DEXA|dexamethasone}} for the {{abbrlink|GR|glucocorticoid receptor}}, [[aldosterone]] for the {{abbrlink|MR|mineralocorticoid receptor}}, {{abbrlink|DHT|dihydrotestosterone}} for {{abbrlink|SHBG|sex hormone-binding globulin}}, and [[hydrocortisone|cortisol]] for {{abbrlink|CBG|Corticosteroid-binding globulin}}. '''Sources:''' <ref name="pmid16112947" />
|}

{{Parenteral potencies of progestogens}}

===Antimineralocorticoid activity===
Progesterone is a potent antimineralocorticoid.<ref name="pmid8282004"/><ref name="pmid14667981"/><ref name="pmid6986604" /> It has 1000% of the affinity of [[aldosterone]], the major [[endogenous]] agonist, for the human MR, and 100% of the affinity of aldosterone for the rat MR.<ref name="pmid11024226">{{cite journal | vauthors = Krattenmacher R | title = Drospirenone: pharmacology and pharmacokinetics of a unique progestogen | journal = Contraception | volume = 62 | issue = 1 | pages = 29–38 | date = July 2000 | pmid = 11024226 | doi = 10.1016/S0010-7824(00)00133-5 }}</ref><ref name="pmid16112947" /><ref name="pmid8282004" /> Progesterone produces antimineralocorticoid effects such as [[natriuresis]] ([[excretion]] of [[sodium]] in the [[urine]]) at normal physiological concentrations.<ref name="pmid14667981"/> A 200&nbsp;mg dose of oral progesterone is considered to be approximately equivalent in antimineralocorticoid effect to a 25 to 50&nbsp;mg dose of the potent antimineralocorticoid [[spironolactone]], which itself is a derivative of progesterone.<ref name="pmid8616985">{{cite journal | vauthors = Simon JA | title = Micronized progesterone: vaginal and oral uses | journal = Clinical Obstetrics and Gynecology | volume = 38 | issue = 4 | pages = 902–14 | date = December 1995 | pmid = 8616985 | doi = 10.1097/00003081-199538040-00024}}</ref> Doses of progesterone of 50 to 200&nbsp;mg by [[intramuscular injection]], which are similar to progesterone exposure in the [[third trimester]] of [[pregnancy]], have also been reported to produce antimineralocorticoid-like effects.<ref name="pmid6986604">{{cite journal | vauthors = Elkik F, Mauvais-Jarvis P | title = Rôle de la progestérone et des progestatifs sur le métabolisme hydroélectrolytique | trans-title = The role of progesterone and progestins in hydroelectrolytic metabolism | language = fr | journal = Nouv Presse Med | volume = 9 | issue = 1 | pages = 35–8 | date = January 1980 | pmid = 6986604 }}</ref> The antimineralocorticoid effects of progesterone underlie its ability to [[antihypertensive|lower blood pressure]] and reduce [[water retention (medicine)|water]] and [[salt retention]] and its potential application in the treatment of [[hypertension]].<ref name="pmid17924777">{{cite journal | vauthors = Goletiani NV, Keith DR, Gorsky SJ | title = Progesterone: review of safety for clinical studies | journal = Exp Clin Psychopharmacol | volume = 15 | issue = 5 | pages = 427–44 | year = 2007 | pmid = 17924777 | doi = 10.1037/1064-1297.15.5.427 | url = https://www.researchgate.net/publication/5919868}}</ref><ref name="pmid16112947" /><ref name="pmid11246598"/><ref name="pmid6986604" /> An [[active metabolite]] of progesterone, [[11-deoxycorticosterone]] (21-hydroxyprogesterone), is a [[precursor (biochemistry)|precursor]] of aldosterone and has strong [[mineralocorticoid]] activity (i.e., is a strong agonist of the MR).<ref name="pmid8616985" /> However, it is formed in relatively small amounts, and any such effects produced by it are usually outweighed by the antimineralocorticoid activity of progesterone.<ref name="pmid8616985" /> Progesterone may be a relatively weak antimineralocorticoid ''in vivo''.<ref name="pmid12530650">{{cite journal | vauthors = Quinkler M, Diederich S | title = Difference of in vivo and in vitro antimineralocorticoid potency of progesterone | journal = Endocr Res | volume = 28 | issue = 4 | pages = 465–70 | date = November 2002 | pmid = 12530650 | doi = 10.1081/erc-120016824 | s2cid = 168394 }}</ref>

===Glucocorticoid activity===
Progesterone is a [[partial agonist]] of the [[glucocorticoid receptor]] (GR).<ref name="pmid16112947" /><ref name="pmid18060946" /><ref name="pmid23209664" /><ref name="pmid17116740">{{cite journal | vauthors = Zerr-Fouineau M, Chataigneau M, Blot C, Schini-Kerth VB | title = Progestins overcome inhibition of platelet aggregation by endothelial cells by down-regulating endothelial NO synthase via glucocorticoid receptors | journal = FASEB J. | volume = 21 | issue = 1 | pages = 265–73 | date = January 2007 | pmid = 17116740 | doi = 10.1096/fj.06-6840com | doi-access = free | s2cid = 22679638 }}</ref><ref name="pmid8922878">{{cite journal | vauthors = Fuhrmann U, Krattenmacher R, Slater EP, Fritzemeier KH | title = The novel progestin drospirenone and its natural counterpart progesterone: biochemical profile and antiandrogenic potential | journal = Contraception | volume = 54 | issue = 4 | pages = 243–51 | date = October 1996 | pmid = 8922878 | doi = 10.1016/s0010-7824(96)00195-3| quote = Drospirenone and progesterone exhibited low binding affinities to the rat GR as is documented by 1% and 11% RBA values compared to the reference dexamethasone, respectively. Similar results were reported elsewhere.8 In accordance with the low affinity to the GR, progesterone and drospirenone showed weak or no detectable agonistic activities, respectively, in the GR-dependent transactivation assay (Figure 2A and Figure 2B). Furthermore, both progestins were devoid of antiglucocorticoid activity in vitro. These data are in agreement with in vivo studies carried out with rats where drospirenone and progesterone showed neither glucocorticoid nor antiglucocorticoid activity.8}}</ref> It has about 35% of the affinity of [[dexamethasone]], a [[corticosteroid]], for the human GR, and about 3 to 11% of the affinity of dexamethasone for the rat GR.<ref name="pmid11024226" /> However, progesterone appears to show weak or no glucocorticoid activity and no [[antiglucocorticoid]] activity ''[[in vitro]]'' and in animals.<ref name="pmid8922878" /> Nonetheless, progesterone has been found to upregulate the [[thrombin receptor]] in [[vascular smooth muscle cell]]s ''in vitro'', a glucocorticoid effect, and this could have clinical relevance in relation to risk of blood clots.<ref name="pmid16112947" /><ref name="pmid15358281">{{cite journal | vauthors = Wiegratz I, Kuhl H | title = Progestogen therapies: differences in clinical effects? | journal = Trends Endocrinol. Metab. | volume = 15 | issue = 6 | pages = 277–85 | date = August 2004 | pmid = 15358281 | doi = 10.1016/j.tem.2004.06.006 | s2cid = 35891204 }}</ref>

{{Glucocorticoid activity of selected steroids in vitro}}

===Androgenic and antiandrogenic activity===
The binding and activity of progesterone at the [[androgen receptor]] (AR), the [[biological target]] of [[androgen]]s like [[testosterone]] and [[dihydrotestosterone]] (DHT) in the body, is controversial.<ref name="pmid23484104">{{cite journal | vauthors = Yeh YT, Chang CW, Wei RJ, Wang SN | title = Progesterone and related compounds in hepatocellular carcinoma: basic and clinical aspects | journal = Biomed Res Int | volume = 2013 | pages = 290575 | date = 2013 | pmid = 23484104 | pmc = 3581253 | doi = 10.1155/2013/290575 | doi-access = free }}</ref> Some studies have found progesterone to bind to the AR, with agonistic and antagonistic activity exerted, whereas other studies have found very low or no affinity for the AR at all.<ref name="pmid23484104" /> In animal studies, no [[androgen]]ic effects have been observed, but weak [[antiandrogen]]ic effects have been reported.<ref name="pmid23484104" /> The weak antiandrogenic activity has been attributed not to antagonism of the AR by progesterone, but rather to its weak [[5α-reductase]] inhibition and consequent inhibition of the conversion of testosterone into the more potent DHT.<ref name="pmid23484104" /> There is no clinical evidence of AR-mediated androgenic or antiandrogenic activity with progesterone.<ref name="pmid23484104" /> Progesterone has not been associated with any classical androgenic effects in clinical studies in women, including no changes in the [[blood lipids|blood lipid]] [[lipid profile|profile]] or [[sex hormone-binding globulin]] levels, [[acne]], [[oily skin]], [[hirsutism]], or [[voice deepening]], nor with [[virilization]] of female fetuses.<ref name="pmid6596830">{{cite journal | vauthors = Ottosson UB | title = Oral progesterone and estrogen/progestogen therapy. Effects of natural and synthetic hormones on subfractions of HDL cholesterol and liver proteins | journal = Acta Obstet Gynecol Scand Suppl | volume = 127 | pages = 1–37 | year = 1984 | pmid = 6596830 | doi = 10.3109/00016348409157016| s2cid = 26138417 | quote = Natural progesterone is devoid of any androgenic activity that might compromise lipoprotein metabolism or induce teratogenicity.}}</ref><ref name="Zutshi2005">{{cite book|author=Zutshi|title=Hormones in Obstetrics and Gynaecology|url=https://books.google.com/books?id=IBxBbaDjXw0C&pg=PA75|year=2005|publisher=Jaypee Brothers, Medical Publishers|isbn=978-81-8061-427-9|pages=74–75|quote=It has been observed that micronized progesterone has no suppressive effects on high-density lipoprotein-cholesterol (HDL-C). Jensen et al have proved that oral micronized progesterone has no adverse effect on serum lipids. These preparations have the same antiestrogenic and antimineralocorticoid effect but no androgenic action. It does not affect aldosterone synthesis, blood pressure, carbohydrate metabolism or mood changes. No side effects have been reported as far as lipid profile, coagulation factors and blood pressure are concerned.}}{{Dead link|date=August 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="pmid11108871">{{cite journal | vauthors = Levy T, Yairi Y, Bar-Hava I, Shalev J, Orvieto R, Ben-Rafael Z | title = Pharmacokinetics of the progesterone-containing vaginal tablet and its use in assisted reproduction | journal = Steroids | volume = 65 | issue = 10–11 | pages = 645–9 | year = 2000 | pmid = 11108871 | doi = 10.1016/s0039-128x(00)00121-5| s2cid = 9627000 | url = http://www.hormonebalance.org/images/documents/Levy%2002%20Vag%20prog%20pharmaco%20Luteal%20support%20Ster.pdf | quote = Natural progesterone is devoid of any androgenic activity and is thus extensively used in assisted reproduction, sometimes for long periods of time.}}</ref><ref name="SamsioeDören2006">{{cite journal|last1=Samsioe|first1=Göran|last2=Dören|first2=Martina|last3=Lobo|first3=Rogerio A|title=Hormone replacement therapy – the agents|journal=Women's Health Medicine|volume=3|issue=5|year=2006|pages=213–216|issn=1744-1870|doi=10.1053/S1744-1870(06)70207-4|quote=Progestogens differ in their relative metabolic and androgenic effects; for example MPA is minimally androgenic, but does counteract the rise in HDL-cholesterol caused by oestrogen therapy. In contrast, oral micronized progesterone does not mitigate against increased HDL-cholesterol levels.}}</ref><ref name="pmid12057716" /> As such, the scientific consensus is that progesterone is clinically neither androgenic nor antiandrogenic.<ref name="pmid16112947" /><ref name="pmid11791081">{{cite journal | vauthors = Sitruk-Ware R | title = Progestogens in hormonal replacement therapy: new molecules, risks, and benefits | journal = Menopause | volume = 9 | issue = 1 | pages = 6–15 | year = 2002 | pmid = 11791081 | doi = 10.1097/00042192-200201000-00003| s2cid = 12136231 }}</ref><ref name="SuminoIchikawa2011">{{cite journal|last1=Sumino|first1=Hiroyuki|last2=Ichikawa|first2=Shuichi|last3=Kasama|first3=Shu|last4=Takahashi|first4=Takashi|last5=Kumakura|first5=Hisao|last6=Takayama|first6=Yoshiaki|last7=Minami|first7=Kazutomo|last8=Kanda|first8=Tsugiyasu|last9=Kurabayashi|first9=Masahiko|last10=Murakami|first10=Masami|title=Hormone Therapy and Blood Pressure in Postmenopausal Women|journal=Journal of Experimental & Clinical Medicine|volume=3|issue=3|year=2011|pages=112–115|issn=1878-3317|doi=10.1016/j.jecm.2011.04.005|quote=Natural progesterone, such as micronized progesterone, has no androgenic properties, whereas some synthetic progestins, such as MPA and norethisterone acetate, possess androgenic side effects, which raise the concern of potentially harmful effects on blood pressure.}}</ref> This is in contrast to many progestins, such as [[19-nortestosterone]] derivatives (e.g., [[norethisterone]], [[levonorgestrel]], [[dienogest]]) and [[17α-hydroxyprogesterone]] derivatives (e.g., [[cyproterone acetate]], [[medroxyprogesterone acetate]]), which do bind to the AR and have been associated with significant androgenic or antiandrogenic effects depending on the progestin in question.<ref name="pmid16112947" /><ref name="SuminoIchikawa2011" /> Due to its lack of androgenic and antiandrogenic activity, and hence lack of [[masculinization|masculinizing]] and [[feminization (biology)|feminizing]] effects, progesterone is one of the few progestogens that is suitable for use during [[pregnancy]] in women at risk for [[preterm birth]] or [[recurrent miscarriage]].<ref name="pmid17964858">{{cite journal | vauthors = Walch KT, Huber JC | title = Progesterone for recurrent miscarriage: truth and deceptions | journal = Best Pract Res Clin Obstet Gynaecol | volume = 22 | issue = 2 | pages = 375–89 | date = April 2008 | pmid = 17964858 | doi = 10.1016/j.bpobgyn.2007.08.009 }}</ref><ref name="pmid19900136">{{cite journal | vauthors = Rode L, Langhoff-Roos J, Andersson C, Dinesen J, Hammerum MS, Mohapeloa H, Tabor A | title = Systematic review of progesterone for the prevention of preterm birth in singleton pregnancies | journal = Acta Obstet Gynecol Scand | volume = 88 | issue = 11 | pages = 1180–9 | date = 2009 | pmid = 19900136 | doi = 10.3109/00016340903280982 | s2cid = 556588 }}</ref>

[[File:Steroidogenesis.svg|thumb|right|225px|[[Steroidogenesis]], showing progesterone as an intermediate in the biosynthesis of the androgens.<ref name="HäggströmRichfield2014">{{cite journal|last2=Richfield|first2=David|year=2014|title=Diagram of the pathways of human steroidogenesis|journal=WikiJournal of Medicine|volume=1|issue=1|doi=10.15347/wjm/2014.005|issn=2002-4436|last1=Häggström|first1=Mikael|doi-access=free}}</ref>]]

Although progesterone does not have significant AR-mediated androgenic or antiandrogenic activity, it is a [[precursor (biochemistry)|precursor]] and [[metabolic intermediate|intermediate]], albeit distant, in the [[biosynthesis]] of androgens from [[cholesterol]].<ref name="HäggströmRichfield2014" /><ref name="Frank1971">{{cite book|author=Samuel B. Frank|title=Acne Vulgaris|url=https://books.google.com/books?id=FulsAAAAMAAJ|year=1971|publisher=Thomas|pages=131|isbn=9780398006020|quote=The chemical structure of progesterone and testosterone are remarkably similar; they differ only in the side chain at the 17-carbon position. The possibility that progesterone can be transformed to testosterone has been considered good by many. If true, it could then be a source of androgens in women. [...] Laboratory evidence exists that progesterone can be converted to testosterone in vitro by human and animal ovarian and testicular tissue.44-47 Although the role of progesterone in acne and its effect on sebaceous gland activity is not fully established, the possibility that endogenous progesterone is a precursor of testosterone or of another androgenic substance invites further exploration.48,49}}</ref> For this reason, there has been some speculation that [[exogenous]] progesterone could be [[biotransformation|transformed]] into androgens by certain [[tissue (biology)|tissue]]s that express the requisite enzymes.<ref name="Frank1971" /><ref name="VermorkenHouben2016">{{cite journal|last1=Vermorken|first1=A. J. M.|last2=Houben|first2=J. J. G.|title=Topical Androgen Treatment for ACNE a Review|journal=Drug Intelligence & Clinical Pharmacy|volume=12|issue=3|year=2016|pages=151–157|issn=0012-6578|doi=10.1177/106002807801200302|s2cid=74413605|quote=The only concern Voigt and Hsia expressed about the use of progesterone as an anti-androgen was the possibility that the small amount of hormone which reached the circulation could be converted into testosterone by the sexual organs, mainly the testes.}}</ref> Progesterone is converted by [[17α-hydroxylase]] into [[17α-hydroxyprogesterone]]; 17α-hydroxyprogesterone is converted by [[17,20-lyase]] into [[androstenedione]]; and androstenedione is converted by [[17β-hydroxysteroid dehydrogenase]]s into testosterone.<ref name="HäggströmRichfield2014" /> [[CYP17A1]], the [[cytochrome P450]] [[gene]] that encodes 17α-hydroxylase and 17,20-lyase, is expressed mainly in the [[gonad]]s ([[ovary|ovaries]] and [[testicle|testes]]) and the [[adrenal gland]]s.<ref name="Zhou2016">{{cite book|author=Shufeng Zhou|title=Cytochrome P450 2D6: Structure, Function, Regulation and Polymorphism|url=https://books.google.com/books?id=UJqmCwAAQBAJ&pg=PA52|date=6 April 2016|publisher=CRC Press|isbn=978-1-4665-9788-4|pages=52–}}</ref> However, while it is theoretically possible that progesterone could be transformed in the body into androgens, no androgenic effects have been observed in animal studies.<ref name="pmid23484104" /> In addition, clinical studies, in which women were treated with 100 to 300&nbsp;mg/day oral progesterone, have found no or only a small increase in levels of 17α-hydroxyprogesterone, and no change in androgen levels, including of [[dehydroepiandrosterone]], androstenedione, and testosterone.<ref name="pmid12057716">{{cite journal | vauthors = Woods KS, Reyna R, Azziz R | title = Effect of oral micronized progesterone on androgen levels in women with polycystic ovary syndrome | journal = Fertil. Steril. | volume = 77 | issue = 6 | pages = 1125–7 | year = 2002 | pmid = 12057716 | doi = 10.1016/s0015-0282(02)03119-9| quote = The mean values of TT, FT, SHBG, DHEAS, A4, and 17-OHP did not change with OMP administration. However, a higher 17-OHP level was observable at the completion of OMP administration (week 2).| doi-access = free }}</ref><ref name="pmid7370683">{{cite journal | vauthors = Whitehead MI, Townsend PT, Gill DK, Collins WP, Campbell S | title = Absorption and metabolism of oral progesterone | journal = Br Med J | volume = 280 | issue = 6217 | pages = 825–7 | year = 1980 | pmid = 7370683 | pmc = 1600943 | doi = 10.1136/bmj.280.6217.825| quote = Plasma concentrations of oestradiol were unchanged by giving progesterone.}}</ref><ref name="pmid6596830" /> In these studies, levels of [[estradiol]] and [[cortisol]], which progesterone is also a precursor of, did not change either, although levels of 11-deoxycorticosterone increased significantly.<ref name="pmid7370683" /><ref name="pmid6596830" /> Levels of androgens, like testosterone and [[dihydrotestosterone]] (DHT), also do not increase going from the follicular phase to the luteal phase of the menstrual cycle in premenopausal women (progesterone levels being high in the luteal phase).<ref name="pmid6542470" />

===5α-Reductase inhibition===
Progesterone is a [[substrate (biochemistry)|substrate]] for [[5α-reductase]], and has been found to act as a [[competitive inhibition|competitive inhibitor]] of this [[enzyme]] ''[[in vitro]]'' in a variety of studies.<ref name="pmid16112947" /> In one study, it showed {{abbrlink|IC<sub>50</sub>|half-maximal inhibitory concentration}} values of 1,375&nbsp;nM and 88&nbsp;nM (in the presence of 50&nbsp;nM [[androstenedione]] as the [[substrate (biochemistry)|substrate]]) for 5α-reductase types [[SRD5A1|1]] and [[SRD5A2|2]], respectively.<ref name="pmid21376746">{{cite journal | vauthors = Rižner TL, Brožič P, Doucette C, Turek-Etienne T, Müller-Vieira U, Sonneveld E, van der Burg B, Böcker C, Husen B | title = Selectivity and potency of the retroprogesterone dydrogesterone in vitro | journal = Steroids | volume = 76 | issue = 6 | pages = 607–15 | date = May 2011 | pmid = 21376746 | doi = 10.1016/j.steroids.2011.02.043 | s2cid = 31609405 }}</ref> 5α-Reductase is highly expressed in [[skin]], [[hair follicle]]s, and [[prostate gland]], and is responsible for the transformation of testosterone into the several-fold more potent androgen DHT in such tissues.<ref name="pmid28472278">{{cite journal | vauthors = Swerdloff RS, Dudley RE, Page ST, Wang C, Salameh WA | title = Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels | journal = Endocr. Rev. | volume = 38 | issue = 3 | pages = 220–254 | year = 2017 | pmid = 28472278 | doi = 10.1210/er.2016-1067 | pmc = 6459338 }}</ref><ref name="pmid16985920">{{cite journal | vauthors = Marks LS | title = 5α-reductase: history and clinical importance | journal = Rev Urol | volume = 6 | pages = S11–21 | year = 2004 | issue = Suppl 9 | pmid = 16985920 | pmc = 1472916 }}</ref> As such, it has been suggested that progesterone might possess some antiandrogenic effect via acting as a [[5α-reductase inhibitor]].<ref name="pmid16112947" /> However, inhibition of 5α-reductase by progesterone is described as a weak effect that has only been demonstrated ''in vitro'' and at supraphysiological concentrations.<ref name="pmid17066418">{{cite journal | vauthors = Golub MS, Kaufman FL, Campbell MA, Li LH, Donald JM | title = "Natural" progesterone: information on fetal effects | journal = Birth Defects Research Part B: Developmental and Reproductive Toxicology | volume = 77 | issue = 5 | pages = 455–70 | date = October 2006 | pmid = 17066418 | doi = 10.1002/bdrb.20089 | quote = Progesterone has been shown to inhibit 5α-reductase, another important enzyme in steroid hormone metabolism, (Dean and Winter, 1984; Beckmann et al., 1993; Cassidenti et al., 1991; Kadohama et al., 1983; Mauvais-Jarvis et al., 1974; Dube et al., 1975). However, this is a weak effect that has only been demonstrated at supra-physiological concentrations and in vitro conditions.}}</ref><ref name="Kincl1990">{{cite book|last1=Kincl|first1=Fred A.|title=Hormone Toxicity in the Newborn|chapter=Control of Reproductive Function in the Adult|volume=31|year=1990|pages=5–120|issn=0077-1015|doi=10.1007/978-3-642-83794-4_2|quote=Progesterone (and other progestational agents) inhibit testosterone from expressing its activity at the target sites (Kincl, 1971a). Mice and rats are the test animals of choice (Dorfman, 1963a,b). Inhibition of 5α-reductase activity of binding to cytosol and nuclear receptors has been shown to be the steps at which antiandrogens express their activity (Neumann and Steinbeck, 1974). Relatively high amounts are needed to achieve a significant effect (Table 2.16).|series=Monographs on Endocrinology|pmid=1965221|isbn=978-3-642-83796-8}}</ref> In accordance, physiological levels of circulating progesterone have not been found to importantly influence circulating DHT concentrations.<ref name="pmid6542470">{{cite journal | vauthors = Dewis P, Newman M, Anderson DC | title = The effect of endogenous progesterone on serum levels of 5α-reduced androgens in hirsute women | journal = Clin. Endocrinol. (Oxf) | volume = 21 | issue = 4 | pages = 383–92 | date = October 1984 | pmid = 6542470 | doi = 10.1111/j.1365-2265.1984.tb03225.x | s2cid = 72895292 | quote = These studies suggest that [...] a rise in serum progesterone has only a minimal effect on circulating levels of the active 5α‐reduced androgen metabolites. [...] Progesterone has been shown to be a potent in vitro inhibitor of cutaneous 5α-reductase (Mauvais-Jarvis et al., 1974). However we found only a small reduction in serum DHT levels in the late luteal phase in ovulatory women and no change in serum 3α-diol. Hence the rise in serum progesterone in ovulatory women has only a minimal effect on the circulating levels of the major active 5α-reduced androgens in vivo.}}</ref><ref name="pmid6543461">{{cite journal | vauthors = Kålund-Jensen H, Myrén CJ | title = Vaginal absorption of oestradiol and progesterone | journal = Maturitas | volume = 6 | issue = 4 | pages = 359–67 | date = December 1984 | pmid = 6543461 | doi = 10.1016/0378-5122(84)90009-4 }}</ref>

[[5α-Reductase deficiency|Congenital 5α-reductase 2 deficiency]] is a rare [[intersex condition]] which is associated with [[ambiguous genitalia]] in male [[fetus]]es due to a deficiency in DHT production during [[genitals|genital]] [[sexual differentiation|differentiation]].<ref name="pmid16985920" /> Experimental prenatal exposure to established 5α-reductase inhibitors like [[finasteride]] has been found to produce similar feminized genital defects in male animals including rodents and monkeys.<ref name="pmid29063715">{{cite journal | vauthors = Picut CA, Ziejewski MK, Stanislaus D | title = Comparative Aspects of Pre- and Postnatal Development of the Male Reproductive System | journal = Birth Defects Res | volume = 110 | issue = 3 | pages = 190–227 | date = February 2018 | pmid = 29063715 | doi = 10.1002/bdr2.1133 | s2cid = 3967093 | doi-access = free }}</ref> In contrast, exogenous administration of progesterone to pregnant rodents and monkeys has resulted in minimal abnormality in either male or female pups.<ref name="pmid29790373" /><ref name="Kincl2012">{{cite book|author=Fred A. Kincl|title=Hormone Toxicity in the Newborn|url=https://books.google.com/books?id=hRQyBwAAQBAJ&pg=PA1948|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-83794-4|page=60}}</ref><ref name="pmid558879">{{cite journal | vauthors = Kawashima K, Nakaura S, Nagao S, Tanaka S, Kuwamura T | title = Virilizing activities of various steroids in female rat fetuses | journal = Endocrinol. Jpn. | volume = 24 | issue = 1 | pages = 77–81 | date = February 1977 | pmid = 558879 | doi = 10.1507/endocrj1954.24.77 | doi-access = free }}</ref><ref name="pmid945344" /> In addition, endogenous progesterone levels naturally increase to extremely high concentrations during pregnancy, yet genital defects do not occur.<ref name="PlantZeleznik2014">{{cite book|author1=Tony M. Plant|author2=Anthony J. Zeleznik|title=Knobil and Neill's Physiology of Reproduction|url=https://books.google.com/books?id=I1ACBAAAQBAJ&pg=PA2386|date=15 November 2014|publisher=Academic Press|isbn=978-0-12-397769-4|pages=2289, 2386}}</ref> In accordance, while total concentrations of progesterone in pregnant women at term are around 150&nbsp;ng/mL (~500&nbsp;nM), free or unbound and hence bioactive concentrations of progesterone are only about 3&nbsp;ng/mL (~10&nbsp;nM) due to the high [[plasma protein binding]] of progesterone, and these concentrations are still well below the aforementioned {{abbr|IC<sub>50</sub>|half-maximal inhibitory concentration}} values for inhibition of 5α-reductase types 1 and 2.<ref name="Elsevier2002">{{cite book|title=Hormones, Brain and Behavior, Five-Volume Set|url=https://books.google.com/books?id=6GgHpQdk8vYC&pg=PA54|date=18 June 2002|publisher=Elsevier|isbn=978-0-08-053415-2|pages=54–}}</ref><ref name="pmid8201129">{{cite journal | vauthors = Heidrich A, Schleyer M, Spingler H, Albert P, Knoche M, Fritze J, Lanczik M | title = Postpartum blues: relationship between not-protein bound steroid hormones in plasma and postpartum mood changes | journal = J Affect Disord | volume = 30 | issue = 2 | pages = 93–8 | date = February 1994 | pmid = 8201129 | doi = 10.1016/0165-0327(94)90036-1}}</ref> As with endogenous progesterone during pregnancy, [[exogenous]] supplemental progesterone during pregnancy has been found not to increase the risk of [[hypospadias]] in male infants.<ref name="BaekRosenwaks2006">{{cite journal|last1=Baek|first1=K.|last2=Rosenwaks|first2=Z.|last3=Poppas|first3=D.P.|last4=Palermo|first4=G.D.|title=P-657|journal=Fertility and Sterility|volume=86|issue=3|year=2006|pages=S377|issn=0015-0282|doi=10.1016/j.fertnstert.2006.07.1033|doi-access=free}}</ref>

Although systemic progesterone does not appear to be an effective 5α-reductase inhibitor, topical progesterone may produce potent inhibition of 5α-reductase in the skin due to the very high local concentrations that occur.<ref name="GreavesShuster1989a">{{cite book|title=Pharmacology of the Skin I: Pharmacology of Skin Systems Autocoids in Normal and Inflamed Skin|url=https://books.google.com/books?id=ax7sCAAAQBAJ&pg=PA249|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-73797-8|pages=249–250}}</ref><ref name="GreavesShuster1989b">{{cite book|title=Pharmacology of the Skin II: Methods, Absorption, Metabolism and Toxicity, Drugs and Diseases|url=https://books.google.com/books?id=GvDxCAAAQBAJ&pg=PA485|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-74054-1|pages=253, 485–}}</ref> A study found that topical progesterone applied to the pubic area in men inhibited 5α-reductase in the skin in this region by 75%.<ref name="GreavesShuster1989b" /><ref name="Unger1995">{{cite book|author=Walter P. Unger|chapter=Androgenetic alopecia and its treatment. A historical overview|pages=1–33|title=Hair Transplantation, Third Edition|url=https://books.google.com/books?id=_KxsAAAAMAAJ|date=1 February 1995|publisher=Taylor & Francis|isbn=978-0-8247-9363-0}}</ref> In addition to inhibition of 5α-reductase, progesterone is metabolized by 5α-reductase into [[5α-dihydroprogesterone]] (5α-DHP), a compound reported to have some [[antagonist]]ic activity at the AR.<ref name="Unger1995" /><ref name="SawayaShapiro2000" /> However, this compound appears to have no systemic antiandrogenic activity.<ref name="ParthasarathyChin1988">{{cite journal|last1=Parthasarathy|first1=Saudhamini|last2=Chin|first2=Andrea|last3=Malloy|first3=Virginia|last4=Matias|first4=Jonathan|title=In Vitro Androgen Receptor Binding Affinity and in Vivo Inhibitory Activity of 5?-Pregnane-3, 20-Dione|journal=Annals of the New York Academy of Sciences|volume=529|issue=1 Fourth Colloq|year=1988|pages=239–241|issn=0077-8923|doi=10.1111/j.1749-6632.1988.tb51470.x|bibcode=1988NYASA.529..239P|s2cid=86039350}}</ref> In spite of its apparent 5α-reductase inhibition, the effectiveness of topical progesterone in the treatment of [[pattern hair loss]] has been poor.<ref name="SawayaShapiro2000">{{cite journal|last1=Sawaya|first1=Marty E.|last2=Shapiro|first2=Jerry|title=Androgenetic alopecia|journal=Dermatologic Clinics|volume=18|issue=1|year=2000|pages=47–61|issn=0733-8635|doi=10.1016/S0733-8635(05)70146-7|pmid=10626111}}</ref><ref name="Price1988">{{cite journal|last1=Price|first1=Vera H.|title=Androgenetic alopecia and hair growth promotion state of the art: Present and future|journal=Clinics in Dermatology|volume=6|issue=4|year=1988|pages=218–227|issn=0738-081X|doi=10.1016/0738-081X(88)90090-9|pmid=3063373}}</ref><ref name="pmid8435919">{{cite journal | vauthors = Sawaya ME, Hordinsky MK | title = The antiandrogens. When and how they should be used | journal = Dermatol Clin | volume = 11 | issue = 1 | pages = 65–72 | date = January 1993 | pmid = 8435919 | doi = 10.1016/S0733-8635(18)30283-3 }}</ref>

===Other activity===
Certain progestins have been found to stimulate the [[cell proliferation|proliferation]] of [[MCF-7]] [[breast cancer]] [[cell (biology)|cell]]s ''[[in vitro]]'', an action that is independent of the classical PRs and is instead mediated via the [[progesterone receptor membrane component-1]] (PGRMC1).<ref name="pmid23758160">{{cite journal | vauthors = Neubauer H, Ma Q, Zhou J, Yu Q, Ruan X, Seeger H, Fehm T, Mueck AO | title = Possible role of PGRMC1 in breast cancer development | journal = Climacteric | volume = 16 | issue = 5 | pages = 509–13 | date = October 2013 | pmid = 23758160 | doi = 10.3109/13697137.2013.800038 | s2cid = 29808177 }}</ref> Progesterone, [[nomegestrol acetate]], and [[chlormadinone acetate]] act neutrally and do not stimulate proliferation, whereas [[norethisterone]], [[desogestrel]], [[levonorgestrel]], and [[drospirenone]] strongly stimulate proliferation and [[medroxyprogesterone acetate]], [[dienogest]], and [[dydrogesterone]] weakly stimulate proliferation.<ref name="pmid23758160" /><ref name="pmid22335423">{{cite journal | vauthors = Ruan X, Neubauer H, Yang Y, Schneck H, Schultz S, Fehm T, Cahill MA, Seeger H, Mueck AO | title = Progestogens and membrane-initiated effects on the proliferation of human breast cancer cells | journal = Climacteric | volume = 15 | issue = 5 | pages = 467–72 | date = October 2012 | pmid = 22335423 | doi = 10.3109/13697137.2011.648232 | s2cid = 11302554 }}</ref> As such, progesterone differs from some but not all progestins in the activity mediating this PGRMC1-dependent effect.<ref name="pmid23758160" /> It is unclear if these findings may explain the different risks of breast cancer observed with progesterone, dydrogesterone, and other progestins such as medroxyprogesterone acetate and norethisterone in [[clinical trial|clinical studies]].<ref name="pmid31512725">{{cite journal | vauthors = Trabert B, Sherman ME, Kannan N, Stanczyk FZ | title = Progesterone and breast cancer | journal = Endocr. Rev. | volume = 41| issue = 2| pages = 320–344| date = September 2019 | pmid = 31512725 | doi = 10.1210/endrev/bnz001 | pmc = 7156851 | doi-access = free }}</ref>

==Effects in the body and brain==
{{See also|Progesterone#Biological function|Progestogen#Biological function}}

The PRs are expressed widely throughout the body, including in the [[uterus]], [[cervix]], [[vagina]], [[fallopian tube]]s, [[breast]]s, [[adipose tissue|fat]], [[skin]], [[pituitary gland]], [[hypothalamus]], and elsewhere throughout the [[brain]].<ref name="pmid16112947" /><ref name="Bentley1980">{{cite book|author=P. J. Bentley|title=Endocrine Pharmacology: Physiological Basis and Therapeutic Applications|url=https://books.google.com/books?id=W6M9AAAAIAAJ&pg=PA264|year=1980|publisher=CUP Archive|isbn=978-0-521-22673-8|pages=264, 274}}</ref> Through activation of the PRs (as well as the mPRs), progesterone has many effects, including the following:<ref name="pmid16112947" /><ref name="Bentley1980" />

* Induces [[endometrial secretory transformation]] in preparation for [[pregnancy]] (>5&nbsp;ng/mL)<ref name="Sperling2014" />
* Prevents estrogen-induced [[endometrial hyperplasia]] and increased [[endometrial cancer]] risk
* Maintains pregnancy via effects in endometrium (with withdrawal resulting in [[miscarriage]])
* Reduces amount and [[spinnbarkeit|fibrosity]] of [[cervical mucus]] and causes cervix to become firmer and more tightly closed<ref name="MacdonaldJohnson2017">{{cite book|author1=Sue Macdonald|author2=Gail Johnson|title=Mayes' Midwifery E-Book|url=https://books.google.com/books?id=mMUmDwAAQBAJ&pg=PA391|date=3 June 2017|publisher=Elsevier Health Sciences|isbn=978-0-7020-6336-7|pages=391–}}</ref>
* Controls motility and composition of fluid in the [[fallopian tube]]s
* Reduced [[cornification]] and maturation of the vaginal lining<ref name="Becker2001">{{cite book|author=Kenneth L. Becker|title=Principles and Practice of Endocrinology and Metabolism|url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA940|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=889, 940}}</ref>
* Causes [[water retention (medicine)|water retention]] in the breasts resulting in temporary [[mammoplasia|enlargement]] during the [[menstrual cycle]]<ref name="Copstead-KirkhornBanasik2014">{{cite book|author1=Lee-Ellen C. Copstead-Kirkhorn|author2=Jacquelyn L. Banasik|title=Pathophysiology - E-Book|url=https://books.google.com/books?id=i7jwAwAAQBAJ&pg=PA660|date=25 June 2014|publisher=Elsevier Health Sciences|isbn=978-0-323-29317-4|pages=660–|quote=Throughout the reproductive years, some women note swelling of the breast around the latter part of each menstrual cycle before the onset of menstruation. The water retention and subsequent swelling of breast tissue during this phase of the menstrual cycle are thought to be due to high levels of circulating progesterone stimulating the secretory cells of the breast.12}}</ref><ref name="pmid19099613">{{cite journal | vauthors = Farage MA, Neill S, MacLean AB | title = Physiological changes associated with the menstrual cycle: a review | journal = Obstet Gynecol Surv | volume = 64 | issue = 1 | pages = 58–72 | year = 2009 | pmid = 19099613 | doi = 10.1097/OGX.0b013e3181932a37 | s2cid = 22293838 }}</ref>
* Mediates [[lobuloalveolar development]] of the breasts necessary for [[lactation]]
* Suppresses lactation initiation and triggers lactation upon withdrawal (as with [[parturition]])
* Maintains skin health, integrity, appearance, and hydration and slows the rate of aging of the skin<ref name="pmid12762829">{{cite journal | vauthors = Raine-Fenning NJ, Brincat MP, Muscat-Baron Y | title = Skin aging and menopause : implications for treatment | journal = Am J Clin Dermatol | volume = 4 | issue = 6 | pages = 371–8 | year = 2003 | pmid = 12762829 | doi = 10.2165/00128071-200304060-00001| s2cid = 20392538 }}</ref><ref name="pmid16120154">{{cite journal | vauthors = Holzer G, Riegler E, Hönigsmann H, Farokhnia S, Schmidt JB, Schmidt B | title = Effects and side-effects of 2% progesterone cream on the skin of peri- and postmenopausal women: results from a double-blind, vehicle-controlled, randomized study | journal = Br. J. Dermatol. | volume = 153 | issue = 3 | pages = 626–34 | year = 2005 | pmid = 16120154 | doi = 10.1111/j.1365-2133.2005.06685.x | s2cid = 6077829 }}</ref>
* Modulates brain function, with effects on [[mood (psychology)|mood]], [[emotionality]], and [[human sexuality|sexuality]], as well as [[cognition]] and [[memory]]
* Exerts [[negative feedback]] on the [[hypothalamic–pituitary–gonadal axis]] (HPG axis) by suppressing the secretion of the gonadotropins FSH and LH from the pituitary gland (including the mid-cycle gonadotropin surge), thereby inhibiting [[gonad]]al [[sex hormone]] production as well as ovulation and [[fertility]] (>2&nbsp;ng/mL)<ref name="SperoffFritz2005" />
* Increases [[basal body temperature]] (by 0.3–0.6&nbsp;°C (0.5–1.0&nbsp;°F) relative to [[preovulation]]) via the hypothalamus (>4&nbsp;ng/mL)<ref name="BeckmannHerbert2013">{{cite book|author1=Charles R. B. Beckmann|author2=William Herbert|author3=Douglas Laube|author4=Frank Ling, Roger Smith|title=Obstetrics and Gynecology|url=https://books.google.com/books?id=dD-emqhOXa0C&pg=PA342|date=21 January 2013|publisher=Lippincott Williams & Wilkins|isbn=978-1-4698-2604-2|pages=342–}}</ref><ref name="pmid3527660">{{cite journal | vauthors = Quigley MM | title = Drugs in the treatment of female infertility. Recent advances | journal = Drugs | volume = 32 | issue = 2 | pages = 169–77 | date = August 1986 | pmid = 3527660 | doi = 10.2165/00003495-198632020-00004 | s2cid = 46972235 | quote = In the presence of circulating levels of approximately 4 μg/L or greater of progesterone, most women experience a 0.5° to 1°F rise in basal body temperature.}}</ref>
* Reduces [[hot flash]]es via the hypothalamus<ref name="pmid12440557">{{cite journal | vauthors = Shanafelt TD, Barton DL, Adjei AA, Loprinzi CL | title = Pathophysiology and treatment of hot flashes | journal = Mayo Clin. Proc. | volume = 77 | issue = 11 | pages = 1207–18 | year = 2002 | pmid = 12440557 | doi = 10.4065/77.11.1207 }}</ref><ref name="pmid20729500">{{cite journal | vauthors = Sassarini J, Lumsden MA | title = Hot flushes: are there effective alternatives to estrogen? | journal = Menopause Int | volume = 16 | issue = 2 | pages = 81–8 | year = 2010 | pmid = 20729500 | doi = 10.1258/mi.2010.010007 | s2cid = 37505358 }}</ref>
* Stimulates [[breathing|respiration]] via the hypothalamus and/or [[respiratory center]]<ref name="pmid1399957">{{cite journal | vauthors = Bayliss DA, Millhorn DE | title = Central neural mechanisms of progesterone action: application to the respiratory system | journal = J. Appl. Physiol. | volume = 73 | issue = 2 | pages = 393–404 | year = 1992 | pmid = 1399957 | doi = 10.1152/jappl.1992.73.2.393}}</ref><ref name="BourjeilyRosene-Montella2009">{{cite book|author1=Ghada Bourjeily|author2=Karen Rosene-Montella|title=Pulmonary Problems in Pregnancy|url=https://books.google.com/books?id=BZhP2peNifcC&pg=PA21|date=21 April 2009|publisher=Springer Science & Business Media|isbn=978-1-59745-445-2|pages=21–}}</ref>
* Influences the risk and/or progression of hormone-sensitive cancers including breast cancer and endometrial cancer

Many of the effects of progesterone require estrogen, as estrogens prime tissues for progesterone by inducing expression of the PRs.<ref name="pmid16112947" /><ref name="Bentley1980" /> The PRs are induced in the breasts by estrogens, and for this reason, it is assumed that progestogens cannot mediate breast changes in the absence of estrogens.<ref name="pmid29852797">{{cite journal | vauthors = Gompel A, Plu-Bureau G | title = Progesterone, progestins and the breast in menopause treatment | journal = Climacteric | volume = 21 | issue = 4 | pages = 326–332 | date = August 2018 | pmid = 29852797 | doi = 10.1080/13697137.2018.1476483 | s2cid = 46922084 }}</ref>

Progesterone also [[antihypertensive|lowers blood pressure]] and reduces [[water retention (medicine)|water]] and [[salt retention]] among other effects via its antimineralocorticoid activity.<ref name="pmid16112947" /><ref name="pmid11246598">{{cite journal | vauthors = Oelkers W | title = Drospirenone--a new progestogen with antimineralocorticoid activity, resembling natural progesterone | journal = Eur J Contracept Reprod Health Care | volume = 5 | pages = 17–24 | year = 2000 | issue = Suppl 3 | doi = 10.1080/14730782.2000.12288986 | pmid = 11246598 }}</ref>

Progesterone can produce [[sedative]], [[hypnotic]], [[anxiolytic]], [[euphoric]], [[cognitive impairment|cognitive-]], [[memory impairment|memory-]], and [[motor impairment|motor-impairing]], [[anticonvulsant]], and even [[anesthetic]] effects via formation of sufficiently high concentrations of its neurosteroid metabolites and consequent GABA<sub>A</sub> receptor potentiation in the brain.<ref name="pmid17924777" /><ref name="Wang-ChengNeuner2007">{{cite book | first1 = Rebekah | last1 = Wang-Cheng | first2 = Joan M. | last2 = Neuner | first3 = Vanessa M. | last3 = Barnabei | name-list-style = vanc | title = Menopause | url = https://books.google.com/books?id=mPs5Ly71OCQC&pg=PA97 | year = 2007 | publisher = ACP Press | isbn = 978-1-930513-83-9 | page = 97}}</ref><ref name="BergemannRiecher-Rössler2005">{{cite book | first1 = Niels | last1 = Bergemann | first2 = Anita | last2 = Ariecher-Rössler | name-list-style = vanc | title = Estrogen Effects in Psychiatric Disorders | url = https://books.google.com/books?id=L4YQ50SbBnsC&pg=PA179 | date = 27 December 2005 | publisher = Springer Science & Business Media | isbn = 978-3-211-27063-9 | page = 179}}</ref><ref name="pmid23978486">{{cite journal | vauthors = Bäckström T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G, Savic I, Strömberg J, Timby E, van Broekhoven F, van Wingen G | title = Allopregnanolone and mood disorders | journal = Prog. Neurobiol. | volume = 113 | pages = 88–94 | year = 2014 | pmid = 23978486 | doi = 10.1016/j.pneurobio.2013.07.005 | s2cid = 207407084 }}</ref>

===Uterine effects===
Under normal physiological circumstances, progesterone secreted by the [[corpus luteum]] during the [[luteal phase]] of the [[menstrual cycle]] produces [[endometrial transformation]] of the estrogen-primed [[uterus]] in preparation for [[implantation (human embryo)|implantation]] and [[pregnancy]].<ref name="BieberSanfilippo2015">{{cite book|author1=Eric J. Bieber|author2=Joseph S. Sanfilippo|author3=Ira R. Horowitz|author4=Mahmood I. Shafi|title=Clinical Gynecology|url=https://books.google.com/books?id=RfkGBwAAQBAJ&pg=PA972|date=23 April 2015|publisher=Cambridge University Press|isbn=978-1-107-04039-7|pages=972–}}</ref> Normal progesterone production during the luteal phase is 25&nbsp;mg/day on average with a range of 15 to 50&nbsp;mg/day.<ref name="Blackburn2007">{{cite book|author=Susan Tucker Blackburn|title=Maternal, Fetal, & Neonatal Physiology: A Clinical Perspective|url=https://books.google.com/books?id=2y6zOSQcn14C&pg=PA44|year=2007|publisher=Elsevier Health Sciences|isbn=978-1-4160-2944-1|pages=44–}}</ref><ref name="pmid945344" /> Progesterone levels during the luteal phase range from 7&nbsp;ng/mL to 22&nbsp;ng/mL using [[liquid chromatography–tandem mass spectrometry]] (LC–MS/MS) per one source.<ref name="JamesonGroot2015">{{cite book|author1=J. Larry Jameson|author2=Leslie J. De Groot|title=Endocrinology: Adult and Pediatric E-Book|url=https://books.google.com/books?id=xmLeBgAAQBAJ&pg=PP1|date=25 February 2015|publisher=Elsevier Health Sciences|isbn=978-0-323-32195-2|pages=1–}}</ref> Sustained progesterone levels of more than 5&nbsp;ng/mL, perhaps approximately 10&nbsp;ng/mL, are required for full endometrial transformation.<ref name="Sperling2014">{{cite book|author=Mark A. Sperling|title=Pediatric Endocrinology E-Book|url=https://books.google.com/books?id=GgXnAgAAQBAJ&pg=PA630|date=10 April 2014|publisher=Elsevier Health Sciences|isbn=978-1-4557-5973-6|pages=630–}}</ref><ref name="pmid8941049">{{cite journal | vauthors = Younis JS, Simon A, Laufer N | title = Endometrial preparation: lessons from oocyte donation | journal = Fertil Steril | volume = 66 | issue = 6 | pages = 873–84 | date = December 1996 | pmid = 8941049 | doi = 10.1016/s0015-0282(16)58677-4 | url = | quote = It seems that [progesterone] levels of approximately 10 ng/mL are sufficient to sustain morphological and functional endometrial development. [...] Oral micronized P (100 mg three times) was investigated in ovarian failure patients in 12 cycles after adequate E2 priming (84). The serum P levels achieved were subphysiologic and incapable of inducing a normal secretory response in the endometrium.| doi-access = free }}</ref> Progesterone levels of more than 10&nbsp;ng/mL are rarely associated with [[luteal-phase defect]] on the basis of [[endometrial biopsy]].<ref name="Carp2007">{{cite book|author=Howard Carp|title=Recurrent Pregnancy Loss: Causes, Controversies and Treatment|url=https://books.google.com/books?id=35I8MdH4V4cC&pg=PA79|date=13 June 2007|publisher=CRC Press|isbn=978-0-415-42130-0|pages=79–}}</ref>

Luteal-phase levels of progesterone are said to be produced by 25&nbsp;mg/day progesterone in oil solution by intramuscular injection or by 100&nbsp;mg/day progesterone by vaginal or rectal administration.<ref name="pmid945344" /><ref name="AllahbadiaDas2017">{{cite book|author1=Gautam N Allahbadia|author2=Rita Basuray Das|author3=Goral Gandhi|author4=Rubina Merchant|title=The Art & Science of Assisted Reproductive Techniques (ART)|url=https://books.google.com/books?id=Gc8nDwAAQBAJ&pg=PA145|date=17 July 2017|publisher=JP Medical Ltd|isbn=978-93-86322-82-1|pages=145–}}</ref> Progesterone by intramuscular injection in oil solution has been found to produce endometrial transformation at a dose of 10 or 20&nbsp;mg/day for 14&nbsp;days (total dose per cycle of 200&nbsp;mg), whereas a single intramuscular injection of 200&nbsp;mg progesterone in microcrystalline aqueous suspension provides endometrial transformation after 10 to 14&nbsp;days.<ref name="BengtssonTausk1971">{{cite book|author1=Lars Philip Bengtsson|author2=M. Tausk|title=Pharmacology of the endocrine system and related drugs: progesterone, progestational drugs and antifertility agents|url=https://books.google.com/books?id=lf1sAAAAMAAJ|date=30 January 1971|publisher=Pergamon Press|page=449|isbn=9780080157450}}</ref> A study found full and equivalent endometrial transformation with [[subcutaneous injection]] of 25&nbsp;mg/day versus 50&nbsp;mg/day progesterone in [[aqueous solution]].<ref name="pmid23806850">{{cite journal | vauthors = de Ziegler D, Sator M, Binelli D, Leuratti C, Cometti B, Bourgain C, Fu YS, Garhöfer G | title = A randomized trial comparing the endometrial effects of daily subcutaneous administration of 25 mg and 50 mg progesterone in aqueous preparation | journal = Fertil. Steril. | volume = 100 | issue = 3 | pages = 860–6 | date = September 2013 | pmid = 23806850 | doi = 10.1016/j.fertnstert.2013.05.029 | doi-access = free }}</ref> Due to a uterine [[first-pass effect]] and markedly higher uterine progesterone levels than with other routes, 45&nbsp;mg/day vaginal progesterone, a dosage that achieves circulating progesterone levels of only 1 to 5&nbsp;ng/mL, provides complete endometrial transformation.<ref name="pmid11108875">{{cite journal | vauthors = de Ziegler D, Fanchin R | title = Progesterone and progestins: applications in gynecology | journal = Steroids | volume = 65 | issue = 10–11 | pages = 671–9 | date = 2000 | pmid = 11108875 | doi = 10.1016/s0039-128x(00)00123-9 | s2cid = 5867301 }}</ref><ref name="AllahbadiaDas2017" /> Conversely, [[intranasal administration]] of progesterone achieving progesterone levels of 2 to 5&nbsp;ng/mL was ineffective.<ref name="pmid11108875" /> Transdermal progesterone achieves very low progesterone levels and is considered to be ineffective for endometrial protection.<ref name="pmid11108875" /><ref name="pmid25196424">{{cite journal | vauthors = Stanczyk FZ | title = Treatment of postmenopausal women with topical progesterone creams and gels: are they effective? | journal = Climacteric | volume = 17 | pages = 8–11 | year = 2014 | issue = Suppl 2 | pmid = 25196424 | doi = 10.3109/13697137.2014.944496 | s2cid = 20019151 }}</ref><ref name="pmid15772572">{{cite journal | vauthors = Stanczyk FZ, Paulson RJ, Roy S | title = Percutaneous administration of progesterone: blood levels and endometrial protection | journal = Menopause | volume = 12 | issue = 2 | pages = 232–7 | year = 2005 | pmid = 15772572 | doi = 10.1097/00042192-200512020-00019 | s2cid = 10982395 }}</ref>

The endometrial transformation dosage of oral micronized progesterone in women has been listed as 200 to 300&nbsp;mg/day or 4,200&nbsp;mg total per cycle.<ref name="AllahbadiaMorimoto2015">{{cite book|author1=Gautam N. Allahbadia|author2=Yoshiharu Morimoto|title=Ovarian Stimulation Protocols|url=https://books.google.com/books?id=_I6QCgAAQBAJ&pg=PA137|date=15 September 2015|publisher=Springer|isbn=978-81-322-1121-1|pages=137–}}</ref><ref name="pmid16112947" /> However, a clinical study found that 300&nbsp;mg/day oral micronized progesterone was insufficient for full endometrial transformation.<ref name="pmid2567713">{{cite journal | vauthors = Devroey P, Palermo G, Bourgain C, Van Waesberghe L, Smitz J, Van Steirteghem AC | title = Progesterone administration in patients with absent ovaries | journal = Int. J. Fertil. | volume = 34 | issue = 3 | pages = 188–93 | date = 1989 | pmid = 2567713 }}</ref> Similarly, 600 to 1,000&nbsp;mg/day oral micronized progesterone has been reported to be ineffective for achieving complete endometrial transformation.<ref name="pmid11108875" /><ref name="pmid23806850"/> Despite inadequate endometrial transformation with oral progesterone, continuous 100&nbsp;mg/day oral micronized progesterone or cyclic 200&nbsp;mg/day oral micronized progesterone is effective for protection of the endometrium against estrogen-induced [[endometrial hyperplasia]].<ref name="pmid27277331">{{cite journal | vauthors = Stute P, Neulen J, Wildt L | title = The impact of micronized progesterone on the endometrium: a systematic review | journal = Climacteric | volume = 19 | issue = 4 | pages = 316–28 | date = August 2016 | pmid = 27277331 | doi = 10.1080/13697137.2016.1187123 | doi-access = free }}</ref> On the other hand, and in contrast to progestins, typical clinical doses of oral micronized progesterone have been associated with failure to prevent increased [[endometrial cancer]] risk caused by estrogen therapy.<ref name="pmid29526116">{{cite journal | vauthors = Davey DA | title = Menopausal hormone therapy: a better and safer future | journal = Climacteric | volume = 21 | issue = 5 | pages = 454–461 | date = October 2018 | pmid = 29526116 | doi = 10.1080/13697137.2018.1439915 | s2cid = 3850275 }}</ref>

===Antiestrogenic effects===
Progesterone, like all progestogens, has [[antiestrogen]]ic effects in certain [[tissue (biology)|tissue]]s such as the [[uterus]], [[cervix]], [[vagina]], and [[breast]]s, and possibly also the [[brain]].<ref name="pmid16112947" /><ref name="pmid17943537">{{cite journal | vauthors = Pasqualini JR | title = Progestins and breast cancer | journal = Gynecol. Endocrinol. | volume = 23 | pages = 32–41 | year = 2007 | issue = Suppl 1 | pmid = 17943537 | doi = 10.1080/09513590701585003 | s2cid = 46634314 }}</ref><ref name="pmid19962254">{{cite journal | vauthors = Pasqualini JR | title = Breast cancer and steroid metabolizing enzymes: the role of progestogens | journal = Maturitas | volume = 65 | pages = S17–21 | year = 2009 | issue = Suppl 1 | pmid = 19962254 | doi = 10.1016/j.maturitas.2009.11.006 }}</ref> These effects are mediated by activation of the PR in these tissues.<ref name="pmid16112947" /> Progesterone does not have antiestrogenic effects in the more conventional sense of [[receptor antagonist|binding to and antagonizing]] the ER or [[enzyme inhibitor|binding to and inhibiting]] [[enzyme]]s involved in estrogen [[biosynthesis]].<ref name="pmid16112947" /> Instead, for instance in the [[endometrium]], progesterone causes [[downregulation]] of the ER and [[upregulation]] of the estrogen-inactivating enzymes [[17β-hydroxysteroid dehydrogenase 2]] (converts estradiol into [[estrone]]) and [[estrone sulfotransferase]] (converts estrone into [[estrone sulfate]]).<ref name="pmid16112947" /> The antiestrogenic effects of progesterone and other progestogens form the basis for their only approved indication in menopausal hormone therapy: prevention of long-term unopposed estrogen-induced endometrial hyperplasia and increased endometrial cancer risk in women with intact uteruses.<ref name="pmid16112947" />

In the breasts, progesterone and other progestogens downregulate the ER as well as the estrogen-activating enzymes [[steroid sulfatase]] (converts estrone sulfate into estrone) and [[17β-hydroxysteroid-dehydrogenase 1]] (converts estrone into estradiol) and upregulates estrone sulfotransferase.<ref name="pmid17943537" /><ref name="pmid19962254" /> However, other studies suggest that progestogens do not downregulate ER expression in the breasts.<ref name="pmid15193461">{{cite journal | vauthors = Kopernik G, Shoham Z | title = Tools for making correct decisions regarding hormone therapy. Part II. Organ response and clinical applications | journal = Fertil. Steril. | volume = 81 | issue = 6 | pages = 1458–77 | date = June 2004 | pmid = 15193461 | doi = 10.1016/j.fertnstert.2003.09.080 | doi-access = free }}</ref><ref name="pmid7794024">{{cite journal | vauthors = Gorins A, Denis C | title = [Effects of progesterone and progestational hormones on the mammary gland] | language = French | journal = Arch Anat Cytol Pathol | volume = 43 | issue = 1–2 | pages = 28–35 | date = 1995 | pmid = 7794024 | doi = | url = }}</ref> When applied directly to the breasts in women, progesterone can block the proliferative effects of estradiol.<ref name="pmid12419080">{{cite journal | vauthors = de Lignières B | title = Effects of progestogens on the postmenopausal breast | journal = Climacteric | volume = 5 | issue = 3 | pages = 229–35 | date = September 2002 | pmid = 12419080 | doi = 10.1080/713605271 }}</ref><ref name="pmid29852797"/><ref name="pmid2345268">{{cite journal | vauthors = Barrat J, de Lignières B, Marpeau L, Larue L, Fournier S, Nahoul K, Linares G, Giorgi H, Contesso G | title = Effet in vivo de l'administration locale de progestérone sur l'activité mitotique des galactophores humains: résultat d'une étude pilote | trans-title = The in vivo effect of the local administration of progesterone on the mitotic activity of human ductal breast tissue. Results of a pilot study | language = fr | journal = J Gynecol Obstet Biol Reprod (Paris) | volume = 19 | issue = 3 | pages = 269–74 | date = 1990 | pmid = 2345268 }}</ref><ref name="pmid7890063">{{cite journal | vauthors = Chang KJ, Lee TT, Linares-Cruz G, Fournier S, de Ligniéres B | title = Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo | journal = Fertil. Steril. | volume = 63 | issue = 4 | pages = 785–91 | date = April 1995 | pmid = 7890063 | doi = 10.1016/S0015-0282(16)57482-2| doi-access = free }}</ref><ref name="pmid8612843">{{cite journal | vauthors = Spicer DV, Ursin G, Pike MC | title = Progesterone concentrations--physiologic or pharmacologic? | journal = Fertil. Steril. | volume = 65 | issue = 5 | pages = 1077–8 | date = May 1996 | pmid = 8612843 | doi = 10.1016/s0015-0282(16)58295-8 | doi-access = free }}</ref><ref name="FoidartColin1996">{{cite book |author=J. M. Foidart |author2=C. Colin |author3=X. Denoo |author4=J. D. Desreux |author5=S. Fournier |author6=B. de Lignieres | chapter = Influence of percutaneous administration of estradiol and progesterone on the proliferation of human breast epithelial cells | pages = 329–334 |editor=F. Calvo |editor2=M. Crepin |editor3=H. Magdelenat | title = Breast Cancer Advances in Biology and Therapeutics | publisher = John Libbey Eurotext | year = 1996 | isbn = 9782742001385 | chapter-url = https://books.google.com/books?id=4_Ly983jXMcC&pg=PA329}}</ref><ref name="pmid9591509">{{cite journal | vauthors = Foidart JM, Colin C, Denoo X, Desreux J, Béliard A, Fournier S, de Lignières B | title = Estradiol and progesterone regulate the proliferation of human breast epithelial cells | journal = Fertil. Steril. | volume = 69 | issue = 5 | pages = 963–9 | date = May 1998 | pmid = 9591509 | doi = 10.1016/s0015-0282(98)00042-9 | doi-access = free }}</ref><ref name="pmid31512725"/> However, the concentrations were supraphysiological and the same may not be the case with more physiological concentrations.<ref name="pmid8612843" /><ref name="pmid31512725" /> Cellular proliferation in the breasts is greatest in the [[luteal phase]] of the [[menstrual cycle]], when progesterone levels are highest.<ref name="pmid31512725" />

It has been hypothesized that progestogens may counteract various effects of estrogens in the brain such as [[psychostimulant|stimulatory]] and [[excitatory postsynaptic potential|excitatory]] effects on [[neuronal activity]].<ref name="pmid16112947" /> Progesterone moreover has a special position among progestogens concerning such actions due to its [[inhibitory postsynaptic potential|inhibitory]] neurosteroid metabolites and their [[central depressant]] effects.<ref name="pmid16112947" /> It has been suggested that these actions of progestogens may explain unfavorable effects on [[mood (psychology)|mood]] that have been reported with these medications in some women.<ref name="pmid16112947" /> However, the mutual interactions of estrogens and progestogens in the brain in general are controversial and require more research.<ref name="pmid16112947" />

Progesterone can produce body-wide antiestrogenic effects at very high doses in both women and men via its [[antigonadotropic]] effects and consequent suppression of gonadal estrogen production (see [[#Antigonadotropic effects|below]]).<ref name="pmid16112947" /><ref name="pmid10997774" /> These antigonadotropic effects are mediated by hyperactivation of the PR.<ref name="pmid16112947" /><ref name="pmid10997774" />

===Effects on the HPG axis===

====Antigonadotropic effects====
Progestogens have [[antigonadotropic]] effects at sufficiently high doses via activation of the PR and consequent [[negative feedback]] on and hence suppression of the [[hypothalamic–pituitary–gonadal axis]] (HPG axis).<ref name="pmid10997774">{{cite journal |vauthors=de Lignières B, Silberstein S | title = Pharmacodynamics of oestrogens and progestogens | journal = Cephalalgia: An International Journal of Headache | volume = 20 | issue = 3 | pages = 200–7 |date=April 2000 | pmid = 10997774 | doi = 10.1046/j.1468-2982.2000.00042.x| s2cid = 40392817 | doi-access = free }}</ref> This results in suppression of [[gonadotropin]] [[secretion]] and by extension interference with [[fertility]] and [[gonad]]al [[sex hormone]] [[biosynthesis|production]].<ref name="pmid10997774" /> Progesterone prevents ovulation by suppressing the mid-cycle surge in gonadotropin secretion during the [[menstrual cycle]].<ref name="pmid365398" /><ref name="SperoffFritz2005">{{cite book|author1=Leon Speroff|author2=Marc A. Fritz|title=Clinical Gynecologic Endocrinology and Infertility|url=https://books.google.com/books?id=8sIkqPT2gh4C&pg=PA211|year=2005|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-4795-0|pages=211–|quote=When administered before the estrogen stimulus, or in high doses (achieving a blood level greater than 2 ng/mL), progesterone blocks the midcycle LH surge.}}</ref>

The [[ovulation]]-inhibiting (i.e., contraceptive) dosage of oral crystalline (non-micronized) progesterone in women is 300&nbsp;mg/day or greater.<ref name="pmid945344">{{cite journal | vauthors = Aufrère MB, Benson H | title = Progesterone: an overview and recent advances | journal = J Pharm Sci | volume = 65 | issue = 6 | pages = 783–800 | date = June 1976 | pmid = 945344 | doi = 10.1002/jps.2600650602 | quote = Early studies on its use as an oral contraceptive showed that, at 300 mg/day (5th to 25th day of the menstrual cycle), progesterone was effective in preventing ovulation through four cycles (263). The related effect of larger doses of progesterone on gonadotropin excretion also has been investigated.  Rothchild  (264) found that continuous or intermittent intravenously administered progesterone (100-400 mg/day) for 10 days depressed the total amount of gonadotropin excreted into  the urine. However, Paulsen et al. (265) found that oral progesterone at 1000 mg/day for 87 days did not have a significant effect on urinary gonadotropin excretion. The efficacy of progesterone as an oral contraceptive was never fully tested, because synthetic progestational agents, which were orally effective, were available.}}</ref><ref name="pmid22078182">{{cite journal | vauthors = Endrikat J, Gerlinger C, Richard S, Rosenbaum P, Düsterberg B | title = Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide | journal = Contraception | volume = 84 | issue = 6 | pages = 549–57 | date = December 2011 | pmid = 22078182 | doi = 10.1016/j.contraception.2011.04.009 | quote = Table 1 Publications on ovulation inhibition doses of progestins: Progestin: Progesterone. Reference: Pincus (1956). Method: Urinary pregnanediol. Daily dose (mg): 300.000. Total number of cycles in all subjects: 61. Total number of ovulation in all subjects: 30. % of ovulation in all subjects: 49.}}</ref><ref name="pmid16112947" /><ref name="StoneKupperman1955">{{cite book|last1=Stone|first1=Abraham|last2=Kupperman|first2=Herbert S.
|chapter=The Effects of Progesterone on Ovulation: A Preliminary Report|title=The Fifth International Conference on Planned Parenthood: Theme, Overpopulation and Family Planning: Report of the Proceedings, 24-29 October, 1955, Tokyo, Japan|year=1955|volume=33 |issue=1 |pages=202 |publisher=International Planned Parenthood Federation|doi=10.1016/0093-691x(90)90626-5 |chapter-url=https://www.popline.org/node/472171|quote=The results of testing the effects of progesterone on ovulation in 13 patients at the Margaret Sanger Research Bureau are presented. The patients had normal menstrual cycles and showed clear evidence of ovulation. Each patient was given 1000 [mg] of [oral] progesterone daily during the midperiod for 10 or 12 days during 16 cycles. Ovulation was inhibited in 6 cycles. No disturbance in menstrual rhythm was observed. 3 of 12 patients with longstanding infertility histories became pregnant within 2-4 months after the cessation of progesterone therapy.}}</ref><ref name="BenagianoDiczfalusy1983">{{cite book|author1=S. Beier|author2= B. Düsterberg|author3=M. F. El Etreby|author4=W. Elger|author5=F. Neumann|author6=Y. Nishino|chapter=Toxicology of Hormonal Fertility Regulating Agents|pages=261–346|editor1=Giuseppe Benagiano|editor2=Egon Diczfalusy|title=Endocrine Mechanisms in Fertility Regulation|url=https://books.google.com/books?id=kpNsAAAAMAAJ|year=1983|publisher=Raven Press|isbn=978-0-89004-464-3}}</ref> However, this figure is based on limited clinical data.<ref name="pmid945344" /> In the clinical research in the 1950s that determined this dosage, ovulation inhibition occurred in 50 to 100% of women when assessed via measures including [[urine|urinary]] [[pregnanediol]] [[excretion]], daily [[basal body temperature]]s, [[endometrial biopsy|endometrial biopsies]], and [[vaginal smear]]s.<ref name="pmid22078182" /><ref name="pmid13394044">{{cite journal | vauthors = Pincus G | title = Some effects of progesterone and related compounds upon reproduction and early development in mammals | journal = Acta Endocrinol Suppl (Copenh) | volume = 23 | issue = Suppl 28 | pages = 18–36 | date = 1956 | pmid = 13394044 | doi = 10.1530/acta.0.023S018 }}</ref><ref name="pmid13614060">{{cite journal | vauthors = Pincus G | title = The hormonal control of ovulation and early development | journal = Postgrad Med | volume = 24 | issue = 6 | pages = 654–60 | date = December 1958 | pmid = 13614060 | doi = 10.1080/00325481.1958.11692305 | quote = Table 1: Effects of oral progesterone on three indexes of ovulation: Medication: Progesterone. Number: 69. Mean cycle length: 25.5 ± 0.59. Per cent positive for ovulation by: Basal temperature: 27. Endometrial biopsy: 18. Vaginal smear: 6. [...] we settled on 300 mg. per day [oral progersterone] as a significantly effective [ovulation inhibition] dosage, and this was administered from the fifth day through the twenty-fourth day of the menstrual cycle. [...] We observed each of 33 volunteer subjects during a control, nontreatment cycle and for one to three successive cycles of medication immediately following the control cycle. As indexes of the occurrence of ovulation, daily basal temperatures and vaginal smears were taken, and at the nineteenth to twenty-second day of the cycle an endometrial biopsy. [...] Although we thus demonstrated the ovulation-inhibiting activity of progesterone in normally ovulating women, oral progesterone medication had two disadvantages: ( l) the large daily dosage ( 300 mg.) which presumably would have to be even larger if one sought 100 per cent inhibition1 [...]}}</ref><ref name="Pincus1959">{{cite book|last1=Pincus|first1=Gregory|title=Progestational Agents and the Control of Fertility|volume=17|year=1959|pages=307–324|issn=0083-6729|doi=10.1016/S0083-6729(08)60274-5|quote=Ishikawa et al. (1957) employing the same regime of progesterone administration also observed suppression of ovulation in a proportion of the cases taken to laparotomy. Although sexual intercourse was practised freely by the subjects of our experiments and those of Ishikawa el al., no pregnancies OCcurred. Since ovulation presumably took place in a proportion of cycles, the lack of any pregnancies may be due to chance, but Ishikawa et al. (1957) have presented data indicating that in women receiving oral progesterone the cervical mucus becomes impenetrable to sperm.|series=Vitamins & Hormones|isbn=9780127098173}}</ref><ref name="pmid13477811">{{cite journal | vauthors = Rock J, Garcia CR, Pincus G | title = Synthetic progestins in the normal human menstrual cycle | journal = Recent Prog. Horm. Res. | volume = 13 | pages = 323–39; discussion 339–46 | date = 1957 | pmid = 13477811 | url = https://www.popline.org/node/476326}}</ref> Another study found that ovulation inhibition with 300&nbsp;mg/day oral non-micronized progesterone occurred in a "proportion of the cases" when assessed via [[laparotomy]].<ref name="Pincus1959" /> A third study found that ovulation was inhibited in only 38% of women treated with 1,000&nbsp;mg/day oral non-micronized progesterone.<ref name="StoneKupperman1955" /> A fourth publication stated that even 750 to 1,000&nbsp;mg/day oral non-micronized progesterone had weak effects as evidenced by poor [[thermogenic]] effect, weak [[endometrial]] effect, and lack of production of [[withdrawal bleeding]] in [[amenorrhea|amenorrheic]] women.<ref name="pmid13640942">{{cite journal | vauthors = Tyler ET, Olson HJ | title = Fertility promoting and inhibiting effects of new steroid hormonal substances | journal = J Am Med Assoc | volume = 169 | issue = 16 | pages = 1843–54 | date = April 1959 | pmid = 13640942 | doi = 10.1001/jama.1959.03000330015003 }}</ref><ref name="Haller1968">{{cite book|last1=Haller|first1=J.|title=Die Gestagene|chapter=Die antikonzeptionelle Therapie|year=1968|pages=1125–1178|doi=10.1007/978-3-642-99941-3_8|isbn=978-3-642-99942-0}}</ref> Neumann and colleagues listed the ovulation-inhibiting dosage of oral non-micronized progesterone in women as 300 to 500&nbsp;mg/day or as 400&nbsp;mg/day but provided no other details.<ref name="BenagianoDiczfalusy1983" /><ref name="NeumannElger1977">{{cite journal | vauthors = Neumann FW, Elger Y, Nishino Y, Steinbeck H | title = Probleme der Dosisfindung: Sexualhormone | trans-title = Problems of Dose-Finding: Sex Hormones | journal = Arzneimittel-Forschung | trans-journal = Drug Research | year = 1977 | volume = 27 | pages = 296–318 | issn = 0004-4172 }}</ref><ref name="pmid368741">{{cite journal | vauthors = Neumann F | title = The physiological action of progesterone and the pharmacological effects of progestogens--a short review | journal = Postgrad Med J | volume = 54 | pages = 11–24 | date = 1978 | issue = Suppl 2 | pmid = 368741 }}</ref><ref name="Neumann1987">{{cite book | last1 = Neumann | first1 = F | chapter = Pharmacology and Clinical Uses of Cyproterone Acetate | pages = 132–159 | editor1-last = Furr | editor1-first = BJA | editor2-last = Wakeling | editor2-first = AE | title = Pharmacology and Clinical Uses of Inhibitors of Hormone Secretion and Action | date = 1987 | location = London | publisher = Baillière Tindall | isbn = 9780702011368 | ol = OL20778637M | oclc = 925173670 | chapter-url = https://archive.org/details/pharmacologyclin0000unse/page/132/mode/1up}}</ref>

In a study of a progesterone vaginal ring alone or in combination with estradiol that released 1.5 to 3&nbsp;mg/day progesterone and achieved mean progesterone levels varying between 0.7 and 1.6&nbsp;ng/mL (mean 0.9&nbsp;ng/mL) during anovulatory cycles, ovulation occurred in 18 of 30 (60%) menstrual cycles.<ref name="pmid729823">{{cite journal | vauthors = Victor A, Jackanicz TM, Johansson ED | title = Vaginal progesterone for contraception | journal = Fertil. Steril. | volume = 30 | issue = 6 | pages = 631–5 | date = December 1978 | pmid = 729823 | doi = 10.1016/S0015-0282(16)43688-5 | doi-access = free }}</ref> A study of a vaginal progesterone ring that released almost 10&nbsp;mg/day progesterone and maintained mean progesterone levels of 4.4&nbsp;ng/mL (range 2.4–6.5&nbsp;ng/mL) found that ovulation was inhibited in some but not all women.<ref name="pmid3320572">{{cite journal | vauthors = Croxatto HB, Díaz S | title = The place of progesterone in human contraception | journal = J. Steroid Biochem. | volume = 27 | issue = 4–6 | pages = 991–4 | date = 1987 | pmid = 3320572 | doi = 10.1016/0022-4731(87)90179-8 }}</ref><ref name="pmid452876">{{cite journal | vauthors = Bäckström T, von Schoultz B, Toivonen J | title = Plasma progesterone concentrations after administration via intravaginal rings | journal = Acta Obstet Gynecol Scand | volume = 58 | issue = 2 | pages = 211–2 | date = 1979 | pmid = 452876 | doi = 10.3109/00016347909154585 | s2cid = 34956863 }}</ref> In another study, a progesterone vaginal ring that released about 10&nbsp;mg/day progesterone and produced progesterone levels of around 4&nbsp;ng/mL (range 3–5.2&nbsp;ng/mL) resulted in ovulation occurring in 25% of treated breastfeeding women compared to a rate of 56% in a control group of breastfeeding women.<ref name="pmid1835650">{{cite journal | vauthors = Shaaban MM | title = Contraception with progestogens and progesterone during lactation | journal = J. Steroid Biochem. Mol. Biol. | volume = 40 | issue = 4–6 | pages = 705–10 | date = 1991 | pmid = 1835650 | doi = 10.1016/0960-0760(91)90294-F | s2cid = 25152238 }}</ref> A study in [[rhesus monkey]]s found that a vaginal ring delivering 0.235 or 1.77&nbsp;mg/day progesterone inhibited ovulation in all monkeys at the higher dose and in a proportion of monkeys at the lower dose.<ref name="pmid29790373">{{cite journal | vauthors = Sitruk-Ware R | title = Non-clinical studies of progesterone | journal = Climacteric | volume = 21 | issue = 4 | pages = 315–320 | date = August 2018 | pmid = 29790373 | pmc = 6281289 | doi = 10.1080/13697137.2018.1463982 }}</ref><ref name="pmid116799">{{cite journal | vauthors = Wadsworth PF, Heywood R, Allen DG, Hossack DJ, Sortwell RJ, Walton RM | title = Treatment of rhesus monkeys (Macaca mulatta) with intravaginal rings impregnated with either progesterone or norethisterone | journal = Contraception | volume = 20 | issue = 4 | pages = 339–51 | date = October 1979 | pmid = 116799 | doi = 10.1016/s0010-7824(79)80044-x }}</ref> A dose of progesterone of 5 to 10&nbsp;mg/day by intramuscular injection has been found to prevent ovulation in women and has been considered effective as a [[progestogen-only injectable contraceptive]].<ref name="Brotherton1976a">{{cite book|author=Janet Brotherton|title=Sex Hormone Pharmacology|url=https://books.google.com/books?id=zt5sAAAAMAAJ|year=1976|publisher=Academic Press|isbn=978-0-12-137250-7|pages=220, 341–342}}</ref><ref name="TaubertKuhl1981">{{cite book | author1 = Hans-Dieter Taubert | author2 = Herbert Kuhl | title = Kontrazeption mit Hormonen | trans-title = Contraception with Hormones | edition = 1 | year = 1981 | publisher = Goerg Thieme Verlag | location = Stuttgart/New York | page = 86 | isbn = 9783136088012 | oclc = 612130880 | url = | quote = Daily intramuscular injection of 5 to 10 mg of progesterone from days 7 to 23 suppresses LH and FSH and prevents ovulation (569). Progestogens also lead to a reduction in gonadotropin levels.}}</ref><ref name="pmid4779738">{{cite journal | vauthors = Netter A, Gorins A, Thomas K, Cohen M, Joubinaux J | title = Blocage du pic d'ovulation de LH et de FSH par la progesterone à faibles doses chez la femme | trans-title = Blockade of LH and FSH peaks by low doses of exogenous progesterone in the human female | language = fr | journal = Ann. Endocrinol. (Paris) | volume = 34 | issue = 4 | pages = 430–5 | date = 1973 | issn = 0003-4266 | pmid = 4779738 }}</ref>

Short-term therapy with 300&nbsp;mg/day oral progesterone had no effect on [[luteinizing hormone]] pulse frequency in women.<ref name="LoboStanczyk1994">{{cite journal|last1=Lobo|first1=Rogerio A.|last2=Stanczyk|first2=Frank Z.|title=New knowledge in the physiology of hormonal contraceptives|journal=American Journal of Obstetrics and Gynecology|volume=170|issue=5|year=1994|pages=1499–1507|issn=0002-9378|doi=10.1016/S0002-9378(12)91807-4|pmid=8178898}}</ref> Treatment with a high dosage of oral progesterone of 100&nbsp;mg four times per day (or 400&nbsp;mg/day total) in men for 10&nbsp;days did not cause any change in [[testosterone]] levels, suggesting that oral progesterone has little or no antigonadotropic effect in males at typical clinical dosages.<ref name="pmid17924777" /><ref name="pmid8300009">{{cite journal | vauthors = Tollan A, Oian P, Kjeldsen SE, Eide I, Maltau JM | title = Progesterone reduces sympathetic tone without changing blood pressure or fluid balance in men | journal = Gynecol. Obstet. Invest. | volume = 36 | issue = 4 | pages = 234–8 | date = 1993 | pmid = 8300009 | doi = 10.1159/000292636 }}</ref> In addition, a study found that administration of 1,000&nbsp;mg/day oral progesterone for 3&nbsp;months had no significant effect on [[urine|urinary]] gonadotropin [[excretion]].<ref name="pmid945344" /> On the other hand, a single 50&nbsp;mg intramuscular injection of progesterone, which is associated with high progesterone levels of approximately 50&nbsp;ng/mL (or early- to mid-pregnancy levels),<ref name="Drugs.com">{{citation | url = https://www.drugs.com/pro/progesterone.html | title = Progesterone - Drugs.com | access-date = 2015-08-23}}</ref><ref name="Josimovich2013">{{cite book | first = J.B. | last = Josimovich | name-list-style = vanc | title = Gynecologic Endocrinology | url = https://books.google.com/books?id=9vv2BwAAQBAJ&pg=PA25|date=11 November 2013|publisher=Springer Science & Business Media|isbn=978-1-4613-2157-6|pages=9, 25–29, 139}}</ref><ref name="StraussBarbieri2009">{{cite book|author1=Jerome Frank Strauss|author2=Robert L. Barbieri|title=Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management|url=https://books.google.com/books?id=NudwnhxY8kYC&pg=PA807|year=2009|publisher=Elsevier Health Sciences|isbn=978-1-4160-4907-4|pages=807–}}</ref> resulted in substantial (50–60%) suppression of [[luteinizing hormone]], [[follicle-stimulating hormone]], and testosterone levels in men.<ref name="pmid12641635">{{cite journal | vauthors = Brady BM, Anderson RA, Kinniburgh D, Baird DT | title = Demonstration of progesterone receptor-mediated gonadotrophin suppression in the human male | journal = Clin. Endocrinol. (Oxf) | volume = 58 | issue = 4 | pages = 506–12 | year = 2003 | pmid = 12641635 | doi = 10.1046/j.1365-2265.2003.01751.x | s2cid = 12567639 | doi-access = free }}</ref><ref name="pmid14400846">{{cite journal | vauthors = Heller CG, Moore DJ, Paulsen CA, Nelson WO, Laidlaw WM | title = Effects of progesterone and synthetic progestins on the reproductive physiology of normal men | journal = Fed. Proc. | volume = 18 | pages = 1057–65 | date = December 1959 | pmid = 14400846 | url = https://www.popline.org/node/472874 | access-date = 2018-12-18 | archive-url = https://web.archive.org/web/20181218193350/https://www.popline.org/node/472874 | archive-date = 2018-12-18 | url-status = dead }}</ref> Similarly, continuous or intermittent [[intravenous injection]]s of 100 to 400&nbsp;mg/day progesterone for 10&nbsp;days significantly decreased urinary gonadotropin excretion.<ref name="pmid945344" /><ref name="pmid13428841">{{cite journal | vauthors = Rothchild I | title = Effect of large doses of intravenously administered progesterone on gonadotropin excretion in the human female | journal = J. Clin. Endocrinol. Metab. | volume = 17 | issue = 6 | pages = 754–9 | date = June 1957 | pmid = 13428841 | doi = 10.1210/jcem-17-6-754 | doi-access = free }}</ref> Progestogens in general are able to suppress gonadal testosterone production in men by a maximum of about 70 to 80% or to just above [[castration|castrate]] levels when used at sufficiently high doses.<ref name="WeinKavoussi2011">{{cite book| first1 = Alan J. | last1 = Wein | first2 = Louis R. | last2 = Kavoussi | first3 = Andrew C. | last3 = Novick | first4 = Alan W. | last4 = Partin | first5 =  Craig A. | last5 = Peters | name-list-style = vanc | title = Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set|url=https://books.google.com/books?id=fu3BBwAAQBAJ&pg=PA2938|date=25 August 2011|publisher=Elsevier Health Sciences|isbn=978-1-4160-6911-9|pages=2938–}}</ref><ref name="pmid519881">{{cite journal | vauthors = Kjeld JM, Puah CM, Kaufman B, Loizou S, Vlotides J, Gwee HM, Kahn F, Sood R, Joplin GF | title = Effects of norgestrel and ethinyloestradiol ingestion on serum levels of sex hormones and gonadotrophins in men | journal = Clinical Endocrinology | volume = 11 | issue = 5 | pages = 497–504 | year = 1979 | pmid = 519881 | doi = 10.1111/j.1365-2265.1979.tb03102.x| s2cid = 5836155 }}</ref>

A study using 50&nbsp;mg/day progesterone by intramuscular injection in five men found that the medication produced [[azoospermia]] or severe [[oligozoospermia]] in all within 10&nbsp;weeks, suppressed [[libido]], [[erectile function]], and [[ejaculate]] volume to minimal levels, produced slight [[gynecomastia]] in two of the men, moderately decreased [[testicular size]], and impaired [[testicle|testicular]] [[morphology (biology)|morphology]].<ref name="Brotherton1976a" /><ref name="NeumannDiallo1976">{{cite journal|last1=Neumann|first1=F.|last2=Diallo|first2=F.A.|last3=Hasan|first3=S.H.|last4=Schenck|first4=B.|last5=Traore|first5=I.|title=The Influence of Pharmaceutical Compounds on Male Fertility*|journal=Andrologia|volume=8|issue=3|year=1976|pages=203–235|issn=0303-4569|doi=10.1111/j.1439-0272.1976.tb02137.x|pmid=793446|s2cid=24859886|doi-access=free}}</ref><ref name="pmid13583821">{{cite journal | vauthors = Heller CG, Laidlaw WM, Harvey HT, Nelson WO | title = Effects of progestational compounds on the reproductive processes of the human male | journal = Ann. N. Y. Acad. Sci. | volume = 71 | issue = 5 | pages = 649–65 | date = July 1958 | pmid = 13583821 | doi = 10.1111/j.1749-6632.1958.tb54641.x | s2cid = 32637425 }}</ref><ref name="pmid14400846"/><ref name="Neumann1985">{{cite book|last1=Neumann|first1=F.|chapter=Steroidal contraception — experimental background |title=Future Aspects in Contraception|year=1985|pages=129–144|doi=10.1007/978-94-009-4910-2_2|isbn=978-94-010-8675-2}}</ref><ref name="Bain1980">{{cite book|last1=Bain|first1=J.|chapter=Androgen-Progestin Combinations: Clinical Trials |title=Regulation of Male Fertility|year=1980|pages=85–91|doi=10.1007/978-94-009-8875-0_9|isbn=978-94-009-8877-4}}</ref><ref name="PetryPfizenmayer1973">{{cite journal|last1=Petry|first1=R.|last2=Pfizenmayer|first2=K.|title=Möglichkeiten der medikamentösen Fertilitätshemmung beim Mann|journal=Deutsche Medizinische Wochenschrift|volume=98|issue=38|year=1973|pages=1775–1779|issn=0012-0472|doi=10.1055/s-0028-1107127|pmid=4742513}}</ref> Upon discontinuation, [[sperm count]]s returned to normal in the men within 14 to 17&nbsp;weeks.<ref name="Brotherton1976a" /><ref name="NeumannDiallo1976" /><ref name="pmid14400846" /><ref name="Neumann1985" /><ref name="PetryPfizenmayer1973" /> <span id="RectalProgesteroneInMen"> In another study, 100&nbsp;mg </span> [[rectal administration|rectal]] [[suppository|suppositories]] of progesterone given five times per day for 9&nbsp;days resulted in progesterone levels of 5.5 to 29&nbsp;ng/mL and suppressed circulating [[testosterone]] and [[growth hormone]] levels by about 50% in men, but did not affect libido or erectile potency with this short duration of therapy.<ref name="Brotherton1976a" /><ref name="pmid5558416">{{cite journal |vauthors=Sundsfjord JA, Aakvaag A, Norman N |title=Reduced plasma testosterone and LH in young men during progesterone administration |journal=J. Reprod. Fertil. |volume=26 |issue=2 |pages=263–5 |date=August 1971 |pmid=5558416 |doi=10.1530/jrf.0.0260263 |doi-access=free}}</ref>

====Progonadotropic effects====
Progesterone can have [[progonadotropic]] effects under certain circumstances.<ref name="pmid365398">{{cite journal | vauthors = Shaw RW | title = Neuroendocrinology of the menstrual cycle in humans | journal = Clin Endocrinol Metab | volume = 7 | issue = 3 | pages = 531–59 | date = November 1978 | pmid = 365398 | doi = 10.1016/S0300-595X(78)80008-5 }}</ref>

===Neurosteroid effects===
Progesterone, through the actions of [[neurosteroid]] [[active metabolite]]s such as [[allopregnanolone]] and [[pregnanolone]], is a potent [[positive allosteric modulator]] of the [[GABAA receptor|GABA<sub>A</sub> receptor]], the major signaling receptor of the [[inhibitory postsynaptic potential|inhibitory]] [[neurotransmitter]] [[γ-aminobutyric acid]] (GABA).<ref name="pmid1347506" /> It can produce [[sedative]], [[hypnotic]], [[anxiolytic]], [[euphoric]], [[cognitive impairment|cognitive-]], [[memory impairment|memory-]], and [[motor impairment|motor-impairing]], [[anticonvulsant]], and even [[anesthetic]] effects with formation of sufficiently high concentrations of its neurosteroid metabolites and consequent GABA<sub>A</sub> receptor potentiation in the brain.<ref name="pmid17924777" /><ref name="Wang-ChengNeuner2007" /><ref name="BergemannRiecher-Rössler2005" /><ref name="pmid23978486" /> These actions and effects are characteristically similar to those of other [[GABAA receptor positive allosteric modulator|GABA<sub>A</sub> receptor positive allosteric modulator]]s like [[alcohol (drug)|alcohol]], [[barbiturate]]s, and [[benzodiazepine]]s.<ref name="pmid23978486" />

Similarly to other GABA<sub>A</sub> receptor positive allosteric modulators like alcohol, barbiturates, and benzodiazepines, [[drug tolerance|tolerance]] has been found to develop with exposure to increased levels of allopregnanolone and related inhibitory neurosteroids.<ref name="pmid20883478">{{cite journal | vauthors = Turkmen S, Backstrom T, Wahlstrom G, Andreen L, Johansson IM | title = Tolerance to allopregnanolone with focus on the GABA-A receptor | journal = Br. J. Pharmacol. | volume = 162 | issue = 2 | pages = 311–27 | year = 2011 | pmid = 20883478 | pmc = 3031054 | doi = 10.1111/j.1476-5381.2010.01059.x }}</ref><ref name="pmid11744076">{{cite journal | vauthors = Follesa P, Concas A, Porcu P, Sanna E, Serra M, Mostallino MC, Purdy RH, Biggio G | title = Role of allopregnanolone in regulation of GABA(A) receptor plasticity during long-term exposure to and withdrawal from progesterone | journal = Brain Res. Brain Res. Rev. | volume = 37 | issue = 1–3 | pages = 81–90 | year = 2001 | pmid = 11744076 | doi = 10.1016/s0165-0173(01)00125-4| s2cid = 362309 }}</ref> This includes [[downregulation and upregulation|downregulation]] and [[desensitization (receptor)|desensitization]] of the GABA<sub>A</sub> receptor, reduced effects of allopregnanolone and other GABA<sub>A</sub> receptor activators (e.g., {{abbrlink|GABA|γ-aminobutyric acid}} and benzodiazepines), and [[rebound effect|rebound]] or [[drug withdrawal|withdrawal]] effects upon falls in allopregnanolone levels.<ref name="pmid20883478" /><ref name="pmid11744076" /> In addition, changes in allopregnanolone levels have been implicated in adverse neuropsychiatric effects associated with the [[menstrual cycle]] (e.g., [[dysphoria]], [[depression (mood)|depression]], [[anxiety]], [[irritability]]) and [[postpartum period]] (e.g., [[postpartum depression]]), as well as in [[catamenial epilepsy]] ([[seizure]]s).<ref name="pmid24846476">{{cite journal | vauthors = Schiller CE, Schmidt PJ, Rubinow DR | title = Allopregnanolone as a mediator of affective switching in reproductive mood disorders | journal = Psychopharmacology | volume = 231 | issue = 17 | pages = 3557–67 | year = 2014 | pmid = 24846476 | pmc = 4135022 | doi = 10.1007/s00213-014-3599-x }}</ref><ref name="pmid21600269">{{cite journal | vauthors = Bäckström T, Haage D, Löfgren M, Johansson IM, Strömberg J, Nyberg S, Andréen L, Ossewaarde L, van Wingen GA, Turkmen S, Bengtsson SK | title = Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons | journal = Neuroscience | volume = 191 | pages = 46–54 | year = 2011 | pmid = 21600269 | doi = 10.1016/j.neuroscience.2011.03.061 | s2cid = 38928854 }}</ref> Low and high levels of allopregnanolone seem to have a neutral effect on mood, whereas moderate levels have a negative effect, which may underlie the symptoms of [[premenstrual syndrome]] and [[premenstrual dysphoric disorder]] that are observed in 30 to 40% of premenopausal women.<ref name="pmid24846476" /><ref name="pmid21600269" /><ref name="pmid15471618">{{cite journal | vauthors = Andréen L, Sundström-Poromaa I, Bixo M, Andersson A, Nyberg S, Bäckström T | title = Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone | journal = Psychoneuroendocrinology | volume = 30 | issue = 2 | pages = 212–24 | date = February 2005 | pmid = 15471618 | doi = 10.1016/j.psyneuen.2004.07.003 | s2cid = 29760633 }}</ref> This U-shaped effect on mood appears to be a common property of GABA<sub>A</sub> receptor positive allosteric modulators.<ref name="pmid24846476" /><ref name="pmid21600269" />

==See also==
* [[Pharmacokinetics of progesterone]]
* [[Pharmacodynamics of estradiol]]
* [[Pharmacokinetics of estradiol]]

==References==
{{Reflist}}

==Further reading==
* {{cite journal | vauthors = Sitruk-Ware R, Bricaire C, De Lignieres B, Yaneva H, Mauvais-Jarvis P | title = Oral micronized progesterone. Bioavailability pharmacokinetics, pharmacological and therapeutic implications--a review | journal = Contraception | volume = 36 | issue = 4 | pages = 373–402 | date = October 1987 | pmid = 3327648 | doi = 10.1016/0010-7824(87)90088-6 }}
* {{cite journal | vauthors = Simon JA | title = Micronized progesterone: vaginal and oral uses | journal = Clinical Obstetrics and Gynecology | volume = 38 | issue = 4 | pages = 902–14 | date = December 1995 | pmid = 8616985 | doi = 10.1097/00003081-199538040-00024}}
* {{cite journal | vauthors = Ruan X, Mueck AO | title = Systemic progesterone therapy--oral, vaginal, injections and even transdermal? | journal = Maturitas | volume = 79 | issue = 3 | pages = 248–55 | date = November 2014 | pmid = 25113944 | doi = 10.1016/j.maturitas.2014.07.009 }}

{{Progesterone}}
{{Progestogens and antiprogestogens}}
{{Mineralocorticoids and antimineralocorticoids}}
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[[Category:Medication pharmacology|progesterone]]
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