View source for Progesterone

{{Short description|Sex hormone}}
{{Use dmy dates|date=December 2023}}
{{About|progesterone as a hormone|its use as a medication|progesterone (medication)}}
{{cs1 config|name-list-style=vanc}}
{{Chembox
<!-- Images -->| Name           =
| ImageFile1     = Progesterone.svg
| ImageClass1    = skin-invert
| ImageSize1     = 225px
| ImageAlt1      = The chemical structure of progesterone
| ImageFile2     = Progesterone-3D-balls.png
| ImageClass2    = bg-transparent
| ImageSize2     = 225px
| ImageAlt2      = A ball-and-stick model of progesterone.
<!-- Names -->| IUPACName      = Pregn-4-ene-3,20-dione<ref name="Adler-2012">{{cite book | vauthors = Adler N, Pfaff D, Goy RW | title = Handbook of Behavioral Neurobiology Volume 7 Reproduction | date = 6 December 2012 | publisher = Plenum Press | location = New York | isbn = 978-1-4684-4834-4 | page = 189 | edition = 1st | url = https://books.google.com/books?id=MoDrBwAAQBAJ&q=pregn-4-ene-3,20-dione;+abbreviated+as+P4&pg=PA189 | access-date = 4 July 2015 | archive-date = 14 January 2023 | archive-url = https://web.archive.org/web/20230114024946/https://books.google.com/books?id=MoDrBwAAQBAJ&q=pregn-4-ene-3,20-dione;+abbreviated+as+P4&pg=PA189 | url-status = live }}</ref><ref name="ChEBI-17026">{{cite web|title=progesterone (CHEBI:17026)|url=http://www.ebi.ac.uk/chebi/searchId.do;jsessionid=309FCC7D184C0AD58410071F3F163155?chebiId=17026&structureView=applet&viewTermLineage=|website=ChEBI|publisher=European Molecular Biology Laboratory-EBI|access-date=4 July 2015|archive-date=20 March 2016|archive-url=https://web.archive.org/web/20160320211423/http://www.ebi.ac.uk/chebi/searchId.do;jsessionid=309FCC7D184C0AD58410071F3F163155?chebiId=17026&structureView=applet&viewTermLineage=|url-status=live}}</ref>
| SystematicName = (1''S'',3a''S'',3b''S'',9a''R'',9b''S'',11a''S'')-1-Acetyl-9a,11a-dimethyl-1,2,3,3a,3b,4,5,8,9,9a,9b,10,11,11a-tetradecahydro-7''H''-cyclopenta[''a'']phenanthren-7-one
| OtherNames     = P4;<ref name="James2015" /> Pregnenedione
| Verifiedfields = changed
| Watchedfields  = changed
| verifiedrevid  = 444066687
<!-- Sections -->| Section1       = {{Chembox Identifiers
| CASNo_Ref = {{cascite|correct|??}}
| CASNo = 57-83-0
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 17026
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 103
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5773
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00396
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = C00410
| PubChem = 5994
| SMILES = CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CCC4=CC(=O)CC[C@]34C)C
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = InChI=1S/C21H30O2/c1-13(22)17-6-7-18-16-5-4-14-12-15(23)8-10-20(14,2)19(16)9-11-21(17,18)3/h12,16-19H,4-11H2,1-3H3/t16-,17+,18-,19-,20-,21+/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = RJKFOVLPORLFTN-LEKSSAKUSA-N
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 4G7DS2Q64Y
  }}
| Section2       = {{Chembox Properties
| C=21 | H=30 | O=2
| MolarMass = 314.469 g/mol
| Appearance =
| Density = 1.171
| MeltingPt = 126
| BoilingPt =
| Solubility =
| LogP = 4.04<ref name="chemsrc">{{cite web|url=https://www.chemsrc.com/en/cas/57-83-0_1068061.html|title=Progesterone_msds|access-date=19 April 2018|archive-date=12 February 2021|archive-url=https://web.archive.org/web/20210212022152/https://www.chemsrc.com/en/cas/57-83-0_1068061.html|url-status=live}}</ref>
  }}
| Section3       = {{Chembox Hazards
| MainHazards =
| FlashPt =
| AutoignitionPt =
  }}
| Section4       =
| Section5       =
| Section6       = {{Chembox Pharmacology
| ATCvet =
| ATCCode_prefix = G03
| ATCCode_suffix = DA04
| ATC_Supplemental =
| AdminRoutes = [[By mouth]], [[topical]]/[[transdermal]], [[Intravaginal administration|vaginal]], [[intramuscular injection]], [[subcutaneous injection]], [[subcutaneous implant]]
| Bioavail = {{abbr|OMP|oral micronized progesterone}}: <10%<ref name="pmid12215716" /><ref name="pmid8513955" />
| Excretion = [[Renal]]
| HalfLife = {{abbr|OMP|oral micronized progesterone}}: 16–18 hours<ref name="pmid12215716" /><ref name="pmid8513955" /><ref name="Zutshi-2005">{{cite book | vauthors = Zutshi V, Rathore AM, Sharma K | title = Hormones in Obstetrics and Gynaecology | url = https://books.google.com/books?id=IBxBbaDjXw0C&pg=PA74 | date = 1 January 2005 | publisher = Jaypee Brothers Publishers | isbn = 978-81-8061-427-9 | page = 74 }}{{Dead link|date=February 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><br />{{abbr|IM|Intramuscular}}: 22–26 hours<ref name="pmid8513955" /><ref name="pmid26342177">{{cite journal | vauthors = Cometti B | title = Pharmaceutical and clinical development of a novel progesterone formulation | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 94 | issue = Suppl 161 | pages = 28–37 | date = November 2015 | pmid = 26342177 | doi = 10.1111/aogs.12765 | s2cid = 31974637 | doi-access = free }}</ref><br />{{abbr|SC|Subcutaneous}}: 13–18 hours<ref name="pmid26342177" />
| Metabolism = [[Hepatic]] ([[CYP2C19]], [[CYP3A4]], [[CYP2C9]], [[5α-reductase]], {{abbrlink|3α-HSD|3α-hydroxysteroid dehydrogenase}}, [[17α-hydroxylase]], [[21-hydroxylase]], {{abbrlink|20α-HSD|20α-hydroxysteroid dehydrogenase}})<ref name="pmid9328296">{{cite journal | vauthors = Yamazaki H, Shimada T | title = Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes | journal = Archives of Biochemistry and Biophysics | volume = 346 | issue = 1 | pages = 161–169 | date = October 1997 | pmid = 9328296 | doi = 10.1006/abbi.1997.0302 }}</ref><ref name="McKayWalters2013">{{cite book | vauthors = McKay GA, Walters MR | title = Lecture Notes: Clinical Pharmacology and Therapeutics | url = https://books.google.com/books?id=OGOqcfN_Cc8C&pg=PT33 | date = 6 February 2013 | publisher = John Wiley & Sons | isbn = 978-1-118-34489-7 | page = 33 | access-date = 27 June 2015 | archive-date = 14 January 2023 | archive-url = https://web.archive.org/web/20230114024939/https://books.google.com/books?id=OGOqcfN_Cc8C&pg=PT33 | url-status = live }}</ref>
| ProteinBound = • [[Human serum albumin|Albumin]]: 80%<br />• [[Transcortin|CBG]]: 18%<br />• [[SHBG]]: <1%<br />• Free: 1–2%<ref name="FritzSperoff2012">{{cite book | vauthors = Fritz MA, Speroff L | title = Clinical Gynecologic Endocrinology and Infertility | url = https://books.google.com/books?id=KZLubBxJEwEC&pg=PA44 | date = 28 March 2012 | publisher = Lippincott Williams & Wilkins | isbn = 978-1-4511-4847-3 | pages = 44– }}</ref><ref name="MarshallD.2008">{{cite book | vauthors = Marshall WJ, Bangert SK | title = Clinical Chemistry | url = https://books.google.com/books?id=Gjc704GR5YEC&pg=PA192 | year = 2008 | publisher = Elsevier Health Sciences | isbn = 978-0-7234-3455-9 | pages = 192– | access-date = 5 October 2016 | archive-date = 14 January 2023 | archive-url = https://web.archive.org/web/20230114024953/https://books.google.com/books?id=Gjc704GR5YEC&pg=PA192 | url-status = live }}</ref>
  }}
}}

'''Progesterone''' ({{IPAc-en|p|r|oʊ|ˈ|dʒ|ɛ|s|t|ər|oʊ|n|audio=LL-Q1860 (eng)-Flame, not lame-progesterone.wav}}; '''P4''') is an [[endogenous]] [[steroid]] and [[progestogen]] [[sex hormone]] involved in the [[menstrual cycle]], [[pregnancy]], and [[embryogenesis]] of humans and other species.<ref name="James2015" /><ref name="KingBrucker2010" /> It belongs to a group of steroid hormones called the [[progestogen]]s<ref name="KingBrucker2010" /> and is the major progestogen in the body. Progesterone has a variety of important functions in the body. It is also a crucial [[metabolic intermediate]] in the production of other endogenous [[steroid]]s, including the [[sex hormone]]s and the [[corticosteroid]]s, and plays an important role in brain function as 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 = 605–612 | year = 2000 | pmid = 11108866 | doi = 10.1016/s0039-128x(00)00173-2 | s2cid = 14952168 }}</ref>

In addition to its role as a natural hormone, progesterone is also used as a medication, such as in combination with [[estrogen]] for [[contraception]], to reduce the risk of [[Uterine cancer|uterine]] or [[cervical cancer]], in [[hormone replacement therapy]], and in [[feminizing hormone therapy]].<ref name="pmid30608551">{{cite journal | vauthors = Prior JC | title = Progesterone Is Important for Transgender Women's Therapy-Applying Evidence for the Benefits of Progesterone in Ciswomen | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 104 | issue = 4 | pages = 1181–1186 | date = April 2019 | pmid = 30608551 | doi = 10.1210/jc.2018-01777 | quote = Evidence has accrued that normal progesterone (and ovulation), as well as physiological estradiol levels, is necessary during ciswomen's premenopausal menstrual cycles for current fertility and long-term health; transgender women may require progesterone therapy and similar potential physiological benefits | s2cid = 58620122 | doi-access = free }}</ref> It was first prescribed in 1934.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=978-3-527-60749-5 |page=47X |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA47X }}</ref>
{{TOC limit}}

==Biological activity==
{{See also|Pharmacodynamics of progesterone#Mechanism of action}}

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

Through its [[neurosteroid]] [[active metabolite]]s, such as [[5α-dihydroprogesterone]] and [[allopregnanolone]], progesterone acts indirectly as a [[positive allosteric modulator]] of the [[GABAA receptor|GABA<sub>A</sub> receptor]].<ref name="pmid1347506">{{cite journal | vauthors = Paul SM, Purdy RH | title = Neuroactive steroids | journal = FASEB Journal | volume = 6 | issue = 6 | pages = 2311–2322 | date = March 1992 | pmid = 1347506 | doi = 10.1096/fasebj.6.6.1347506 | bibcode = 1992FASEJ...6.2311P | s2cid = 221753076 | doi-access = free }}</ref>

Progesterone and some of its metabolites, such as [[5β-dihydroprogesterone]], are agonists of the [[pregnane X receptor]] (PXR),<ref name="pmid12372848">{{cite journal | vauthors = Kliewer SA, Goodwin B, Willson TM | title = The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism | journal = Endocrine Reviews | volume = 23 | issue = 5 | pages = 687–702 | date = October 2002 | pmid = 12372848 | doi = 10.1210/er.2001-0038 | doi-access = free }}</ref> albeit weakly so ([[EC50|EC<sub>50</sub>]] >10&nbsp;μM).<ref name="pmid9727070">{{cite journal | vauthors = Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA | title = The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions | journal = The Journal of Clinical Investigation | volume = 102 | issue = 5 | pages = 1016–1023 | date = September 1998 | pmid = 9727070 | pmc = 508967 | doi = 10.1172/JCI3703 | bibcode = 1998JCliI.102.1016L }}</ref> In accordance, progesterone [[Enzyme inducer|induces]] several [[hepatic]] [[cytochrome P450]] [[enzyme]]s,<ref name="Meanwell2014">{{cite book|vauthors=Meanwell NA|title=Tactics in Contemporary Drug Design|url=https://books.google.com/books?id=j2HEBQAAQBAJ&pg=PA161|date=8 December 2014|publisher=Springer|isbn=978-3-642-55041-6|pages=161–|access-date=1 February 2016|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114024941/https://books.google.com/books?id=j2HEBQAAQBAJ&pg=PA161|url-status=live}}</ref> such as [[CYP3A4]],<ref name="LegatoBilezikian2004">{{cite book|vauthors=Legato MJ, Bilezikian JP|title=Principles of Gender-specific Medicine|url=https://books.google.com/books?id=TiLxa8nPbLkC&pg=PA146|year=2004|publisher=Gulf Professional Publishing|isbn=978-0-12-440906-4|pages=146–|access-date=1 February 2016|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114024928/https://books.google.com/books?id=TiLxa8nPbLkC&pg=PA146|url-status=live}}</ref><ref name="LemkeWilliams2012 p164">{{cite book | vauthors = Williams DA | chapter = Drug Metabolism | veditors = Lemke TL, Williams DA | title = Foye's Principles of Medicinal Chemistry | chapter-url = https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA164|date=24 January 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-345-0|page=164}}</ref> especially during [[pregnancy]] when concentrations are much higher than usual.<ref name="ScholarlyEditions2013">{{cite book|title=Estrogens—Advances in Research and Application: 2013 Edition: ScholarlyBrief|url=https://books.google.com/books?id=9WdGK_3ujQMC&pg=PA4|date=21 June 2013|publisher=ScholarlyEditions|isbn=978-1-4816-7550-5|pages=4–|access-date=1 February 2016|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114024941/https://books.google.com/books?id=9WdGK_3ujQMC&pg=PA4|url-status=live}}</ref> Perimenopausal women have been found to have greater CYP3A4 activity relative to men and postmenopausal women, and it has been inferred that this may be due to the higher progesterone levels present in perimenopausal women.<ref name="LegatoBilezikian2004" />

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

==Biological function==
[[File:Estradiol and progesterone % changes across the menstrual cycle.tif|class=skin-invert-image|thumb|upright=1.55|During the menstrual cycle, levels of estradiol (an estrogen) vary by 200 percent. Levels of progesterone vary by over 1200 percent.<ref name="Prior-2020">{{cite journal | vauthors = Prior JC | title = Women's reproductive system as balanced estradiol and progesterone actions—A revolutionary, paradigm-shifting concept in women's health | journal = Drug Discovery Today: Disease Models | volume = 32 |issue=Part B | year = 2020 | pages = 31–40 | doi = 10.1016/j.ddmod.2020.11.005 | doi-access = free }}</ref>]]

===Hormonal interactions===
Progesterone has a number of physiological effects that are amplified in the presence of [[estrogen]]s. Estrogens through [[estrogen receptor]]s (ERs) induce or [[upregulate]] the [[Gene expression|expression]] of the PR.<ref name="pmid2328727">{{cite journal | vauthors = Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, Chambon P | title = Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B | journal = The EMBO Journal | volume = 9 | issue = 5 | pages = 1603–1614 | date = May 1990 | pmid = 2328727 | pmc = 551856 | doi = 10.1002/j.1460-2075.1990.tb08280.x | bibcode = 1990EMBO....9.1603K }}</ref> One example of this is in [[breast tissue]], where estrogens allow progesterone to mediate [[lobuloalveolar]] development.<ref name="pmid16917139">{{cite journal | vauthors = Cline JM, Wood CE | title = Hormonal effects on the mammary gland of postmenopausal nonhuman primates | journal = Breast Disease | volume = 24 | pages = 59–70 | date = 1 January 2006 | pmid = 16917139 | doi = 10.3233/bd-2006-24105 | publisher = IOS Press | isbn = 978-1-58603-653-9 | veditors = Hallam SZ, Osuch JR | url = https://books.google.com/books?id=wGaKtDw50K0C&pg=PA61 | url-access = subscription | access-date = 2 August 2023 | archive-date = 27 November 2023 | archive-url = https://web.archive.org/web/20231127222130/https://books.google.com/books?id=wGaKtDw50K0C&pg=PA61 | url-status = live }}</ref><ref name="Johnson2003">{{cite book | vauthors = Johnson LR | title = Essential Medical Physiology | url = https://books.google.com/books?id=j9e-tkdHeUoC&pg=PA770 | year = 2003 | publisher = Academic Press | isbn = 978-0-12-387584-6 | page = 770 | access-date = 1 February 2016 | archive-date = 14 January 2023 | archive-url = https://web.archive.org/web/20230114025047/https://books.google.com/books?id=j9e-tkdHeUoC&pg=PA770 | url-status = live }}</ref><ref name="CoadDunstall2011">{{cite book| vauthors = Coad J, Dunstall M | title = Anatomy and Physiology for Midwives, with Pageburst online access,3: Anatomy and Physiology for Midwives|url=https://books.google.com/books?id=OmSKoYD-iW0C&pg=PA413|year=2011|publisher=Elsevier Health Sciences|isbn=978-0-7020-3489-3|page=413}}</ref>

Elevated levels of progesterone potently reduce the sodium-retaining activity of aldosterone, resulting in natriuresis and a reduction in extracellular fluid volume. Progesterone withdrawal, on the other hand, is associated with a temporary increase in sodium retention (reduced natriuresis, with an increase in extracellular fluid volume) due to the compensatory increase in aldosterone production, which combats the blockade of the mineralocorticoid receptor by the previously elevated level of progesterone.<ref name="pmid13263410">{{cite journal | vauthors = Landau RL, Bergenstal DM, Lugibihl K, Kascht ME | title = The metabolic effects of progesterone in man | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 15 | issue = 10 | pages = 1194–1215 | date = October 1955 | pmid = 13263410 | doi = 10.1210/jcem-15-10-1194 }}</ref>

===Early sexual differentiation===
[[Placenta]]l progesterone can be converted into [[5α-dihydrotestosterone]] (DHT), a potent [[androgen]] that is responsible for the development of male genitalia.<ref name=wj>{{cite journal|doi=10.15347/WJM/2023.003 |doi-access=free |title=Alternative androgen pathways |year=2023 | vauthors = Masiutin M, Yadav M |journal=WikiJournal of Medicine |volume=10 |pages=X |s2cid=257943362}}</ref> This can be done both by conversion into testosterone, which is then converted to DHT, and via the [[androgen backdoor pathway]], which is particularly important for [[fetal development]].<ref name="pmid30763313">{{cite journal | vauthors = O'Shaughnessy PJ, Antignac JP, Le Bizec B, Morvan ML, Svechnikov K, Söder O, Savchuk I, Monteiro A, Soffientini U, Johnston ZC, Bellingham M, Hough D, Walker N, Filis P, Fowler PA | display-authors = 6 | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | volume = 17 | issue = 2 | article-number = e3000002 | date = February 2019 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002 | doi-access = free }}</ref> Progesterone is the precursor for both pathways and therefore plays a key role in sexual differentiation.<ref name="pmid24793988">{{cite journal | vauthors = Flück CE, Pandey AV | title = Steroidogenesis of the testis -- new genes and pathways | journal = Annales d'Endocrinologie | volume = 75 | issue = 2 | pages = 40–47 | date = May 2014 | pmid = 24793988 | doi = 10.1016/j.ando.2014.03.002 }}</ref><ref name="pmid8636249">{{cite journal | vauthors = Zachmann M | title = Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 81 | issue = 2 | pages = 457–459 | date = February 1996 | pmid = 8636249 | doi = 10.1210/jcem.81.2.8636249 | doi-access = free }}</ref>

===Reproductive system===
[[File:Endometrium ocp use3.jpg|thumb|[[Micrograph]] showing changes to the [[endometrium]] due to progesterone ([[decidualization]]) [[H&E stain]]]]
Progesterone has key effects via non-genomic signalling on human sperm as they migrate through the female reproductive tract before [[fertilization]] occurs, though the receptor(s) as yet remain unidentified.<ref name="pmid17447210">{{cite journal | vauthors = Correia JN, Conner SJ, Kirkman-Brown JC | title = Non-genomic steroid actions in human spermatozoa. "Persistent tickling from a laden environment" | journal = Seminars in Reproductive Medicine | volume = 25 | issue = 3 | pages = 208–219 | date = May 2007 | pmid = 17447210 | doi = 10.1055/s-2007-973433 | s2cid = 260318879 }}</ref> Detailed characterisation of the events occurring in sperm in response to progesterone has elucidated certain events including intracellular calcium transients and maintained changes,<ref name="pmid10837122">{{cite journal | vauthors = Kirkman-Brown JC, Bray C, Stewart PM, Barratt CL, Publicover SJ | title = Biphasic elevation of [Ca(2+)](i) in individual human spermatozoa exposed to progesterone | journal = Developmental Biology | volume = 222 | issue = 2 | pages = 326–335 | date = June 2000 | pmid = 10837122 | doi = 10.1006/dbio.2000.9729 | doi-access = free }}</ref> slow calcium oscillations,<ref name="pmid14606954">{{cite journal | vauthors = Kirkman-Brown JC, Barratt CL, Publicover SJ | title = Slow calcium oscillations in human spermatozoa | journal = The Biochemical Journal | volume = 378 | issue = Pt 3 | pages = 827–832 | date = March 2004 | pmid = 14606954 | pmc = 1223996 | doi = 10.1042/BJ20031368 }}</ref> now thought to possibly regulate motility.<ref name="pmid15322137">{{cite journal | vauthors = Harper CV, Barratt CL, Publicover SJ | title = Stimulation of human spermatozoa with progesterone gradients to simulate approach to the oocyte. Induction of [Ca(2+)](i) oscillations and cyclical transitions in flagellar beating | journal = The Journal of Biological Chemistry | volume = 279 | issue = 44 | pages = 46315–46325 | date = October 2004 | pmid = 15322137 | doi = 10.1074/jbc.M401194200 | doi-access = free }}</ref> It is produced by the ovaries.<ref name=Marieb>{{cite book | vauthors = Marieb E | title = Anatomy & physiology | publisher = Benjamin-Cummings | page= 903 | year = 2013 | isbn = 978-0-321-88760-3 }}</ref> Progesterone has also been shown to demonstrate effects on octopus spermatozoa.<ref name="pmid11335951">{{cite journal | vauthors = Tosti E, Di Cosmo A, Cuomo A, Di Cristo C, Gragnaniello G | title = Progesterone induces activation in Octopus vulgaris spermatozoa | journal = Molecular Reproduction and Development | volume = 59 | issue = 1 | pages = 97–105 | date = May 2001 | pmid = 11335951 | doi = 10.1002/mrd.1011 | s2cid = 28390608 }}</ref>

Progesterone is sometimes called the "[[Pregnancy hormones|hormone of pregnancy]]",<ref name="colostate">{{cite web | url = http://www.vivo.colostate.edu/hbooks/pathphys/reprod/placenta/endocrine.html | title = Placental Hormones | access-date = 12 March 2008 | last = Bowen | first = R. | date = 6 August 2000 | archive-date = 17 May 2007 | archive-url = https://web.archive.org/web/20070517165244/http://www.vivo.colostate.edu/hbooks/pathphys/reprod/placenta/endocrine.html }}</ref> and it has many roles relating to the development of the fetus:
* Progesterone converts the [[endometrium]] to its secretory stage to prepare the uterus for implantation. At the same time progesterone affects the [[vaginal epithelium]] and [[cervical mucus]], making it thick and impenetrable to [[sperm]]. Progesterone is anti-[[Mitosis|mitogenic]] in endometrial epithelial cells, and as such, mitigates the tropic effects of [[estrogen]].<ref name="pmid25406186">{{cite journal | vauthors = Patel B, Elguero S, Thakore S, Dahoud W, Bedaiwy M, Mesiano S | title = Role of nuclear progesterone receptor isoforms in uterine pathophysiology | journal = Human Reproduction Update | volume = 21 | issue = 2 | pages = 155–173 | year = 2014 | pmid = 25406186 | pmc = 4366574 | doi = 10.1093/humupd/dmu056 }}</ref> If [[pregnancy]] does not occur, progesterone levels will decrease, leading to [[menstruation]]. Normal menstrual bleeding is progesterone-withdrawal bleeding. If ovulation does not occur, and the [[corpus luteum]] does not develop, levels of progesterone may be low, leading to [[Dysfunctional uterine bleeding#Anovulatory DUB|anovulatory dysfunctional uterine bleeding]].
* During implantation and [[gestation]], progesterone appears to decrease the maternal [[immune system|immune]] response to allow for the acceptance of the pregnancy.<ref name="pmid27662646">{{cite journal | vauthors = Di Renzo GC, Giardina I, Clerici G, Brillo E, Gerli S | title = Progesterone in normal and pathological pregnancy | journal = Hormone Molecular Biology and Clinical Investigation | volume = 27 | issue = 1 | pages = 35–48 | date = July 2016 | pmid = 27662646 | doi = 10.1515/hmbci-2016-0038 | s2cid = 32239449 }}</ref>
* Progesterone decreases contractility of the uterine [[smooth muscle]].<ref name="colostate"/> This effect contributes to prevention of [[preterm labor]].<ref name="pmid27662646" /> Studies have shown that in individuals who are pregnant with a single fetus, asymptomatic in the prenatal stage, and at a high risk of giving pre-term birth spontaneously, vaginal progesterone medication has been found to be effective in preventing spontaneous pre-term birth. Individuals who are at a high risk of giving pre-term birth spontaneously are those who have a short cervix of less than 25&nbsp;mm or have previously given pre-term birth spontaneously. Although pre-term births are generally considered to be less than 37 weeks, these studies found that vaginal progesterone is associated with fewer pre-term births of less than 34 weeks.<ref name="pmid35168930">{{cite journal | vauthors = Care A, Nevitt SJ, Medley N, Donegan S, Good L, Hampson L, Tudur Smith C, Alfirevic Z | display-authors = 6 | title = Interventions to prevent spontaneous preterm birth in women with singleton pregnancy who are at high risk: systematic review and network meta-analysis | journal = BMJ | volume = 376 | article-number = e064547 | date = February 2022 | pmid = 35168930 | pmc = 8845039 | doi = 10.1136/bmj-2021-064547 }}</ref>
* A drop in progesterone levels is possibly one step that facilitates the onset of [[Labor (childbirth)|labor]].{{cn|date=February 2025}}
* In addition, progesterone inhibits [[lactation]] during pregnancy. The fall in progesterone levels following delivery is one of the triggers for milk production.{{cn|date=February 2025}}

The [[fetus]] [[metabolize]]s placental progesterone in the production of [[adrenal]] steroids.<ref name="pmid30763313"/>

===Breasts===
{{See also|Breast development#Biochemistry}}

====Lobuloalveolar development====
Progesterone plays an important role in [[breast development]]. In conjunction with [[prolactin]], it mediates [[lobuloalveolar]] maturation of the [[mammary gland]]s during pregnancy to allow for milk production, and thus [[lactation]] and [[breastfeeding]] of [[offspring]] following [[parturition]] (childbirth).<ref name="pmid22844349">{{cite journal | vauthors = Macias H, Hinck L | title = Mammary gland development | journal = Wiley Interdisciplinary Reviews. Developmental Biology | volume = 1 | issue = 4 | pages = 533–557 | year = 2012 | pmid = 22844349 | pmc = 3404495 | doi = 10.1002/wdev.35 }}</ref> [[Estrogen]] induces expression of the progesterone receptors (PR) in breast tissue, and hence progesterone is dependent on estrogen to mediate lobuloalveolar development.<ref name="pmid16917139" /><ref name="Johnson2003" /><ref name="CoadDunstall2011" /> It has been found that [[RANKL]] is a critical downstream mediator of progesterone-induced lobuloalveolar maturation.<ref name="pmid26266959">{{cite journal | vauthors = Hilton HN, Graham JD, Clarke CL | title = Minireview: Progesterone Regulation of Proliferation in the Normal Human Breast and in Breast Cancer: A Tale of Two Scenarios? | journal = Molecular Endocrinology | volume = 29 | issue = 9 | pages = 1230–1242 | date = September 2015 | pmid = 26266959 | pmc = 5414684 | doi = 10.1210/me.2015-1152 }}</ref> RANKL [[knockout mice]] show an almost identical mammary phenotype to PR knockout mice, including normal mammary ductal development, but complete failure of the development of lobuloalveolar structures.<ref name="pmid26266959" />

====Ductal development====
Though to a far lesser extent than estrogen, which is the major mediator of mammary ductal development (via the [[ERα]]),<ref name="StraussBarbieri2013">{{cite book|vauthors=Barbieri RL|chapter=The Breast|veditors=Strauss JF, Barbieri RL|title=Yen and Jaffe's Reproductive Endocrinology|chapter-url=https://books.google.com/books?id=KZ95AAAAQBAJ&pg=PA236|date=13 September 2013|publisher=Elsevier Health Sciences|isbn=978-1-4557-2758-2|pages=236–|access-date=1 February 2016|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114025044/https://books.google.com/books?id=KZ95AAAAQBAJ&pg=PA236|url-status=live}}</ref><ref name="pmid24718936">{{cite journal | vauthors = Scaling AL, Prossnitz ER, Hathaway HJ | title = GPER mediates estrogen-induced signaling and proliferation in human breast epithelial cells and normal and malignant breast | journal = Hormones & Cancer | volume = 5 | issue = 3 | pages = 146–160 | date = June 2014 | pmid = 24718936 | pmc = 4091989 | doi = 10.1007/s12672-014-0174-1 }}</ref> progesterone may also be involved in ductal development of the mammary glands to some extent.<ref name="pmid23705924">{{cite journal | vauthors = Aupperlee MD, Leipprandt JR, Bennett JM, Schwartz RC, Haslam SZ | title = Amphiregulin mediates progesterone-induced mammary ductal development during puberty | journal = Breast Cancer Research | volume = 15 | issue = 3 | article-number = R44 | date = May 2013 | pmid = 23705924 | pmc = 3738150 | doi = 10.1186/bcr3431 | doi-access = free }}</ref> PR knockout mice or mice treated with the [[Antiprogestogen|PR antagonist]] [[mifepristone]] show delayed although otherwise normal mammary ductal development at puberty.<ref name="pmid23705924" /> In addition, mice modified to have [[overexpression]] of [[Progesterone receptor A|PRA]] display ductal hyperplasia,<ref name="pmid26266959" /> and progesterone induces ductal growth in the mouse mammary gland.<ref name="pmid23705924" /> Progesterone mediates ductal development mainly via induction of the [[Gene expression|expression]] of [[amphiregulin]], the same [[growth factor]] that estrogen primarily induces the expression of to mediate ductal development.<ref name="pmid23705924" /> These animal findings suggest that, while not essential for full mammary ductal development, progesterone seems to play a potentiating or accelerating role in estrogen-mediated mammary ductal development.<ref name="pmid23705924" />

====Breast cancer risk====
Progesterone also appears to be involved in the [[pathophysiology]] of [[breast cancer]], though its role, and whether it is a promoter or inhibitor of breast cancer risk, has not been fully elucidated.<ref name="pmid23336704">{{cite journal | vauthors = Kuhl H, Schneider HP | title = Progesterone--promoter or inhibitor of breast cancer | journal = Climacteric | volume = 16 | issue = Suppl 1 | pages = 54–68 | date = August 2013 | pmid = 23336704 | doi = 10.3109/13697137.2013.768806 | s2cid = 20808536 }}</ref><ref name="pmid31512725">{{cite journal | vauthors = Trabert B, Sherman ME, Kannan N, Stanczyk FZ | title = Progesterone and Breast Cancer | journal = Endocrine Reviews | volume = 41 | issue = 2 | pages = 320–344 | date = April 2020 | pmid = 31512725 | pmc = 7156851 | doi = 10.1210/endrev/bnz001 }}</ref> Most [[progestin]]s, or [[Synthetic compound|synthetic]] progestogens, like [[medroxyprogesterone acetate]], have been found to increase the risk of breast cancer in postmenopausal people in combination with estrogen as a component of [[menopausal hormone therapy]].<ref name="pmid31474332">{{cite journal | title = Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence | journal = Lancet | volume = 394 | issue = 10204 | pages = 1159–1168 | date = September 2019 | pmid = 31474332 | pmc = 6891893 | doi = 10.1016/S0140-6736(19)31709-X | author1 = Collaborative Group on Hormonal Factors in Breast Cancer }}</ref><ref name="pmid31512725" /> The combination of natural oral progesterone or the atypical progestin [[dydrogesterone]] with estrogen has been associated with less risk of breast cancer than progestins plus estrogen.<ref name="pmid29384406">{{cite journal | vauthors = Stute P, Wildt L, Neulen J | title = The impact of micronized progesterone on breast cancer risk: a systematic review | journal = Climacteric | volume = 21 | issue = 2 | pages = 111–122 | date = April 2018 | pmid = 29384406 | doi = 10.1080/13697137.2017.1421925 | s2cid = 3642971 | doi-access = free | url = https://boris.unibe.ch/125894/1/29384406.pdf | access-date = 2 February 2024 | archive-date = 2 February 2024 | archive-url = https://web.archive.org/web/20240202143017/https://boris.unibe.ch/125894/1/29384406.pdf | url-status = live }}</ref><ref name="pmid27456847">{{cite journal | vauthors = Asi N, Mohammed K, Haydour Q, Gionfriddo MR, Vargas OL, Prokop LJ, Faubion SS, Murad MH | display-authors = 6 | title = Progesterone vs. synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis | journal = Systematic Reviews | volume = 5 | issue = 1 | article-number = 121 | date = July 2016 | pmid = 27456847 | pmc = 4960754 | doi = 10.1186/s13643-016-0294-5 | doi-access = free }}</ref><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> However, this may simply be an artifact of the low progesterone levels produced with oral progesterone.<ref name="pmid23336704" /><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> More research is needed on the role of progesterone in breast cancer.<ref name="pmid31512725" />

===Skin health===
The [[estrogen receptor]], as well as the [[progesterone receptor]], have been detected in the [[Human skin|skin]], including in [[keratinocyte]]s and [[fibroblast]]s.<ref name="pmid12762829">{{cite journal | vauthors = Raine-Fenning NJ, Brincat MP, Muscat-Baron Y | title = Skin aging and menopause: implications for treatment | journal = American Journal of Clinical Dermatology | volume = 4 | issue = 6 | pages = 371–378 | 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 | 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 = The British Journal of Dermatology | volume = 153 | issue = 3 | pages = 626–634 | date = September 2005 | pmid = 16120154 | doi = 10.1111/j.1365-2133.2005.06685.x | s2cid = 6077829 }}</ref> At [[menopause]] and thereafter, decreased levels of female [[sex hormone]]s result in [[atrophy]], thinning, and increased [[wrinkling]] of the skin, and a reduction in skin [[Elasticity (physics)|elasticity]], firmness, and strength.<ref name="pmid12762829" /><ref name="pmid16120154" /> These skin changes constitute an acceleration in [[skin aging]] and are the result of decreased [[collagen]] content, irregularities in the [[Morphology (biology)|morphology]] of [[epidermal]] [[skin cell]]s, decreased [[ground substance]] between [[skin fiber]]s, and reduced [[capillaries]] and [[blood flow]].<ref name="pmid12762829" /><ref name="pmid16120154" /> The skin also becomes more [[Xeroderma|dry]] during menopause, as a result of reduced skin [[Tissue hydration|hydration]] and [[Sebum|surface lipids]] (sebum production).<ref name="pmid12762829" /> Along with chronological aging and photoaging, estrogen deficiency in menopause is one of the three main factors that predominantly influences skin aging.<ref name="pmid12762829" />

Hormone replacement therapy, consisting of systemic treatment with estrogen alone or in combination with a progestogen, has well-documented and considerable beneficial effects on the skin of postmenopausal people.<ref name="pmid12762829" /><ref name="pmid16120154" /> These benefits include increased skin collagen content, skin thickness and elasticity, and skin hydration and surface lipids.<ref name="pmid12762829" /><ref name="pmid16120154" /> Topical estrogen has been found to have similar beneficial effects on the skin.<ref name="pmid12762829" /> In addition, a study has found that topical 2% progesterone cream significantly increases skin elasticity and firmness and observably decreases wrinkles in peri- and postmenopausal people.<ref name="pmid16120154" /> Skin hydration and surface lipids, on the other hand, did not significantly change with topical progesterone.<ref name="pmid16120154" />

These findings suggest that progesterone, like estrogen, also has beneficial effects on the skin and may be independently protective against skin aging.<ref name="pmid16120154" />

===Sexuality===

====Libido====
{{See also|Sexual motivation and hormones}}
Progesterone and its [[neurosteroid]] [[active metabolite]], [[allopregnanolone]], appear to be importantly involved in [[libido]] in females.<ref name="King2012">{{cite book |vauthors=King SR |title=Neurosteroids and the Nervous System |url=https://books.google.com/books?id=D1fOTC6CP3kC&pg=PA44 |date=9 November 2012 |publisher=Springer Science & Business Media |isbn=978-1-4614-5559-2 |pages=44–46}}</ref>

====Homosexuality====
Dr. [[Diana Fleischman]], of the [[University of Portsmouth]], and colleagues looked for a relationship between progesterone and sexual attitudes in 92 women. Their research, published in the [[Archives of Sexual Behavior]] found that women who had higher levels of progesterone scored higher on a questionnaire measuring homoerotic motivation. They also found that men who had high levels of progesterone were more likely to have higher homoerotic motivation scores after affiliative priming compared to men with low levels of progesterone.<ref name="pmid25420899">{{cite journal | vauthors = Fleischman DS, Fessler DM, Cholakians AE | title = Testing the Affiliation Hypothesis of Homoerotic Motivation in Humans: The Effects of Progesterone and Priming | journal = Archives of Sexual Behavior | volume = 44 | issue = 5 | pages = 1395–1404 | date = July 2015 | pmid = 25420899 | doi = 10.1007/s10508-014-0436-6 | s2cid = 9864224 | url = https://researchportal.port.ac.uk/portal/en/publications/testing-the-affiliation-hypothesis-of-homoerotic-motivation-in-humans(d1eb5448-5664-4d2d-8694-18f970836cbb).html | access-date = 2 August 2023 | archive-date = 23 September 2020 | archive-url = https://web.archive.org/web/20200923005905/https://researchportal.port.ac.uk/portal/en/publications/testing-the-affiliation-hypothesis-of-homoerotic-motivation-in-humans(d1eb5448-5664-4d2d-8694-18f970836cbb).html | url-status = live }}</ref><ref name="UoP-News-Homos">{{cite news |title=Homosexuality may help us bond | work = UoP News |url=https://uopnews.port.ac.uk/2014/11/25/homosexuality-may-help-us-bond/ |access-date=2 July 2019 |archive-date=2 July 2019 |archive-url=https://web.archive.org/web/20190702203503/https://uopnews.port.ac.uk/2014/11/25/homosexuality-may-help-us-bond/ }}</ref><ref name="The-Telegraph-2014">{{Cite web|url=https://www.telegraph.co.uk/news/science/11251206/Having-homosexual-thoughts-is-an-essential-part-of-human-evolution-study-suggests.html|title=Having homosexual thoughts 'is an essential part of human evolution' study suggests|date=25 November 2014|website=The Telegraph|access-date=4 April 2018|archive-date=15 February 2018|archive-url=https://web.archive.org/web/20180215160336/http://www.telegraph.co.uk/news/science/11251206/Having-homosexual-thoughts-is-an-essential-part-of-human-evolution-study-suggests.html|url-status=live}}</ref><ref name="HuffPost-2014">{{Cite web|url=https://www.huffpost.com/entry/homosexuality-evolution-social-bonding_n_6218406|title=New Study Identifies Evolutionary Basis Of Homosexuality|date=26 November 2014|website=HuffPost|access-date=21 October 2023|archive-date=27 November 2023|archive-url=https://web.archive.org/web/20231127222130/https://www.huffpost.com/entry/homosexuality-evolution-social-bonding_n_6218406|url-status=live}}</ref>

===Nervous system===
Progesterone, like [[pregnenolone]] and [[dehydroepiandrosterone]] (DHEA), belongs to an important group of endogenous steroids called [[neurosteroid]]s. It can be metabolized within all parts of the [[central nervous system]].<ref name="pmid558037">{{cite journal | vauthors = Hanukoglu I, Karavolas HJ, Goy RW | title = Progesterone metabolism in the pineal, brain stem, thalamus and corpus callosum of the female rat | journal = Brain Research | volume = 125 | issue = 2 | pages = 313–324 | date = April 1977 | pmid = 558037 | doi = 10.1016/0006-8993(77)90624-2 | s2cid = 35814845 | url = https://zenodo.org/record/890908 | access-date = 28 June 2019 | archive-date = 5 March 2021 | archive-url = https://web.archive.org/web/20210305233844/https://zenodo.org/record/890908 | url-status = live }}</ref>

Neurosteroids are [[neuromodulator]]s and are [[neuroprotective]], [[neurogenic]], and regulate [[neurotransmission]] and [[myelination]].<ref name="pmid15135772">{{cite journal | vauthors = Schumacher M, Guennoun R, Robert F, Carelli C, Gago N, Ghoumari A, Gonzalez Deniselle MC, Gonzalez SL, Ibanez C, Labombarda F, Coirini H, Baulieu EE, De Nicola AF | display-authors = 6 | title = Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination | journal = Growth Hormone & IGF Research | volume = 14 | issue = Suppl A | pages = S18–S33 | date = June 2004 | pmid = 15135772 | doi = 10.1016/j.ghir.2004.03.007 }}</ref> The effects of progesterone as a neurosteroid are mediated predominantly through its interactions with non-nuclear PRs, namely the mPRs and [[PGRMC1]], as well as certain other receptors, such as the σ<sub>1</sub> and nACh receptors.<ref name="pmid24065876">{{cite journal | vauthors = Singh M, Su C, Ng S | title = Non-genomic mechanisms of progesterone action in the brain | journal = Frontiers in Neuroscience | volume = 7 | page = 159 | date = September 2013 | pmid = 24065876 | pmc = 3776940 | doi = 10.3389/fnins.2013.00159 | doi-access = free }}</ref>

===Brain damage===
{{See also|Progesterone (medication)#Other uses}}

Previous studies have shown that progesterone supports the normal development of neurons in the brain, and that the hormone has a protective effect on damaged brain tissue. It has been observed in animal models that females have reduced susceptibility to [[traumatic brain injury]], and this protective effect has been hypothesized to be caused by increased circulating levels of [[estrogen]] and progesterone in females.<ref name="pmid10833057">{{cite journal | vauthors = Roof RL, Hall ED | title = Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone | journal = Journal of Neurotrauma | volume = 17 | issue = 5 | pages = 367–388 | date = May 2000 | pmid = 10833057 | doi = 10.1089/neu.2000.17.367 }}</ref>

====Proposed mechanism====
The mechanism of progesterone protective effects may be the reduction of inflammation that follows brain trauma and hemorrhage.<ref name="pmid18188998">{{cite journal | vauthors = Pan DS, Liu WG, Yang XF, Cao F | title = Inhibitory effect of progesterone on inflammatory factors after experimental traumatic brain injury | journal = Biomedical and Environmental Sciences | volume = 20 | issue = 5 | pages = 432–438 | date = October 2007 | pmid = 18188998 }}</ref><ref name="pmid27143417">{{cite journal | vauthors = Jiang C, Zuo F, Wang Y, Wan J, Yang Z, Lu H, Chen W, Zang W, Yang Q, Wang J | display-authors = 6 | title = Progesterone exerts neuroprotective effects and improves long-term neurologic outcome after intracerebral hemorrhage in middle-aged mice | journal = Neurobiology of Aging | volume = 42 | pages = 13–24 | date = June 2016 | pmid = 27143417 | pmc = 4857017 | doi = 10.1016/j.neurobiolaging.2016.02.029 }}</ref>

Damage incurred by traumatic brain injury is believed to be caused in part by mass [[depolarization]] leading to [[excitotoxicity]]. One way in which progesterone helps to alleviate some of this excitotoxicity is by blocking the [[voltage-dependent calcium channel]]s that trigger [[neurotransmitter]] release.<ref name="pmid22101209">{{cite journal | vauthors = Luoma JI, Stern CM, Mermelstein PG | title = Progesterone inhibition of neuronal calcium signaling underlies aspects of progesterone-mediated neuroprotection | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 131 | issue = 1–2 | pages = 30–36 | date = August 2012 | pmid = 22101209 | pmc = 3303940 | doi = 10.1016/j.jsbmb.2011.11.002 }}</ref> It does so by manipulating the signaling pathways of [[transcription factor]]s involved in this release. Another method for reducing the excitotoxicity is by up-regulating the [[GABAA receptor|GABA<sub>A</sub>]], a widespread inhibitory neurotransmitter receptor.<ref name="pmid17826842">{{cite journal | vauthors = Stein DG | title = Progesterone exerts neuroprotective effects after brain injury | journal = Brain Research Reviews | volume = 57 | issue = 2 | pages = 386–397 | date = March 2008 | pmid = 17826842 | pmc = 2699575 | doi = 10.1016/j.brainresrev.2007.06.012 }}</ref>

Progesterone has also been shown to prevent [[apoptosis]] in neurons, a common consequence of brain injury. It does so by inhibiting enzymes involved in the apoptosis pathway specifically concerning the mitochondria, such as activated [[caspase-3]] and [[cytochrome&nbsp;c]].<ref name="pmid22088981">{{cite journal | vauthors = Espinoza TR, Wright DW | title = The role of progesterone in traumatic brain injury | journal = The Journal of Head Trauma Rehabilitation | volume = 26 | issue = 6 | pages = 497–499 | year = 2011 | pmid = 22088981 | pmc = 6025750 | doi = 10.1097/HTR.0b013e31823088fa }}</ref>

Not only does progesterone help prevent further damage, it has also been shown to aid in [[neuroregeneration]].<ref name="pmid26746666">{{cite journal | vauthors = Jiang C, Zuo F, Wang Y, Lu H, Yang Q, Wang J | title = Progesterone Changes VEGF and BDNF Expression and Promotes Neurogenesis After Ischemic Stroke | journal = Molecular Neurobiology | volume = 54 | issue = 1 | pages = 571–581 | date = January 2016 | pmid = 26746666 | pmc = 4938789 | doi = 10.1007/s12035-015-9651-y }}</ref> One of the serious effects of traumatic brain injury includes edema. Animal studies show that progesterone treatment leads to a decrease in [[edema]] levels by increasing the concentration of [[macrophage]]s and [[microglia]] sent to the injured tissue.<ref name="pmid22101209"/><ref name="pmid19401954">{{cite journal | vauthors = Herson PS, Koerner IP, Hurn PD | title = Sex, sex steroids, and brain injury | journal = Seminars in Reproductive Medicine | volume = 27 | issue = 3 | pages = 229–239 | date = May 2009 | pmid = 19401954 | pmc = 2675922 | doi = 10.1055/s-0029-1216276 }}</ref> This was observed in the form of reduced leakage from the [[blood brain barrier]] in secondary recovery in progesterone treated rats. In addition, progesterone was observed to have [[antioxidant]] properties, reducing the concentration of [[Reactive oxygen species|oxygen free radicals]] faster than without.<ref name="pmid17826842"/> There is also evidence that the addition of progesterone can also help re[[myelinate]] damaged [[axon]]s due to trauma, restoring some lost neural signal conduction.<ref name="pmid17826842"/> Another way progesterone aids in regeneration includes increasing the circulation of endothelial progenitor cells in the brain. This aids the growth of new [[vasculature]] around scar tissue, helping to repair the area of insult.<ref name="pmid21534727">{{cite journal | vauthors = Li Z, Wang B, Kan Z, Zhang B, Yang Z, Chen J, Wang D, Wei H, Zhang JN, Jiang R | display-authors = 6 | title = Progesterone increases circulating endothelial progenitor cells and induces neural regeneration after traumatic brain injury in aged rats | journal = Journal of Neurotrauma | volume = 29 | issue = 2 | pages = 343–353 | date = January 2012 | pmid = 21534727 | pmc = 3261789 | doi = 10.1089/neu.2011.1807 }}</ref>

===Addiction===

Progesterone enhances the function of [[serotonin receptor]]s in the brain, so an excess or deficit of progesterone has the potential to result in significant neurochemical issues. This provides an explanation for why some people resort to substances that enhance [[serotonin]] activity such as [[nicotine]], [[Alcohol (drug)|alcohol]], and [[Cannabis (drug)|cannabis]] when their progesterone levels fall below optimal levels.<ref name="pmid21186920">{{cite journal | vauthors = Lynch WJ, Sofuoglu M | title = Role of progesterone in nicotine addiction: evidence from initiation to relapse | journal = Experimental and Clinical Psychopharmacology | volume = 18 | issue = 6 | pages = 451–461 | date = December 2010 | pmid = 21186920 | pmc = 3638762 | doi = 10.1037/a0021265 }}</ref>
* Sex differences in hormone levels may induce women to respond differently than men to nicotine. When women undergo cyclic changes or different hormonal transition phases (menopause, pregnancy, adolescence), there are changes in their progesterone levels.<ref name="pmid22474108">{{cite journal | vauthors = Cosgrove KP, Esterlis I, McKee SA, Bois F, Seibyl JP, Mazure CM, Krishnan-Sarin S, Staley JK, Picciotto MR, O'Malley SS | display-authors = 6 | title = Sex differences in availability of β2*-nicotinic acetylcholine receptors in recently abstinent tobacco smokers | journal = Archives of General Psychiatry | volume = 69 | issue = 4 | pages = 418–427 | date = April 2012 | pmid = 22474108 | pmc = 3508698 | doi = 10.1001/archgenpsychiatry.2011.1465 }}</ref> Therefore, females have an increased biological vulnerability to nicotine's reinforcing effects compared to males, and progesterone may be used to counter this enhanced vulnerability. This information supports the idea that progesterone can affect behavior.<ref name="pmid21186920"/>
* Similar to nicotine, cocaine also increases the release of dopamine in the brain. The neurotransmitter is involved in the reward center and is one of the main neurotransmitters involved with substance abuse and reliance. In a study of cocaine users, it was reported that progesterone reduced craving and the feeling of being stimulated by cocaine. Thus, progesterone was suggested as an agent that decreases cocaine craving by reducing the dopaminergic properties of the drug.<ref name="pmid21796112">{{cite journal | vauthors = Mello NK, Knudson IM, Kelly M, Fivel PA, Mendelson JH | title = Effects of progesterone and testosterone on cocaine self-administration and cocaine discrimination by female rhesus monkeys | journal = Neuropsychopharmacology | volume = 36 | issue = 11 | pages = 2187–2199 | date = October 2011 | pmid = 21796112 | pmc = 3176575 | doi = 10.1038/npp.2011.130 }}</ref>

===Societal===
In a 2012 University of Amsterdam study of 120 women, the women's luteal phase (higher levels of progesterone, and increasing levels of estrogen) was correlated with a lower level of competitive behavior in gambling and math contest scenarios, while their premenstrual phase (sharply-decreasing levels of progesterone, and decreasing levels of estrogen) was correlated with a higher level of competitive behavior.<ref name="Buser-2012">{{Cite journal|vauthors=Buser T|date=1 June 2012|title=The impact of the menstrual cycle and hormonal contraceptives on competitiveness|journal=Journal of Economic Behavior & Organization|series=Gender Differences in Risk Aversion and Competition|volume=83|issue=1|pages=1–10|doi=10.1016/j.jebo.2011.06.006|issn=0167-2681|url=https://pure.uva.nl/ws/files/1864146/117489_376503.pdf|access-date=2 February 2024|archive-date=2 February 2024|archive-url=https://web.archive.org/web/20240202143019/https://pure.uva.nl/ws/files/1864146/117489_376503.pdf|url-status=live}}</ref>

===Other effects===
* Progesterone also has a role in skin elasticity and bone strength, in [[Respiration (physiology)|respiration]], in nerve tissue and in [[female sexuality]], and the presence of progesterone receptors in certain muscle and fat tissue may hint at a role in [[sexually dimorphic]] proportions of those.<ref name="medicinalchem">{{cite book |title= Medicinal Chemistry| vauthors = Sriram D |year=2007 |publisher=Dorling Kindersley India Pvt. Ltd.|location= New Delhi| isbn= 978-81-317-0031-0 |page=432}}<!--this seems to have copied from WP?, see [[Special:Diff/1252663285|Wikipedia:Copyright_problems/2024_October_22]]--></ref>
* During pregnancy, progesterone is said to decrease uterine irritability.<ref name="Blackburn2014">{{cite book | vauthors = Blackburn S | title = Maternal, Fetal, & Neonatal Physiology | url = https://books.google.com/books?id=RNLsAwAAQBAJ&pg=PA92|date=14 April 2014|publisher=Elsevier Health Sciences|isbn=978-0-323-29296-2|pages=92–}}</ref>
* During pregnancy, progesterone helps to suppress immune responses of the mother to fetal antigens, thus preventing rejection of the fetus.<ref name="Blackburn2014" />
* Progesterone raises [[epidermal growth factor-1]] (EGF-1) levels, a factor often used to induce proliferation of [[stem cell]]s, and used to sustain stem cell cultures.<ref name="pmid17074804">{{cite journal | vauthors = Faivre EJ, Lange CA | title = Progesterone receptors upregulate Wnt-1 to induce epidermal growth factor receptor transactivation and c-Src-dependent sustained activation of Erk1/2 mitogen-activated protein kinase in breast cancer cells | journal = Molecular and Cellular Biology | volume = 27 | issue = 2 | pages = 466–480 | date = January 2007 | pmid = 17074804 | pmc = 1800800 | doi = 10.1128/MCB.01539-06 }}</ref>
* Progesterone increases core temperature (thermogenic function) during ovulation.<ref name="GeorgiaPhysiology">{{cite book| title= Essentials of Human Physiology| vauthors = Nosek TM | chapter=Section 5/5ch9/s5ch9_13 |chapter-url=http://humanphysiology.tuars.com/program/section5/5ch9/s5ch9_13.htm |archive-url=https://web.archive.org/web/20160324124828/http://humanphysiology.tuars.com/program/section5/5ch9/s5ch9_13.htm|archive-date=24 March 2016}}</ref><ref name="Rothchild-1969">{{Citation|vauthors=Rothchild I|title=The Physiologic Basis for the Temperature Raising Effect of Progesterone|date=1969|work=Metabolic Effects of Gonadal Hormones and Contraceptive Steroids|pages=668–675|veditors=Salhanick HA, Kipnis DM, Wiele RL|place=Boston, MA|publisher=Springer US|language=en|doi=10.1007/978-1-4684-1782-1_49|isbn=978-1-4684-1782-1}}</ref>
* Progesterone reduces [[spasm]] and relaxes [[smooth muscle]]. [[Bronchi]] are widened and [[mucus]] regulated. (PRs are widely present in [[Mucous membrane|submucosal tissue]].)<ref>{{Citation |last1=Lam |first1=Maggie |title=Regulation of Airway Smooth Muscle Contraction in Health and Disease |date=2019 |work=Smooth Muscle Spontaneous Activity: Physiological and Pathological Modulation |pages=381–422 |editor-last=Hashitani |editor-first=Hikaru |url=https://doi.org/10.1007/978-981-13-5895-1_16 |access-date=2025-10-19 |place=Singapore |publisher=Springer |language=en |doi=10.1007/978-981-13-5895-1_16 |isbn=978-981-13-5895-1 |last2=Lamanna |first2=Emma |last3=Bourke |first3=Jane E. |volume=1124 |pmid=31183836 |editor2-last=Lang |editor2-first=Richard J.|url-access=subscription }}</ref>
* Progesterone acts as an [[anti-inflammatory]] agent and regulates the [[immune response]].<ref>{{Cite journal |last=Straub |first=Rainer H. |date=2007-08-01 |title=The Complex Role of Estrogens in Inflammation |url=https://doi.org/10.1210/er.2007-0001 |journal=Endocrine Reviews |volume=28 |issue=5 |pages=521–574 |doi=10.1210/er.2007-0001 |pmid=17640948 |issn=0163-769X|url-access=subscription }}</ref>
* Progesterone reduces [[gallbladder]] activity.<ref name="pmid3184927">{{cite journal | vauthors = Hould FS, Fried GM, Fazekas AG, Tremblay S, Mersereau WA | title = Progesterone receptors regulate gallbladder motility | journal = The Journal of Surgical Research | volume = 45 | issue = 6 | pages = 505–512 | date = December 1988 | pmid = 3184927 | doi = 10.1016/0022-4804(88)90137-0 }}</ref>
* Progesterone normalizes [[blood clotting]] and [[vascular tone]], [[zinc]] and [[copper]] levels, [[Cell (biology)|cell]] [[oxygen]] levels, and use of fat stores for energy.{{cn|date=February 2025}}
* Progesterone may affect gum health, increasing risk of gingivitis (gum inflammation).<ref name="WebMD-Hormones-Oral-Health">{{cite web|url=http://www.webmd.com/oral-health/hormones-oral-health|title=Hormones and Oral Health|website=WebMD|access-date=22 July 2013|archive-date=18 June 2016|archive-url=https://web.archive.org/web/20160618171445/http://www.webmd.com/oral-health/hormones-oral-health|url-status=live}}</ref>
* Progesterone appears to prevent [[endometrial cancer]] (involving the uterine lining) by regulating the effects of estrogen.
* Progesterone plays an important role in the signaling of insulin release and pancreatic function, and it may affect the susceptibility to diabetes or gestational diabetes.<ref name="pmid12438645">{{cite journal | vauthors = Picard F, Wanatabe M, Schoonjans K, Lydon J, O'Malley BW, Auwerx J | title = Progesterone receptor knockout mice have an improved glucose homeostasis secondary to beta -cell proliferation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 24 | pages = 15644–15648 | date = November 2002 | pmid = 12438645 | pmc = 137770 | doi = 10.1073/pnas.202612199 | doi-access = free }}</ref><ref name="pmid12591170">{{cite journal | vauthors = Brănişteanu DD, Mathieu C | title = Progesterone in gestational diabetes mellitus: guilty or not guilty? | journal = Trends in Endocrinology and Metabolism | volume = 14 | issue = 2 | pages = 54–56 | date = March 2003 | pmid = 12591170 | doi = 10.1016/S1043-2760(03)00003-1 | s2cid = 38209977 }}</ref>
* Progesterone levels in the blood were found to be lower in those who had higher weight and higher BMI among those who became pregnant through in vitro fertilization.<ref name="pmid34278354">{{cite journal | vauthors = Whynott RM, Summers KM, Jakubiak M, Van Voorhis BJ, Mejia RB | title = The effect of weight and body mass index on serum progesterone values and live birth rate in cryopreserved in vitro fertilization cycles | journal = F&S Reports | volume = 2 | issue = 2 | pages = 195–200 | date = June 2021 | pmid = 34278354 | pmc = 8267385 | doi = 10.1016/j.xfre.2021.02.005 }}</ref>
* Current data shows that micronized progesterone, which is chemically identical to the progesterone produced in the human body, in combination with estrogen in menopausal hormone therapy does not seem to have significant effects on venous thromboembolism (blood clots in veins) and ischemic stroke (lack of blood flow to the brain due to blockage of a blood vessel that supplies the brain). However, more studies need to be conducted to see whether or not micronized progesterone alone or in combined menopausal hormone therapy changes the risk of myocardial infarctions (heart attacks).<ref name="pmid35112635">{{cite journal | vauthors = Kaemmle LM, Stadler A, Janka H, von Wolff M, Stute P | title = The impact of micronized progesterone on cardiovascular events - a systematic review | journal = Climacteric | volume = 25 | issue = 4 | pages = 327–336 | date = August 2022 | pmid = 35112635 | doi = 10.1080/13697137.2021.2022644 | s2cid = 246487187 }}</ref>
* There have not been any studies done yet on the effects of micronized progesterone on hair loss due to menopause.<ref name="pmid33527841">{{cite journal | vauthors = Gasser S, Heidemeyer K, von Wolff M, Stute P | title = Impact of progesterone on skin and hair in menopause - a comprehensive review | journal = Climacteric | volume = 24 | issue = 3 | pages = 229–235 | date = June 2021 | pmid = 33527841 | doi = 10.1080/13697137.2020.1838476 | s2cid = 231757325 }}</ref>
* Despite suggestions for using hormone therapy to prevent loss of muscle mass in post-menopausal individuals (age 50+), menopausal hormone therapy involving either estrogen alone, or estrogen and progesterone combined, has not been found to preserve muscle mass.<ref name="pmid31461147">{{cite journal | vauthors = Javed AA, Mayhew AJ, Shea AK, Raina P | title = Association Between Hormone Therapy and Muscle Mass in Postmenopausal Women: A Systematic Review and Meta-analysis | journal = JAMA Network Open | volume = 2 | issue = 8 | pages = e1910154 | date = August 2019 | pmid = 31461147 | pmc = 6716293 | doi = 10.1001/jamanetworkopen.2019.10154 }}</ref> Menopausal hormone therapy also does not result in body weight reduction, BMI reduction, or change in glucose metabolism.<ref name="pmid30477366">{{cite journal | vauthors = Coquoz A, Gruetter C, Stute P | title = Impact of micronized progesterone on body weight, body mass index, and glucose metabolism: a systematic review | journal = Climacteric | volume = 22 | issue = 2 | pages = 148–161 | date = April 2019 | pmid = 30477366 | doi = 10.1080/13697137.2018.1514003 | s2cid = 53782622 }}</ref>

==Biochemistry==
===Biosynthesis===
[[File:Steroidogenesis.svg|thumb|upright=1.9|class=skin-invert-image|[[Steroidogenesis]], showing progesterone among the progestogens (yellow area)<ref name="HäggströmRichfield2014">{{cite journal | vauthors = Häggström M, Richfield D |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|doi-access=free}}</ref>]]

In mammals, progesterone, like all other [[steroid]] [[hormone]]s, is synthesized from [[pregnenolone]], which itself is derived from [[cholesterol]].{{cn|date=February 2025}}

Cholesterol undergoes double oxidation to produce [[22R-hydroxycholesterol|22''R''-hydroxycholesterol]] and then [[20α,22R-dihydroxycholesterol|20α,22''R''-dihydroxycholesterol]]. This vicinal [[diol]] is then further oxidized with loss of the side chain starting at position C22 to produce pregnenolone. This reaction is catalyzed by [[cytochrome]] [[P450scc]].{{cn|date=February 2025}}

The conversion of pregnenolone to progesterone takes place in two steps. First, the 3β-[[hydroxyl]] group is oxidized to a [[ketone|keto]] group and second, the [[double bond]] is moved to C4, from C5 through a keto/[[enol]] [[tautomerization]] reaction.<ref name="isbn0-471-49641-3">{{cite book | vauthors = Bewick PM | title = Medicinal natural products: a biosynthetic approach | publisher = Wiley | location = New York | year = 2002 | page = 244 | isbn = 0-471-49641-3 }}</ref> This reaction is catalyzed by [[3β-hydroxysteroid dehydrogenase|3β-hydroxysteroid dehydrogenase/δ<sup>5-4</sup>-isomerase]].{{cn|date=February 2025}}

Progesterone in turn is the precursor of the mineralocorticoid [[aldosterone]], and after conversion to [[17α-hydroxyprogesterone]], of [[cortisol]] and [[androstenedione]]. Androstenedione can be converted to [[testosterone]], [[estrone]], and [[estradiol]], highlighting the critical role of progesterone in testosterone synthesis.{{cn|date=February 2025}}

Pregnenolone and progesterone can also be synthesized by [[yeast]].<ref name="pmid9487528">{{cite journal | vauthors = Duport C, Spagnoli R, Degryse E, Pompon D | title = Self-sufficient biosynthesis of pregnenolone and progesterone in engineered yeast | journal = Nature Biotechnology | volume = 16 | issue = 2 | pages = 186–189 | date = February 1998 | pmid = 9487528 | doi = 10.1038/nbt0298-186 | s2cid = 852617 }}</ref>

Approximately 30&nbsp;mg of progesterone is secreted from the ovaries per day in reproductive-age women, while the adrenal glands produce about 1&nbsp;mg of progesterone per day.<ref name="LemkeWilliams2012 p1397">{{cite book|vauthors=Zavod RM|chapter=Women's Health|veditors=Lemke TL, Williams DA|title=Foye's Principles of Medicinal Chemistry|chapter-url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA1397|date=24 January 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-345-0|pages=1397–|access-date=19 July 2018|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114025043/https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA1397|url-status=live}}</ref>

{{Production rates, secretion rates, clearance rates, and blood levels of major sex hormones}}

===Distribution===
Progesterone binds extensively to [[plasma protein]]s, including [[albumin]] (50{{nbnd}}54%) and [[transcortin]] (43{{nbnd}}48%).<ref name="Drugs.com">{{citation | url = https://www.drugs.com/pro/progesterone.html | title = Progesterone - Drugs.com | access-date = 23 August 2015 | archive-date = 27 March 2019 | archive-url = https://web.archive.org/web/20190327091744/https://www.drugs.com/pro/progesterone.html | url-status = live }}</ref> It has similar affinity for albumin relative to the PR.<ref name="Josimovich2013" />

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

The major [[metabolic pathway]] of progesterone is reduction by [[5α-reductase]]<ref name="pmid558037" /> and [[5β-reductase]], into the dihydrogenated [[5α-dihydroprogesterone]] and [[5β-dihydroprogesterone]], respectively.<ref name="Cupps1991" /><ref name="pmid14667980">{{cite journal | vauthors = Stanczyk FZ | title = All progestins are not created equal | journal = Steroids | volume = 68 | issue = 10–13 | pages = 879–890 | date = November 2003 | pmid = 14667980 | doi = 10.1016/j.steroids.2003.08.003 | s2cid = 44601264 }}</ref><ref name="PlantZeleznik2014">{{cite book| vauthors = Plant TM, Zeleznik AJ |title=Knobil and Neill's Physiology of Reproduction|url=https://books.google.com/books?id=I1ACBAAAQBAJ&pg=PA304|date=15 November 2014|publisher=Academic Press|isbn=978-0-12-397769-4|pages=304–}}</ref><ref name="SantoroNeal-Perry2010">{{cite book|vauthors=Santoro NF, Neal-Perry G|title=Amenorrhea: A Case-Based, Clinical Guide|url=https://books.google.com/books?id=4836MLkPoIYC&pg=PA13|date=11 September 2010|publisher=Springer Science & Business Media|isbn=978-1-60327-864-5|pages=13–|access-date=6 November 2016|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114025033/https://books.google.com/books?id=4836MLkPoIYC&pg=PA13|url-status=live}}</ref> This is followed by the further reduction of these metabolites via [[3α-hydroxysteroid dehydrogenase]] and [[3β-hydroxysteroid dehydrogenase]] into the tetrahydrogenated [[allopregnanolone]], [[pregnanolone]], [[isopregnanolone]], and [[epipregnanolone]].<ref name="pmid21094889">{{cite book | vauthors = Reddy DS | title = Sex Differences in the Human Brain, their Underpinnings and Implications | chapter = Neurosteroids | series = Progress in Brain Research | volume = 186 | pages = 113–137 | year = 2010 | publisher = Elsevier | pmid = 21094889 | pmc = 3139029 | doi = 10.1016/B978-0-444-53630-3.00008-7 | isbn = 978-0-444-53630-3 }}</ref><ref name="Cupps1991" /><ref name="pmid14667980" /><ref name="PlantZeleznik2014" /> Subsequently, [[20α-hydroxysteroid dehydrogenase]] and [[20β-hydroxysteroid dehydrogenase]] reduce these metabolites to form the corresponding hexahydrogenated [[pregnanediol]]s (eight different [[isomer]]s in total),<ref name="Cupps1991" /><ref name="SantoroNeal-Perry2010" /> which are then conjugated via [[glucuronidation]] and/or [[sulfation]], released from the liver into circulation, and [[excreted]] by the [[kidney]]s into the [[urine]].<ref name="FalconeHurd2007" /><ref name="pmid14667980" /> The major metabolite of progesterone in the urine is the 3α,5β,20α isomer of [[pregnanediol glucuronide]], which has been found to constitute 15{{nbnd}}30% of an injection of progesterone.<ref name="Josimovich2013" /><ref name="BaulieuKelly1990">{{cite book| vauthors = Baulieu E, Kelly PA |title=Hormones: From Molecules to Disease|url=https://books.google.com/books?id=Seddp4-dulIC&pg=PA401|date=30 November 1990|publisher=Springer Science & Business Media|isbn=978-0-412-02791-8|pages=401–}}</ref> Other metabolites of progesterone formed by the enzymes in this pathway include [[3α-dihydroprogesterone]], [[3β-dihydroprogesterone]], [[20α-dihydroprogesterone]], and [[20β-dihydroprogesterone]], as well as various combination products of the enzymes aside from those already mentioned.<ref name="Josimovich2013" /><ref name="pmid14667980" /><ref name="BaulieuKelly1990" /><ref name="pmid21182831">{{cite journal | vauthors = Beranič N, Gobec S, Rižner TL | title = Progestins as inhibitors of the human 20-ketosteroid reductases, AKR1C1 and AKR1C3 | journal = Chemico-Biological Interactions | volume = 191 | issue = 1–3 | pages = 227–233 | date = May 2011 | pmid = 21182831 | doi = 10.1016/j.cbi.2010.12.012 | bibcode = 2011CBI...191..227B }}</ref> Progesterone can also first be [[hydroxylated]] (see below) and then reduced.<ref name="pmid14667980" /> Endogenous progesterone is metabolized approximately 50% into 5α-dihydroprogesterone in the [[corpus luteum]], 35% into 3β-dihydroprogesterone in the liver, and 10% into 20α-dihydroprogesterone.<ref name="pmid15492972">{{cite journal | vauthors = Anderson GD, Odegard PS | title = Pharmacokinetics of estrogen and progesterone in chronic kidney disease | journal = Advances in Chronic Kidney Disease | volume = 11 | issue = 4 | pages = 357–360 | date = October 2004 | pmid = 15492972 | doi = 10.1053/j.ackd.2004.07.001 }}</ref>

Relatively small portions of progesterone are hydroxylated via [[17α-hydroxylase]] (CYP17A1) and [[21-hydroxylase]] (CYP21A2), into [[17α-hydroxyprogesterone]] and [[11-deoxycorticosterone]] (21-hydroxyprogesterone), respectively,<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }}</ref> and [[pregnanetriol]]s are formed secondarily to 17α-hydroxylation.<ref name="GreenblattBrogan2016">{{cite book| vauthors = Greenblatt JM, Brogan K |title=Integrative Therapies for Depression: Redefining Models for Assessment, Treatment and Prevention|url=https://books.google.com/books?id=GpHwCgAAQBAJ&pg=PA201|date=27 April 2016|publisher=CRC Press|isbn=978-1-4987-0230-0|pages=201–}}</ref><ref name="Graham2012">{{cite book|vauthors=Graham C|title=Reproductive Biology of the Great Apes: Comparative and Biomedical Perspectives|url=https://books.google.com/books?id=iUA0CdGhYksC&pg=PA179|date=2 December 2012|publisher=Elsevier|isbn=978-0-323-14971-6|pages=179–|access-date=6 November 2016|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114024936/https://books.google.com/books?id=iUA0CdGhYksC&pg=PA179|url-status=live}}</ref> Even smaller amounts of progesterone may also be hydroxylated via [[11β-hydroxylase]] (CYP11B1) and, to a lesser extent, via [[aldosterone synthase]] (CYP11B2) into [[11β-hydroxyprogesterone]].<ref name="pmid23322723">{{cite journal | vauthors = Strushkevich N, Gilep AA, Shen L, Arrowsmith CH, Edwards AM, Usanov SA, Park HW | title = Structural insights into aldosterone synthase substrate specificity and targeted inhibition | journal = Molecular Endocrinology | volume = 27 | issue = 2 | pages = 315–324 | date = February 2013 | pmid = 23322723 | pmc = 5417327 | doi = 10.1210/me.2012-1287 }}</ref><ref name="pmid29277707">{{cite journal | vauthors = van Rooyen D, Gent R, Barnard L, Swart AC | title = The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 178 | pages = 203–212 | date = April 2018 | pmid = 29277707 | doi = 10.1016/j.jsbmb.2017.12.014 | s2cid = 3700135 }}</ref><ref name=wj/> In addition, progesterone can be hydroxylated in the liver by other [[cytochrome P450]] enzymes that are not steroid-specific.<ref name="Piccinato2008">{{cite book| vauthors = de Azevedo Piccinato C |title=Regulation of Steroid Metabolism and the Hepatic Transcriptome by Estradiol and Progesterone|url=https://books.google.com/books?id=2nlbQ12QrSsC&pg=PA24|year=2008|isbn=978-1-109-04632-8|pages=24–25 }}{{Dead link|date=February 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> Catalyzed mainly by [[CYP3A4]], 6β-Hydroxylation is the major transformation and is responsible for approximately 70% of cytochrome P450-mediated progesterone metabolism.<ref name="Piccinato2008" /> Other routes include 6α-, 16α-, and 16β-hydroxylation.<ref name="pmid14667980" /> However, treatment of women with [[ketoconazole]] (a strong CYP3A4 inhibitor) had minimal effects on progesterone levels, producing only a slight and non-significant increase, suggesting that cytochrome P450 enzymes play only a small role in progesterone metabolism.<ref name="pmid1825737">{{cite journal | vauthors = Akalin S | title = Effects of ketoconazole in hirsute women | journal = Acta Endocrinologica | volume = 124 | issue = 1 | pages = 19–22 | date = January 1991 | pmid = 1825737 | doi = 10.1530/acta.0.1240019 | s2cid = 9831739 }}</ref>
{{Progesterone metabolism||align=center|caption=This diagram illustrates the [[metabolic pathway]]s involved in the [[metabolism]] of progesterone in humans. In addition to the [[Biotransformation|transformations]] shown in the diagram, [[Bioconjugation|conjugation]] (specifically [[glucuronidation]] and [[sulfation]]) occurs with [[metabolite]]s of progesterone that have one or more available [[Hydroxyl group|hydroxyl]] (–OH) [[Functional group|groups]].}}
===Levels===
[[File:Progesterone levels across the normal menstrual cycle in women.png|class=skin-invert-image|thumb|upright=1.9|Progesterone levels across the menstrual cycle in normally cycling and ovulatory women.<ref name="pmid16776638">{{cite journal | vauthors = Stricker R, Eberhart R, Chevailler MC, Quinn FA, Bischof P, Stricker R | title = Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT analyzer | journal = Clinical Chemistry and Laboratory Medicine | volume = 44 | issue = 7 | pages = 883–887 | date = 2006 | pmid = 16776638 | doi = 10.1515/CCLM.2006.160 | s2cid = 524952 }}</ref> The horizontal lines are the mean integrated levels for each curve; the vertical line is mid-cycle.]]

Relatively low during the preovulatory phase of the [[menstrual cycle]], progesterone levels rise after [[ovulation]] and are elevated during the [[luteal phase]], as shown in the diagram. Progesterone levels tend to be less than 2&nbsp;ng/mL prior to ovulation and greater than 5&nbsp;ng/mL after ovulation. If [[pregnancy]] occurs, [[human chorionic gonadotropin]] is released, maintaining the corpus luteum and allowing it to maintain levels of progesterone. Between seven and nine weeks gestation, the placenta begins to produce progesterone in place of the corpus luteum in a process called the luteal-placental shift.<ref name="pmid4688578">{{cite journal | vauthors = Csapo AI, Pulkkinen MO, Wiest WG | title = Effects of luteectomy and progesterone replacement therapy in early pregnant patients | journal = American Journal of Obstetrics and Gynecology | volume = 115 | issue = 6 | pages = 759–765 | date = March 1973 | pmid = 4688578 | doi = 10.1016/0002-9378(73)90517-6 }}</ref>

After the luteal-placental shift, progesterone levels start to rise further and may reach 100 to 200&nbsp;ng/mL at term. Whether a decrease in progesterone levels is critical for the initiation of [[Labor (childbirth)|labor]] has been argued and may be species-specific. After delivery of the placenta and during lactation, progesterone levels are very low.{{cn|date=February 2025}}

Progesterone levels are low in children and postmenopausal people.<ref>{{cite web |title=Progesterone Historical Reference Ranges |author=NIH Clinical Center |date=16 August 2004 |publisher=United States National Institutes of Health |url=http://cclnprod.cc.nih.gov/dlm/testguide.nsf/Index/CB26894E1EB28DEF85256BA5005B000E?OpenDocument |archive-url=https://web.archive.org/web/20090109072721/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/Index/CB26894E1EB28DEF85256BA5005B000E?OpenDocument |archive-date=9 January 2009 |access-date=12 March 2008}}</ref> Adult males have levels similar to those in women during the follicular phase of the menstrual cycle.
{{clear}}
{| class="wikitable sortable mw-collapsible" style="text-align:left; margin-left:auto; margin-right:auto; border:none;"
|+ class="nowrap" | Endogenous <noinclude>[[progesterone (medication)|progesterone]]</noinclude><includeonly>progesterone</includeonly> production rates and plasma progesterone levels
|-
! Group !! {{abbr|P4|Progesterone}} production !! {{abbr|P4|Progesterone}} levels
|-
| [[Prepubertal]] children || {{abbr|ND|No data}} || 0.06–0.5&nbsp;ng/mL
|-
| [[Pubertal]] girls<br />&nbsp;&nbsp;[[Tanner stage I]] (childhood)<br />&nbsp;&nbsp;[[Tanner stage II]] (ages 8–12)<br />&nbsp;&nbsp;[[Tanner stage III]] (ages 10–13)<br />&nbsp;&nbsp;[[Tanner stage IV]] (ages 11–14)<br />&nbsp;&nbsp;[[Tanner stage V]] (ages 12–15)<br />&nbsp;&nbsp;&nbsp;&nbsp;[[Follicular phase]] (days 1–14)<br />&nbsp;&nbsp;&nbsp;&nbsp;[[Luteal phase]] (days 15–28) || &nbsp;<br />{{abbr|ND|No data}}<br />{{abbr|ND|No data}}<br />{{abbr|ND|No data}}<br />{{abbr|ND|No data}}<br />&nbsp;<br />{{abbr|ND|No data}}<br />{{abbr|ND|No data}} || &nbsp;<br />0.22 (<0.10–0.32) ng/mL<br />0.30 (0.10–0.51) ng/mL<br />0.36 (0.10–0.75) ng/mL<br />1.75 (<0.10–25.0) ng/mL<br />&nbsp;<br />0.35 (0.13–0.75) ng/mL<br />2.0–25.0&nbsp;ng/mL
|-
| [[Premenopausal]] women<br />&nbsp;&nbsp;[[Follicular phase]] (days 1–14)<br />&nbsp;&nbsp;[[Luteal phase]] (days 15–28)<br />&nbsp;&nbsp;[[Oral contraceptive]] ([[anovulatory]]) || &nbsp;<br />0.75–5.4&nbsp;mg/day<br />15–50&nbsp;mg/day<br />{{abbr|ND|No data}} || &nbsp;<br />0.02–1.2&nbsp;ng/mL<br />4–30&nbsp;ng/mL<br />0.1–0.3&nbsp;ng/mL
|-
| [[Postmenopausal]] women<br />[[Oophorectomy|Oophorectomized]] women<br />[[Oophorectomy|Oophorectomized]] and [[Adrenalectomy|adrenalectomized]] women || {{abbr|ND|No data}}<br />1.2&nbsp;mg/day<br /><0.3&nbsp;mg/day || 0.03–0.3&nbsp;ng/mL<br />0.39&nbsp;ng/mL<br />{{abbr|ND|No data}}
|-
| [[Pregnant]] women<br />&nbsp;&nbsp;[[First trimester]] (weeks 1–12)<br />&nbsp;&nbsp;[[Second trimester]] (weeks 13–26)<br />&nbsp;&nbsp;[[Third trimester]] (weeks 27–40)<br />&nbsp;&nbsp;[[Postpartum]] (at 24 hours) || &nbsp;<br />55&nbsp;mg/day<br />92–100&nbsp;mg/day<br />190–563&nbsp;mg/day<br />{{abbr|ND|No data}} || &nbsp;<br />9–75&nbsp;ng/mL<br />17–146&nbsp;ng/mL<br />55–255&nbsp;ng/mL<br />19&nbsp;ng/mL
|-
| Men || 0.75–3&nbsp;mg/day || 0.1–0.3&nbsp;ng/mL
|- class="sortbottom"
| colspan="5" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Notes:''' Mean levels are given as a single value and ranges are given after in parentheses. '''Sources:''' <noinclude><ref name="pmid945344" /><ref name="Chernecky_Berger_2012">{{cite book|vauthors=Chernecky CC, Berger BJ|title=Laboratory Tests and Diagnostic Procedures - E-Book|url=https://books.google.com/books?id=dWHYcOJK-cgC&pg=PA908|date=31 October 2012|publisher=Elsevier Health Sciences|isbn=978-1-4557-4502-9|pages=908–|access-date=23 August 2023|archive-date=27 February 2024|archive-url=https://web.archive.org/web/20240227031646/https://books.google.com/books?id=dWHYcOJK-cgC&pg=PA908#v=onepage&q&f=false|url-status=live}}</ref><ref name="Becker_2001">{{cite book|vauthors=Becker KL|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|access-date=23 August 2023|archive-date=27 February 2024|archive-url=https://web.archive.org/web/20240227031703/https://books.google.com/books?id=FVfzRvaucq8C&pg=PA940#v=onepage&q&f=false|url-status=live}}</ref><ref name="Josimovich2013b" /><ref name="KeepUtian2012">{{cite book|vauthors=van Keep P, Utian W|title=The Premenstrual Syndrome: Proceedings of a workshop held during the Sixth International Congress of Psychosomatic Obstetrics and Gynecology, Berlin, September 1980|url=https://books.google.com/books?id=0IAJBgAAQBAJ&pg=PA51|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-6255-5|pages=51–52|access-date=1 February 2016|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114025337/https://books.google.com/books?id=0IAJBgAAQBAJ&pg=PA51|url-status=live}}</ref><ref name="StraussBarbieri2009">{{cite book|vauthors=Strauss JF, Barbieri RL|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–|access-date=23 August 2023|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110014157/https://books.google.com/books?id=NudwnhxY8kYC&pg=PA807|url-status=live}}</ref><ref name="Bajaj_Berman2011">{{cite book|vauthors=Bajaj L, Berman S|title=Berman's Pediatric Decision Making|url=https://books.google.com/books?id=NPhnHrDQ1_kC&pg=PA160|date=1 January 2011|publisher=Elsevier Health Sciences|isbn=978-0-323-05405-8|pages=160–|access-date=23 August 2023|archive-date=11 January 2023|archive-url=https://web.archive.org/web/20230111143033/https://books.google.com/books?id=NPhnHrDQ1_kC&pg=PA160|url-status=live}}</ref><ref name="Lauritzen1988">{{cite book | vauthors = Lauritzen C | chapter = Natürliche und Synthetische Sexualhormone – Biologische Grundlagen und Behandlungsprinzipien | pages = 229–306 | trans-chapter = Natural and Synthetic Sexual Hormones – Biological Basis and Medical Treatment Principles | editor1 = Hermann P. G. Schneider | editor2 = Christian Lauritzen | editor3 = Eberhard Nieschlag | title = Grundlagen und Klinik der Menschlichen Fortpflanzung | trans-title = Foundations and Clinic of Human Reproduction | language = de | year = 1988 | publisher = Walter de Gruyter | isbn = 978-3-11-010968-9 | oclc = 35483492 | url = https://books.google.com/books?id=v4HvAQAACAAJ | access-date = 23 August 2023 | archive-date = 1 October 2023 | archive-url = https://web.archive.org/web/20231001111615/https://books.google.com/books?id=v4HvAQAACAAJ | url-status = live }}</ref><ref name="LittleBilliar1983">Little, A. B., & Billiar, R. B. (1983). Progestagens. In Endocrinology of Pregnancy, 3rd Edition (pp. 92–111). Harper and Row Philadelphia. https://scholar.google.com/scholar?cluster=2512291948467467634 {{Webarchive|url=https://web.archive.org/web/20220222083312/https://scholar.google.com/scholar?cluster=2512291948467467634 |date=22 February 2022 }}</ref></noinclude><includeonly>See template.</includeonly>
|}

====Ranges====
Blood test results should always be interpreted using the reference ranges provided by the laboratory that performed the results. Example reference ranges are listed below.

{|class="wikitable" align="center"
!rowspan=2| Person type !!colspan=3| [[Reference range for blood test]]
|-
! Lower limit !! Upper limit !! Unit
|-
| Female - menstrual cycle ||colspan=3| (see diagram below)
|-
| rowspan=2| Female - postmenopausal || [[less than|<]]0.2<ref name=nih2009>[https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument Progesterone Reference Ranges], Performed at the Clinical Center at the National Institutes of Health, Bethesda MD, 03Feb09</ref> || 1<ref name=nih2009/> || [[Nanogram|ng]]/[[Millilitre|mL]]
|-
| <0.6<ref name="mass-converted">Converted from mass values using molar mass of 314.46 g/mol</ref> || 3<ref name="mass-converted"/> || [[nmol]]/[[Litre|L]]
|-
| rowspan=2| Female on [[oral contraceptive]]s || 0.34<ref name=nih2009/> || 0.92<ref name=nih2009/> || ng/mL
|-
| 1.1<ref name="mass-converted"/> || 2.9<ref name="mass-converted"/> || nmol/L
|-
| rowspan=2| Males [[≥]]16 years || 0.27<ref name=nih2009/> || 0.9<ref name=nih2009/> || ng/mL
|-
| 0.86<ref name="mass-converted"/> || 2.9<ref name="mass-converted"/> || nmol/L
|-
| rowspan=2| Female or male 1–9 years || 0.1<ref name=nih2009/> || 4.1<ref name=nih2009/> or 4.5<ref name=nih2009/> || ng/mL
|-
| 0.3<ref name="mass-converted"/> || 13<ref name="mass-converted"/> || nmol/L
|}

{{Hidden begin|toggle=left|title=Reference ranges for the blood content of progesterone during the menstrual cycle}}
[[File:Progesterone during menstrual cycle.png|thumb|upright=3.65|left|Progesterone levels during the [[menstrual cycle]]<ref name="Häggström2014">{{cite journal|year=2014|title=Reference ranges for estradiol, progesterone, luteinizing hormone and follicle-stimulating hormone during the menstrual cycle|journal=WikiJournal of Medicine|volume=1|issue=1|doi=10.15347/wjm/2014.001|issn=2002-4436| vauthors = Häggström M |doi-access=free|s2cid=88035135 }}</ref>
<small><br />• The ranges denoted '''By biological stage''' may be used in closely monitored menstrual cycles in regard to other markers of its biological progression, with the time scale being compressed or stretched to how much faster or slower, respectively, the cycle progresses compared to an average cycle.
<br />• The ranges denoted '''Inter-cycle variability''' are more appropriate to use in non-monitored cycles with only the beginning of menstruation known, but where the woman accurately knows her average cycle lengths and time of ovulation, and that they are somewhat averagely regular, with the time scale being compressed or stretched to how much a woman's average cycle length is shorter or longer, respectively, than the average of the population.
<br />• The ranges denoted '''Inter-woman variability''' are more appropriate to use when the average cycle lengths and time of ovulation are unknown, but only the beginning of menstruation is given.</small>]]{{Clear}}
{{Hidden end}}

===Sources===

====Animal====
{{citation needed span|
Progesterone is produced in high amounts in the [[ovaries]] (by the [[corpus luteum]]) from the onset of [[puberty]] to [[menopause]]. It is produced in smaller amounts by the [[adrenal gland]]s after the onset of [[adrenarche]] in both males and females. To a lesser extent, progesterone is produced in [[nervous tissue]], especially in the brain, and also in [[adipose tissue]] (fat).|date=October 2025}}

{{citation needed span|During human [[pregnancy]], progesterone is produced in increasingly high amounts by the ovaries and [[placenta]]. At first, the source is the corpus luteum that has been "rescued" by the presence of [[human chorionic gonadotropin]] (hCG) from the conceptus. However, after the eighth week, production of progesterone shifts to the placenta which utilizes maternal cholesterol as the initial substrate, and most of the produced progesterone enters the maternal circulation, but some is picked up by the fetal circulation and used as substrate for fetal corticosteroids. At term, the placenta produces about 250&nbsp;mg progesterone per day.|date=October 2025}}

An additional animal source of progesterone is milk products. After consumption of milk products the level of bioavailable progesterone goes up.<ref name="titleResult Content View">{{cite web | url = http://www.docguide.com/news/content.nsf/news/852571020057CCF6852573B1007803AD | title = Milk products are a source of dietary progesterone | access-date = 12 March 2008 | vauthors = Goodson III WH, Handagama P, Moore II DH, Dairkee S | date = 13 December 2007 | publisher = 30th Annual San Antonio Breast Cancer Symposium | pages = abstract # 2028 | archive-date = 20 September 2008 | archive-url = https://web.archive.org/web/20080920110341/http://www.docguide.com/news/content.nsf/news/852571020057CCF6852573B1007803AD | url-status = live }}</ref>

====Plants====
Progesterone has been positively identified in the plant ''[[Juglans regia]]'', a species of walnut.<ref name="pmid20108949">{{cite journal | vauthors = Pauli GF, Friesen JB, Gödecke T, Farnsworth NR, Glodny B | title = Occurrence of progesterone and related animal steroids in two higher plants | journal = Journal of Natural Products | volume = 73 | issue = 3 | pages = 338–345 | date = March 2010 | pmid = 20108949 | doi = 10.1021/np9007415 | bibcode = 2010JNAtP..73..338P | s2cid = 26467578 }}</ref> In addition, progesterone-like [[steroid]]s are found in the plant ''[[Dioscorea mexicana]]'', part of the [[Yam (vegetable)|yam]] family native to [[Mexico]].<ref name="pmid12255132">{{cite journal | vauthors = Applezweig N | title = Steroids | journal = Chemical Week | volume = 104 | pages = 57–72 | date = May 1969 | pmid = 12255132 }}</ref> ''Dioscorea mexicana'' contains a steroid called [[diosgenin]] which is taken from the plant and converted into progesterone.<ref name="pmid16946542">{{cite journal | vauthors = Noguchi E, Fujiwara Y, Matsushita S, Ikeda T, Ono M, Nohara T | title = Metabolism of tomato steroidal glycosides in humans | journal = Chemical & Pharmaceutical Bulletin | volume = 54 | issue = 9 | pages = 1312–1314 | date = September 2006 | pmid = 16946542 | doi = 10.1248/cpb.54.1312 | doi-access = free }}</ref> Diosgenin and progesterone are also found in other ''[[Dioscorea]]'' species, as well as in other plants that are not closely related, such as [[fenugreek]].

Another plant that contains substances readily convertible to progesterone is ''[[Dioscorea pseudojaponica]]'', native to [[Taiwan]]. Research has shown that the Taiwanese yam contains [[saponin]]s—steroids that can be converted to diosgenin and thence to progesterone.<ref name="pmid14558759">{{cite journal | vauthors = Yang DJ, Lu TJ, Hwang LS | title = Isolation and identification of steroidal saponins in Taiwanese yam cultivar (Dioscorea pseudojaponica Yamamoto) | journal = Journal of Agricultural and Food Chemistry | volume = 51 | issue = 22 | pages = 6438–6444 | date = October 2003 | pmid = 14558759 | doi = 10.1021/jf030390j | bibcode = 2003JAFC...51.6438Y | url = http://ntur.lib.ntu.edu.tw/bitstream/246246/189462/1/58.pdf | access-date = 2 April 2022 | archive-date = 3 August 2022 | archive-url = https://web.archive.org/web/20220803163123/http://ntur.lib.ntu.edu.tw/bitstream/246246/189462/1/58.pdf | url-status = live }}</ref>

Many other ''Dioscorea'' species of the yam family contain steroidal substances from which progesterone can be produced. Among the more notable of these are ''[[Dioscorea villosa]]'' and ''[[Dioscorea polygonoides]]''. One study showed that the ''Dioscorea villosa'' contains 3.5% diosgenin.<ref name="pmid15513824">{{cite journal | vauthors = | title = Final report of the amended safety assessment of Dioscorea Villosa (Wild Yam) root extract | journal = International Journal of Toxicology | volume = 23 | issue = Suppl 2 | pages = 49–54 | year = 2004 | pmid = 15513824 | doi = 10.1080/10915810490499055 | s2cid = 962216 | doi-access = free }}</ref> ''Dioscorea polygonoides'' has been found to contain 2.64% diosgenin, as shown by [[gas chromatography-mass spectrometry]].<ref name="Nino-2007">{{cite journal | title = Diosgenin quantification by HPLC in a Dioscorea polygonoides tuber collection from colombian flora | year = 2007 | journal = Journal of the Brazilian Chemical Society | pages = 1073–1076 | volume = 18 | issue = 5 | doi = 10.1590/S0103-50532007000500030 |vauthors=Niño J, Jiménez DA, Mosquera OM, Correa YM | doi-access = free | s2cid = 95193700 }}</ref> Many of the ''Dioscorea'' species that originate from the yam family grow in countries with tropical and subtropical climates.<ref name="Myoda-2005">{{Cite journal | title = Properties of starches in yam (Dioscorea spp.) tuber | year = 2005 | journal = Current Topics in Food Science and Technology | pages = 105–114 | isbn = 81-308-0003-9 |vauthors=Myoda T, Nagai T, Nagashima T }}</ref>

==Medical use==
{{Main|Progesterone (medication)|Pharmacodynamics of progesterone|Pharmacokinetics of progesterone}}

Progesterone is used as a [[medication]]. It is used in combination with [[Estrogen (medication)|estrogens]] mainly in [[Hormone replacement therapy|hormone therapy]] for [[menopausal symptoms]] and [[Hypogonadism|low sex hormone levels]].<ref name="pmid16112947" /><ref name="pmid28159148">{{cite journal | vauthors = Wesp LM, Deutsch MB | title = Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons | journal = The Psychiatric Clinics of North America | volume = 40 | issue = 1 | pages = 99–111 | date = March 2017 | pmid = 28159148 | doi = 10.1016/j.psc.2016.10.006 }}</ref> It may also be used alone to treat menopausal symptoms. Studies have shown that transdermal progesterone (skin patch) and oral micronized progesterone are effective treatments for certain symptoms of menopause such as hot flashes and night sweats, otherwise referred to as vasomotor symptoms or VMS.<ref name="pmid33109992">{{cite journal | vauthors = Dolitsky SN, Cordeiro Mitchell CN, Stadler SS, Segars JH | title = Efficacy of progestin-only treatment for the management of menopausal symptoms: a systematic review | journal = Menopause | volume = 28 | issue = 2 | pages = 217–224 | date = November 2020 | pmid = 33109992 | doi = 10.1097/GME.0000000000001676 | s2cid = 225100434 }}</ref>

It is also used to support [[pregnancy]] and [[fertility]] and to treat [[gynecological disorder]]s.<ref name="pmid25113944">{{cite journal | vauthors = Ruan X, Mueck AO | title = Systemic progesterone therapy--oral, vaginal, injections and even transdermal? | journal = Maturitas | volume = 79 | issue = 3 | pages = 248–255 | date = November 2014 | pmid = 25113944 | doi = 10.1016/j.maturitas.2014.07.009 }}</ref><ref name="pmid26443945">{{cite journal | vauthors = Filicori M | title = Clinical roles and applications of progesterone in reproductive medicine: an overview | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 94 | issue = Suppl 161 | pages = 3–7 | date = November 2015 | pmid = 26443945 | doi = 10.1111/aogs.12791 | doi-access = free }}</ref><ref name="pmid26345161">{{cite journal | vauthors = Ciampaglia W, Cognigni GE | title = Clinical use of progesterone in infertility and assisted reproduction | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 94 | issue = Suppl 161 | pages = 17–27 | date = November 2015 | pmid = 26345161 | doi = 10.1111/aogs.12770 | s2cid = 40753277 | doi-access = free }}</ref><ref name="pmid28989916">{{cite journal | vauthors = Choi SJ | title = Use of progesterone supplement therapy for prevention of preterm birth: review of literatures | journal = Obstetrics & Gynecology Science | volume = 60 | issue = 5 | pages = 405–420 | date = September 2017 | pmid = 28989916 | pmc = 5621069 | doi = 10.5468/ogs.2017.60.5.405 }}</ref> Progesterone has been shown to prevent miscarriage in those with vaginal bleeding early in their current pregnancy and having a previous history of miscarriage.<ref name="pmid32609084">{{cite journal | vauthors = Coomarasamy A, Harb HM, Devall AJ, Cheed V, Roberts TE, Goranitis I, Ogwulu CB, Williams HM, Gallos ID, Eapen A, Daniels JP, Ahmed A, Bender-Atik R, Bhatia K, Bottomley C, Brewin J, Choudhary M, Crosfill F, Deb S, Duncan WC, Ewer A, Hinshaw K, Holland T, Izzat F, Johns J, Lumsden MA, Manda P, Norman JE, Nunes N, Overton CE, Kriedt K, Quenby S, Rao S, Ross J, Shahid A, Underwood M, Vaithilingham N, Watkins L, Wykes C, Horne AW, Jurkovic D, Middleton LJ | display-authors = 6 | title = Progesterone to prevent miscarriage in those with early pregnancy bleeding: the PRISM RCT | language = EN | journal = Health Technology Assessment | volume = 24 | issue = 33 | pages = 1–70 | date = June 2020 | pmid = 32609084 | pmc = 7355406 | doi = 10.3310/hta24330 | doi-access = free }}</ref> Progesterone can be taken [[by mouth]], [[Intravaginal administration|through the vagina]], and by [[Injection (medicine)|injection]] into [[muscle]] or [[fat]], among other [[Route of administration|routes]].<ref name="pmid16112947" />

==Chemistry==
[[File:Sample of Progesterone.jpg|thumb|upright=0.7|A sample of progesterone]]
{{See also|List of neurosteroids}}

Progesterone is a [[naturally occurring]] [[pregnane]] [[steroid]] and is also known as pregn-4-ene-3,20-dione.<ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies |url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1024 |date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=1024–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory |url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA880 |date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=880–}}</ref> It has a [[double bond]] ([[-ene|4-ene]]) between the C4 and C5 positions, and two [[ketone]] [[Functional group|groups]] (3,20-[[Dicarbonyl|dione]]), one at the C3 position and the other at the C20 position.<ref name="Elks2014" /><ref name="IndexNominum2000" />

===Synthesis===
Progesterone is commercially produced by semisynthesis. Two main routes are used: one from yam [[diosgenin]] first pioneered by Marker in 1940, and one based on soy [[phytosterol]]s scaled up in the 1970s. Additional (not necessarily economical) semisyntheses of progesterone have also been reported starting from a variety of steroids. For the example, [[cortisone]] can be simultaneously deoxygenated at the C-17 and C-21 position by treatment with iodotrimethylsilane in [[chloroform]] to produce 11-keto-progesterone (ketogestin), which in turn can be reduced at position-11 to yield progesterone.<ref name="pmid3815593">{{cite journal | vauthors = Numazawa M, Nagaoka M, Kunitama Y | title = Regiospecific deoxygenation of the dihydroxyacetone moiety at C-17 of corticoid steroids with iodotrimethylsilane | journal = Chemical & Pharmaceutical Bulletin | volume = 34 | issue = 9 | pages = 3722–3726 | date = September 1986 | pmid = 3815593 | doi = 10.1248/cpb.34.3722 | doi-access = free }}</ref>

====Marker semisynthesis====
{{main|Marker degradation}}
An economical [[semisynthesis]] of progesterone from the plant steroid [[diosgenin]] isolated from yams was developed by [[Russell Marker]] in 1940 for the [[Parke-Davis]] pharmaceutical company.<ref name="Marker1940">{{cite journal |vauthors=Marker RE, Krueger J | title = Sterols. CXII. Sapogenins. XLI. The Preparation of Trillin and its Conversion to Progesterone | journal = J. Am. Chem. Soc. | volume = 62 | issue = 12 | pages = 3349–3350 | year = 1940| doi = 10.1021/ja01869a023 | bibcode = 1940JAChS..62.3349M }}</ref> This synthesis is known as the [[Marker degradation]].
[[File:Marker snythesis.png|class=skin-invert-image|thumb|center|upright=3.65|The Marker [[semisynthesis]] of progesterone from [[diosgenin]]<ref name="Marker1940"/>]]

The [[16-DPA]] intermediate is important to the synthesis of many other medically important steroids. A very similar approach can produce 16-DPA from [[solanine]].<ref name="Goswami-2003">{{cite journal | vauthors = Goswami A, Kotoky R, Rastogi RC, Ghosh AC |title=A One-Pot Efficient Process for 16-Dehydropregnenolone Acetate |journal=Organic Process Research & Development |date=1 May 2003 |volume=7 |issue=3 |pages=306–308 |doi=10.1021/op0200625}}</ref>

====Soy semisynthesis====
Progesterone can also be made from the [[stigmasterol]] found in [[soybean oil]] also. c.f. [[Percy Julian]].

[[File:Stigmasterol to progesterone synthesis.png|class=skin-invert-image|thumb| center |upright=3.65|[[Stigmasterol]] to progesterone synthesis<ref name=Heyl>{{cite journal | vauthors = Heyl FW | title = Progesterone from 3-Acetoxybisnor-5-cholenaldehyde and 3-Ketobisnor-4-cholenaldehyde | journal = Journal of the American Chemical Society | volume = 72 | issue = 6 | pages = 2617–2619 | date = 1950 | doi = 10.1021/ja01162a076 | bibcode = 1950JAChS..72.2617H }}</ref><ref name="Slomp-1958">{{cite journal | vauthors = Slomp G | title = Ozonolysis. II. 1 The Effect of Pyridine on the Ozonolysis of 4,22-Stigmastadien-3-one 2 | journal = Journal of the American Chemical Society | volume = 80 | issue = 4 | pages = 915–921 | date = 1958 | doi = 10.1021/ja01537a041 | bibcode = 1958JAChS..80..915S }}</ref><ref name="pmid915584">{{cite journal | vauthors = Sundararaman P, Djerassi C | title = A convenient synthesis of progesterone from stigmasterol | journal = The Journal of Organic Chemistry | volume = 42 | issue = 22 | pages = 3633–3634 | date = October 1977 | pmid = 915584 | doi = 10.1021/jo00442a044 }}</ref><ref name="PBS.org-2007">{{cite web | url = https://www.pbs.org/wgbh/nova/video/forgotten-genius/ | date = 6 February 2007 | title = Nova Transcripts: Forgotten Genius | publisher = PBS.org | access-date = 8 September 2017 | archive-date = 11 October 2018 | archive-url = https://web.archive.org/web/20181011224654/http://www.pbs.org/wgbh/nova/transcripts/3402_julian.html | url-status = live }}</ref><ref name="lipidlibrary.aocs.org">{{cite web | url = http://lipidlibrary.aocs.org/history/Julian/index.htm | title = Giants of the Past | publisher = lipidlibrary.aocs.org | archive-url = https://web.archive.org/web/20120415001340/http://lipidlibrary.aocs.org/history/Julian/index.htm | archive-date = 15 April 2012 }}</ref>]]

====Total synthesis====
[[File:Progesterone Synthesis.png|class=skin-invert-image|thumb|upright=2|The Johnson total synthesis of progesterone<ref name="pmid5131151"/>]]

A [[total synthesis]] of progesterone was reported in 1971 by [[William Summer Johnson|William S. Johnson]].<ref name="pmid5131151">{{cite journal | vauthors = Johnson WS, Gravestock MB, McCarry BE | title = Acetylenic bond participation in biogenetic-like olefinic cyclizations. II. Synthesis of dl-progesterone | journal = Journal of the American Chemical Society | volume = 93 | issue = 17 | pages = 4332–4334 | date = August 1971 | pmid = 5131151 | doi = 10.1021/ja00746a062 | bibcode = 1971JAChS..93.4332J }}</ref> The synthesis begins with reacting the [[phosphonium salt]] '''<u>7</u>''' with [[Organolithium reagent|phenyl lithium]] to produce the [[phosphonium ylide]] '''<u>8</u>'''. The ylide '''<u>8</u>''' is reacted with an [[aldehyde]] to produce the [[alkene]] '''<u>9</u>'''. The [[ketal]] [[protecting group]]s of '''<u>9</u>''' are hydrolyzed to produce the diketone '''<u>10</u>''', which in turn is cyclized to form the cyclopentenone '''<u>11</u>'''. The ketone of '''<u>11</u>''' is reacted with methyl lithium to yield the tertiary alcohol '''<u>12</u>''', which in turn is treated with acid to produce the tertiary cation '''<u>13</u>'''. The key step of the synthesis is the π-cation cyclization of '''<u>13</u>''' in which the B-, C-, and D-rings of the steroid are simultaneously formed to produce '''<u>14</u>'''. This step resembles the cationic cyclization reaction used in the biosynthesis of steroids and hence is referred to as ''biomimetic''. In the next step the [[enol]] [[orthoester]] is hydrolyzed to produce the ketone '''<u>15</u>'''. The cyclopentene A-ring is then opened by oxidizing with ozone to produce '''<u>16</u>'''. Finally, the diketone '''<u>17</u>''' undergoes an intramolecular [[aldol condensation]] by treating with aqueous potassium hydroxide to produce progesterone.<ref name="pmid5131151"/>

==History==
[[George W. Corner]] and [[Willard M. Allen]] discovered the hormonal action of progesterone in 1929.<ref name="Josimovich2013" /><ref name="Corner-1929">{{Cite journal|vauthors=Corner GW, Allen WM|date=1 March 1929|title=Physiology of the corpus luteum|journal=American Journal of Physiology. Legacy Content|volume=88|issue=2|pages=326–339|url=https://journals.physiology.org/doi/abs/10.1152/ajplegacy.1929.88.2.326|doi=10.1152/ajplegacy.1929.88.2.326|issn=0002-9513|url-access=subscription|access-date=12 August 2021|archive-date=12 August 2021|archive-url=https://web.archive.org/web/20210812022335/https://journals.physiology.org/doi/abs/10.1152/ajplegacy.1929.88.2.326|url-status=live}}</ref><ref name="CoutinhoSegal1999">{{cite book | vauthors = Coutinho EM, Segal SJ | title = Is Menstruation Obsolete? | url = https://books.google.com/books?id=1ZzmCwAAQBAJ&pg=PA31 | year = 1999 | publisher = Oxford University Press | isbn = 978-0-19-513021-8 | pages = 31– | access-date = 5 October 2016 | archive-date = 14 January 2023 | archive-url = https://web.archive.org/web/20230114024937/https://books.google.com/books?id=1ZzmCwAAQBAJ&pg=PA31 | url-status = live }}</ref><ref name="Walker2008">{{cite book | vauthors = Walker A | title = The Menstrual Cycle |url=https://books.google.com/books?id=7HQBAwAAQBAJ&pg=PA49 |date=7 March 2008 |publisher=Routledge |isbn=978-1-134-71411-7 |pages=49–}}</ref> By 1931–1932, nearly pure crystalline material of high progestational activity had been isolated from the [[corpus luteum]] of animals; by 1934, pure crystalline progesterone had been refined and obtained, and the [[chemical structure]] of progesterone was determined.<ref name="Josimovich2013" /><ref name="CoutinhoSegal1999" /> This was achieved by [[Adolf Butenandt]] at the ''Chemisches Institut'' of [[Gdańsk University of Technology|Gdańsk Technical University]] in [[Danzig]], who extracted this new compound from several thousand liters of [[urine]].<ref name="Piosik-2003">{{Cite journal | vauthors = Piosik R | title = Adolf Butenandt und sein Wirken an der Technischen Hochschule Danzig | doi = 10.1002/ckon.200390038 | journal = CHEMKON | volume = 10 | issue = 3 | pages = 135–138 | year = 2003 }}</ref>

[[Chemical synthesis]] of progesterone from [[stigmasterol]] and [[pregnanediol]] was accomplished later that year.<ref name="CoutinhoSegal1999"/><ref name="Ginsburg2012">{{cite book|vauthors=Ginsburg B|title=Premenstrual Syndrome: Ethical and Legal Implications in a Biomedical Perspective|url=https://books.google.com/books?id=HTLoBwAAQBAJ&pg=PA274|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4684-5275-4|pages=274–|access-date=5 October 2016|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114025025/https://books.google.com/books?id=HTLoBwAAQBAJ&pg=PA274|url-status=live}}</ref> Up to this point, progesterone, known generically as corpus luteum hormone, had been being referred to by several groups by different names, including corporin, lutein, luteosterone, and progestin.<ref name="Josimovich2013" /><ref name="Rolleston1936">{{cite book |vauthors=Rolleston HD |title=The Endocrine Organs in Health and Disease: With an Historical Review |url=https://books.google.com/books?id=tkgbAAAAIAAJ |year=1936 |publisher=Oxford University Press, H. Milford |page=406 |access-date=5 October 2016 |archive-date=14 January 2023 |archive-url=https://web.archive.org/web/20230114024937/https://books.google.com/books?id=tkgbAAAAIAAJ |url-status=live }}</ref> In 1935, at the time of the Second International Conference on the Standardization of Sex Hormones in [[London, England]], a compromise was reached between the groups, and the name 'progesterone' (progestational steroidal ketone) was created.<ref name="Josimovich2013" /><ref name="pmid4922128">{{cite journal | vauthors = Allen WM | title = Progesterone: how did the name originate? | journal = Southern Medical Journal | volume = 63 | issue = 10 | pages = 1151–1155 | date = October 1970 | pmid = 4922128 | doi = 10.1097/00007611-197010000-00012 | s2cid = 35867375 }}</ref>

===Veterinary use===
The use of progesterone tests in dog breeding to pinpoint ovulation is becoming more widely used. There are several tests available, the most reliable being a blood test with the blood sample drawn by a veterinarian and sent to a lab for processing. Results can usually be obtained within 24 to 72 hours. The rationale for using progesterone tests is that increased numbers begin in close proximity to preovulatory surge in gonadotrophins and continue through ovulation and estrus. When progesterone levels reach certain levels they can signal the stage of estrus the female is. Prediction of birth date of the pending litter can be very accurate if ovulation date is known. Puppies deliver within a day or two of nine weeks gestation in most cases. It is not possible to determine pregnancy using progesterone tests once a breeding has taken place, however. This is due to the fact that, in dogs, progesterone levels remain elevated throughout the estrus period.<ref name="Refsal-2009">{{Cite journal|vauthors=Refsal K|date=February 2009|title=Interpretation of Serum Progesterone Results for Management of Breeding in Dogs|url=https://www.dcpah.msu.edu/sections/endocrinology/Progesterone_Guidelines.pdf|journal=Webcd.endo.ref|access-date=26 February 2018|archive-date=29 August 2021|archive-url=https://web.archive.org/web/20210829011032/https://cvm.msu.edu/vdl|url-status=live}}</ref>

=== Pricing ===
Pricing for progesterone can vary depending location, insurance coverage, discount coupons, quantity, shortages, manufacturers, brand or generic versions, different pharmacies, and so on. As of 2023, 30 capsules of 100&nbsp;mg of the generic version, Progesterone, from CVS Pharmacy is around $40 without any discounts or insurance applied. The brand version, Prometrium, is around $450 for 30 capsules without any discounts or insurance applied.<ref name="www.goodrx.com-prices">{{cite web |title=Progesterone Prices, Coupons & Savings Tips - GoodRx |url=https://www.goodrx.com/progesterone |access-date=1 August 2023 |website=goodrx.com |archive-date=30 March 2023 |archive-url=https://web.archive.org/web/20230330054318/https://www.goodrx.com/progesterone |url-status=live }}</ref> In comparison, Walgreens offers 30 capsules of 100&nbsp;mg in the generic version for $51 without insurance or coupons applied. The brand name costs around $431 for 30 capsules of 100&nbsp;mg.<ref name="www.goodrx.com-prices-2">{{Cite web |title=Progesterone Prices, Coupons & Savings Tips - GoodRx |url=https://www.goodrx.com/progesterone |access-date=1 August 2023 |website=goodrx.com |archive-date=30 March 2023 |archive-url=https://web.archive.org/web/20230330054318/https://www.goodrx.com/progesterone |url-status=live }}</ref> {{Clear}}

== References ==
* {{Creative Commons text attribution notice|cc=bysa3|url=https://en.wikiversity.org/wiki?curid=269289}}
<references>
<ref name="James2015">{{cite book |vauthors=Jameson JL, De Groot LJ |title=Endocrinology: Adult and Pediatric E-Book |url=https://books.google.com/books?id=xmLeBgAAQBAJ&pg=PA2179 |date=25 February 2015 |publisher=Elsevier Health Sciences |isbn=978-0-323-32195-2 |page=2179 |access-date=29 October 2017 |archive-date=14 January 2023 |archive-url=https://web.archive.org/web/20230114025031/https://books.google.com/books?id=xmLeBgAAQBAJ&pg=PA2179 |url-status=live }}</ref>

<ref name="Josimovich2013">{{cite book |vauthors=Josimovich JB |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 |access-date=1 February 2016 |archive-date=14 January 2023 |archive-url=https://web.archive.org/web/20230114024947/https://books.google.com/books?id=9vv2BwAAQBAJ&pg=PA25 |url-status=live }}</ref>

<ref name="Josimovich2013b">{{cite book |vauthors=Josimovich JB |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 |access-date=1 February 2016 |archive-date=14 January 2023 |archive-url=https://web.archive.org/web/20230114024947/https://books.google.com/books?id=9vv2BwAAQBAJ&pg=PA25 |url-status=live }}</ref>

<ref name="KingBrucker2010">{{cite book |vauthors=King TL, Brucker MC |title=Pharmacology for Women's Health |url=https://books.google.com/books?id=E9qVyrNPsBkC&pg=PA373 |date=25 October 2010 |publisher=Jones & Bartlett Publishers |isbn=978-1-4496-5800-7 |pages=372–373}}</ref>

<!--This ref is defined in a template <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}}</ref>-->

<ref name="pmid8513955">{{cite journal |vauthors=Simon JA, Robinson DE, Andrews MC, Hildebrand JR, Rocci ML, Blake RE, Hodgen GD |title=The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone |journal=Fertility and Sterility |volume=60 |issue=1 |pages=26–33 |date=July 1993 |pmid=8513955 |doi=10.1016/S0015-0282(16)56031-2 |doi-access=free}}</ref>

<ref name="pmid12215716">{{cite journal |vauthors=Stanczyk FZ |title=Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception |journal=Reviews in Endocrine & Metabolic Disorders |volume=3 |issue=3 |pages=211–224 |date=September 2002 |pmid=12215716 |doi=10.1023/A:1020072325818 |s2cid=27018468}}</ref>
</references>

== External links ==
* [http://gmd.mpimp-golm.mpg.de/Spectrums/5e8993d3-17a1-4a05-96f5-03ba3c2270af.aspx Progesterone MS Spectrum]
* {{MeshName|Progesterone}}
* {{Cite web | url = http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Progesterone.html | title = Progesterone | vauthors = Kimball JW | date = 27 May 2007 | work = Kimball's Biology Pages | access-date = 18 June 2008 | archive-url = https://web.archive.org/web/20080618062909/http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Progesterone.html | archive-date = 18 June 2008 }}

{{Progesterone}}
{{Hormones}}
{{Endogenous steroids}}
{{Progestogens and antiprogestogens}}
{{Mineralocorticoids and antimineralocorticoids}}
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| titlestyle = background:#ccccff
| list1 =
{{GABAA receptor positive modulators}}
{{Glucocorticoid receptor modulators}}
{{Mineralocorticoid receptor modulators}}
{{Nicotinic acetylcholine receptor modulators}}
{{Progesterone receptor modulators}}
{{Sigma receptor modulators}}
{{Xenobiotic-sensing receptor modulators}}
}}

[[Category:Progesterone| ]]
[[Category:5α-Reductase inhibitors]]
[[Category:11β-Hydroxysteroid dehydrogenase inhibitors]]
[[Category:Alkene derivatives]]
[[Category:Antimineralocorticoids]]
[[Category:Diketones]]
[[Category:GABAA receptor positive allosteric modulators]]
[[Category:Glucocorticoids]]
[[Category:Glycine receptor antagonists]]
[[Category:Neurosteroids]]
[[Category:Hepatotoxins]]
[[Category:Hormones of the hypothalamus-pituitary-adrenal axis]]
[[Category:Hormones of the hypothalamus-pituitary-gonad axis]]
[[Category:Hormones of the hypothalamic-pituitary-prolactin axis]]
[[Category:Hormones of the ovary]]
[[Category:Hormones of the placenta]]
[[Category:Hormones of the suprarenal cortex]]
[[Category:Hormones of the brain]]
[[Category:Hormones of the pregnant female]]
[[Category:Human female endocrine system]]
[[Category:Human hormones]]
[[Category:Pregnane X receptor agonists]]
[[Category:Pregnanes]]
[[Category:Progestogens]]
[[Category:Prolactin releasers]]
[[Category:Sex hormones]]
[[Category:Sigma antagonists]]
[[Category:Steroid hormones]]
[[Category:Total synthesis]]