Progesterone#Levels

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

Progesterone is the most important progestogen in the body. As a potent agonist of the nuclear progesterone receptor (nPR) (with an affinity of K_D = 1 nM) the resulting effects on ribosomal transcription plays a major role in regulation of female reproduction. In addition, progesterone is an agonist of the more recently discovered membrane progesterone receptors (mPRs),{{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 }} 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.{{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 }} It also functions as a ligand of the PGRMC1 (progesterone receptor membrane component 1) which impacts tumor progression, metabolic regulation, and viability control of nerve cells.{{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 }}{{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 }}{{cite journal | vauthors = Ryu CS, Klein K, Zanger UM | title = Membrane Associated Progesterone Receptors: Promiscuous Proteins with Pleiotropic Functions - Focus on Interactions with Cytochromes P450 | journal = Frontiers in Pharmacology | volume = 8 | pages = 159 | date = 27 March 2017 | pmid = 28396637 | pmc = 5366339 | doi = 10.3389/fphar.2017.00159 | doi-access = free }} Moreover, progesterone is also known to be an antagonist of the sigma σ₁ receptor,{{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 }}{{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 }} a negative allosteric modulator of nicotinic acetylcholine receptors, and a potent antagonist of the mineralocorticoid receptor (MR).{{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 }} Progesterone prevents MR activation by binding to this receptor with an affinity exceeding even those of aldosterone and glucocorticoids such as cortisol and corticosterone, and produces antimineralocorticoid effects, such as natriuresis, at physiological concentrations.{{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 }} In addition, progesterone binds to and behaves as a partial agonist of the glucocorticoid receptor (GR), albeit with very low potency (EC₅₀ >100-fold less relative to cortisol).{{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 }}{{cite journal | vauthors = Lei K, Chen L, Georgiou EX, Sooranna SR, Khanjani S, Brosens JJ, Bennett PR, Johnson MR | display-authors = 6 | title = Progesterone acts via the nuclear glucocorticoid receptor to suppress IL-1β-induced COX-2 expression in human term myometrial cells | journal = PLOS ONE | volume = 7 | issue = 11 | pages = e50167 | year = 2012 | pmid = 23209664 | pmc = 3509141 | doi = 10.1371/journal.pone.0050167 | doi-access = free | bibcode = 2012PLoSO...750167L }}

Progesterone, through its neurosteroid active metabolites such as 5α-dihydroprogesterone and allopregnanolone, acts indirectly as a positive allosteric modulator of the GABA_A receptor.{{cite journal | vauthors = Paul SM, Purdy RH | title = Neuroactive steroids | journal = FASEB Journal | volume = 6 | issue = 6 | pages = 2311–2322 | date = March 1992 | pmid = 1347506 | doi = 10.1096/fasebj.6.6.1347506 | s2cid = 221753076 | doi-access = free }}

Progesterone and some of its metabolites, such as 5β-dihydroprogesterone, are agonists of the pregnane X receptor (PXR),{{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 }} albeit weakly so (EC₅₀ >10 μM).{{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 }} In accordance, progesterone induces several hepatic cytochrome P450 enzymes,{{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}} such as CYP3A4,{{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}}{{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}} especially during pregnancy when concentrations are much higher than usual.{{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}} 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.

Progesterone modulates the activity of CatSper (cation channels of sperm) voltage-gated Ca²⁺ 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.{{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 }}{{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 }}

File:Estradiol and progesterone % changes across the menstrual cycle.tif

Progesterone has a number of physiological effects that are amplified in the presence of estrogens. Estrogens through estrogen receptors (ERs) induce or upregulate the expression of the PR.{{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 }} One example of this is in breast tissue, where estrogens allow progesterone to mediate lobuloalveolar development.{{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 }}{{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 | pages = 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 }}{{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|pages=413}}

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.{{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 }}

Progesterone plays a role in early human sexual differentiation.{{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}} Placental progesterone is the feedstock for the 5α-dihydrotestosterone (DHT) produced via the backdoor pathway found operating in multiple non-gonadal tissues of the fetus,{{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 | pages = e3000002 | date = February 2019 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002 | doi-access = free }} whereas deficiencies in this pathway lead to undervirilization of the male fetus, resulting in incomplete development of the male genitalia.{{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 }}{{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 }} DHT is a potent androgen that is responsible for the development of male genitalia, including the penis and scrotum.{{cn|date=February 2025}}

During early fetal development, the undifferentiated gonads can develop into either testes or ovaries. The presence of the Y chromosome leads to the development of testes. The testes then produce testosterone, which is converted to DHT via the enzyme 5α-reductase. DHT is a potent androgen that is responsible for the masculinization of the external genitalia and the development of the prostate gland. Progesterone, produced by the placenta during pregnancy, plays a role in fetal sexual differentiation by serving as a precursor molecule for the synthesis of DHT via the backdoor pathway. In the absence of adequate levels of steroidogenic enzymes during fetal development, the backdoor pathway for DHT synthesis can become deficient, leading to undermasculinization of the male fetus. This can result in the development of ambiguous genitalia or even female genitalia in some cases. Therefore, both DHT and progesterone play crucial roles in early fetal sexual differentiation, with progesterone acting as a precursor molecule for DHT synthesis and DHT promoting the development of male genitalia.

File:Endometrium ocp use3.jpg 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.{{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 }} Detailed characterisation of the events occurring in sperm in response to progesterone has elucidated certain events including intracellular calcium transients and maintained changes,{{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 }} slow calcium oscillations,{{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 }} now thought to possibly regulate motility.{{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 }} It is produced by the ovaries.{{cite book | vauthors = Marieb E | title = Anatomy & physiology | publisher = Benjamin-Cummings | page= 903 | year = 2013 | isbn = 9780321887603 }} Progesterone has also been shown to demonstrate effects on octopus spermatozoa.{{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 }}

Progesterone is sometimes called the "hormone of pregnancy",{{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 | url-status = dead }} 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-mitogenic in endometrial epithelial cells, and as such, mitigates the tropic effects of estrogen.{{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 }} 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 anovulatory dysfunctional uterine bleeding.
• During implantation and gestation, progesterone appears to decrease the maternal immune response to allow for the acceptance of the pregnancy.{{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 }}
• Progesterone decreases contractility of the uterine smooth muscle. This effect contributes to prevention of preterm labor. 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 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.{{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 | pages = e064547 | date = February 2022 | pmid = 35168930 | pmc = 8845039 | doi = 10.1136/bmj-2021-064547 }}
• A drop in progesterone levels is possibly one step that facilitates the onset of 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 metabolizes placental progesterone in the production of adrenal steroids.

{{See also|Breast development#Biochemistry}}

Progesterone plays an important role in breast development. In conjunction with prolactin, it mediates lobuloalveolar maturation of the mammary glands during pregnancy to allow for milk production and thus lactation and breastfeeding of offspring following parturition (childbirth).{{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 }} Estrogen induces expression of the PR in breast tissue and hence progesterone is dependent on estrogen to mediate lobuloalveolar development. It has been found that {{abbrlink|RANKL|Receptor activator of nuclear factor kappa-B ligand}} is a critical downstream mediator of progesterone-induced lobuloalveolar maturation.{{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 }} 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.

Though to a far lesser extent than estrogen, which is the major mediator of mammary ductal development (via the ERα),{{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}}{{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 }} progesterone may be involved in ductal development of the mammary glands to some extent as well.{{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 | pages = R44 | date = May 2013 | pmid = 23705924 | pmc = 3738150 | doi = 10.1186/bcr3431 | doi-access = free }} PR knockout mice or mice treated with the PR antagonist mifepristone show delayed although otherwise normal mammary ductal development at puberty. In addition, mice modified to have overexpression of PRA display ductal hyperplasia, and progesterone induces ductal growth in the mouse mammary gland. Progesterone mediates ductal development mainly via induction of the expression of amphiregulin, the same growth factor that estrogen primarily induces the expression of to mediate ductal development. 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.

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.{{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 }}{{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 }} Most progestins, or 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.{{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 }} 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.{{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 }}{{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 | pages = 121 | date = July 2016 | pmid = 27456847 | pmc = 4960754 | doi = 10.1186/s13643-016-0294-5 | doi-access = free }}{{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 }} However, this may simply be an artifact of the low progesterone levels produced with oral progesterone.{{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 }} More research is needed on the role of progesterone in breast cancer.

The estrogen receptor, as well as the progesterone receptor, have been detected in the skin, including in keratinocytes and fibroblasts.{{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 }}{{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 }} At menopause and thereafter, decreased levels of female sex hormones result in atrophy, thinning, and increased wrinkling of the skin and a reduction in skin elasticity, firmness, and strength. These skin changes constitute an acceleration in skin aging and are the result of decreased collagen content, irregularities in the morphology of epidermal skin cells, decreased ground substance between skin fibers, and reduced capillaries and blood flow. The skin also becomes more dry during menopause, which is due to reduced skin hydration and surface lipids (sebum production). Along with chronological aging and photoaging, estrogen deficiency in menopause is one of the three main factors that predominantly influences skin aging.

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. These benefits include increased skin collagen content, skin thickness and elasticity, and skin hydration and surface lipids. Topical estrogen has been found to have similar beneficial effects on the skin. 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. Skin hydration and surface lipids, on the other hand, did not significantly change with topical progesterone.

These findings suggest that progesterone, like estrogen, also has beneficial effects on the skin, and may be independently protective against skin aging.

{{See also|Sexual motivation and hormones}}

Progesterone and its neurosteroid active metabolite allopregnanolone appear to be importantly involved in libido in females.{{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}}

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.{{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 }}{{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/ |url-status=dead }}{{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}}{{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}}

Progesterone, like pregnenolone and dehydroepiandrosterone (DHEA), belongs to an important group of endogenous steroids called neurosteroids. It can be metabolized within all parts of the central nervous system.{{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 }}

Neurosteroids are neuromodulators, and are neuroprotective, neurogenic, and regulate neurotransmission and myelination.{{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 }} 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 σ₁ and nACh receptors.{{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 | pages = 159 | date = September 2013 | pmid = 24065876 | pmc = 3776940 | doi = 10.3389/fnins.2013.00159 | doi-access = free }}

{{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.{{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 }}

The mechanism of progesterone protective effects may be the reduction of inflammation that follows brain trauma and hemorrhage.{{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 }}{{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 }}

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 channels that trigger neurotransmitter release.{{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 }} It does so by manipulating the signaling pathways of transcription factors involved in this release. Another method for reducing the excitotoxicity is by up-regulating the GABA_A, a widespread inhibitory neurotransmitter receptor.{{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 }}

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 c.{{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 }}

Not only does progesterone help prevent further damage, it has also been shown to aid in neuroregeneration.{{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 }} 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 macrophages and microglia sent to the injured tissue.{{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 }} 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 oxygen free radicals faster than without. There is also evidence that the addition of progesterone can also help remyelinate damaged axons due to trauma, restoring some lost neural signal conduction. Another way progesterone aids in regeneration includes increasing the circulation of endothelial progenitor cells in the brain. This helps new vasculature to grow around scar tissue which helps repair the area of insult.{{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 }}

Progesterone enhances the function of serotonin receptors 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, and cannabis when their progesterone levels fall below optimal levels.{{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 }}

• 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.{{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 }} 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.
• 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.{{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 }}

In a 2012 University of Amsterdam study of 120 women, 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.{{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}}

• Progesterone also has a role in skin elasticity and bone strength, in 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.{{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}}
• During pregnancy, progesterone is said to decrease uterine irritability.{{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–}}
• During pregnancy, progesterone helps to suppress immune responses of the mother to fetal antigens, which prevents rejection of the fetus.
• Progesterone raises epidermal growth factor-1 (EGF-1) levels, a factor often used to induce proliferation, and used to sustain cultures, of stem cells.{{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 }}
• Progesterone increases core temperature (thermogenic function) during ovulation.{{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}}{{Citation|vauthors=Rothchild I|title=The Physiologic Basis for the Temperature Raising Effect of Progesterone|date=1969|url=https://doi.org/10.1007/978-1-4684-1782-1_49|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|access-date=22 March 2021|url-access=subscription|archive-date=29 August 2021|archive-url=https://web.archive.org/web/20210829011027/https://link.springer.com/chapter/10.1007%2F978-1-4684-1782-1_49|url-status=live}}
• Progesterone reduces spasm and relaxes smooth muscle. Bronchi are widened and mucus regulated. (PRs are widely present in submucosal tissue.){{cn|date=February 2025}}
• Progesterone acts as an antiinflammatory agent and regulates the immune response.{{cn|date=February 2025}}
• Progesterone reduces gall-bladder activity.{{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 }}
• Progesterone normalizes blood clotting and vascular tone, zinc and copper levels, 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).{{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}}
• 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 may affect the susceptibility to diabetes or gestational diabetes.{{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 }}{{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 }}
• 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.{{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 }}
• Current data shows that micronized progesterone, which is chemically identical to the progesterone produced in people's bodies, 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).{{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 }}
• There have not been any studies done yet on the effects of micronized progesterone on hair loss due to menopause.{{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 }}
• Despite suggestions for using hormone therapy to prevent loss of muscle mass in post-menopausal individuals (50 and older), menopausal hormone therapy involving either estrogen alone or estrogen and progesterone has not been found to preserve muscle mass.{{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 }} Menopausal hormone therapy also does not result in body weight reduction, BMI reduction, or change in glucose metabolism.{{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 }}

File:Steroidogenesis.svg, showing progesterone among the progestogens in yellow area.{{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}}]]

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

Cholesterol undergoes double oxidation to produce 22R-hydroxycholesterol and then 20α,22R-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 keto group and second, the double bond is moved to C4, from C5 through a keto/enol tautomerization reaction.{{cite book | vauthors = Bewick PM | title = Medicinal natural products: a biosynthetic approach | publisher = Wiley | location = New York | year = 2002 | pages = 244 | isbn = 0-471-49641-3 }} This reaction is catalyzed by 3β-hydroxysteroid dehydrogenase/δ^5-4-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.{{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 }}

Approximately 25 mg of progesterone is secreted from the ovaries per day, while the adrenal glands produce about 2 mg of progesterone per day.{{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}}

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

Progesterone binds extensively to plasma proteins, including albumin (50–54%) and transcortin (43–48%).{{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 }} It has similar affinity for albumin relative to the PR.

The metabolism of progesterone is rapid and extensive and occurs mainly in the liver,{{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}}{{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–}} though enzymes that metabolize progesterone are also expressed widely in the brain, skin, and various other extrahepatic tissues.{{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–}} Progesterone has an elimination half-life of only approximately 5 minutes in circulation. The metabolism of progesterone is complex, and it may form as many as 35 different unconjugated metabolites when it is ingested orally. Progesterone is highly susceptible to enzymatic reduction via reductases and hydroxysteroid dehydrogenases due to its double bond (between the C4 and C5 positions) and its two ketones (at the C3 and C20 positions).

The major metabolic pathway of progesterone is reduction by 5α-reductase and 5β-reductase into the dihydrogenated 5α-dihydroprogesterone and 5β-dihydroprogesterone, respectively.{{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 }}{{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–}}{{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}} 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.{{cite book | vauthors = Reddy DS | title = Sex Differences in the Human Brain, their Underpinnings and Implications | chapter = Neurosteroids | series = Progress in Brain Research | volume = 186 | pages = 113–37 | year = 2010 | publisher = Elsevier | pmid = 21094889 | pmc = 3139029 | doi = 10.1016/B978-0-444-53630-3.00008-7 | isbn = 9780444536303 }} Subsequently, 20α-hydroxysteroid dehydrogenase and 20β-hydroxysteroid dehydrogenase reduce these metabolites to form the corresponding hexahydrogenated pregnanediols (eight different isomers in total), which are then conjugated via glucuronidation and/or sulfation, released from the liver into circulation, and excreted by the kidneys into the urine. The major metabolite of progesterone in the urine is the 3α,5β,20α isomer of pregnanediol glucuronide, which has been found to constitute 15 to 30% of an injection of progesterone.{{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–}} 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.{{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 }} Progesterone can also first be hydroxylated (see below) and then reduced. 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.{{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 }}

Relatively small portions of progesterone are hydroxylated via 17α-hydroxylase (CYP17A1) and 21-hydroxylase (CYP21A2) into 17α-hydroxyprogesterone and 11-deoxycorticosterone (21-hydroxyprogesterone), respectively,{{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 }} and pregnanetriols are formed secondarily to 17α-hydroxylation.{{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–}}{{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}} Even smaller amounts of progesterone may be also hydroxylated via 11β-hydroxylase (CYP11B1) and to a lesser extent via aldosterone synthase (CYP11B2) into 11β-hydroxyprogesterone.{{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 }}{{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 }} In addition, progesterone can be hydroxylated in the liver by other cytochrome P450 enzymes which are not steroid-specific.{{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 }} 6β-Hydroxylation, which is catalyzed mainly by CYP3A4, is the major transformation, and is responsible for approximately 70% of cytochrome P450-mediated progesterone metabolism. Other routes include 6α-, 16α-, and 16β-hydroxylation. However, treatment of women with ketoconazole, a strong CYP3A4 inhibitor, had minimal effects on progesterone levels, producing only a slight and non-significant increase, and this suggests that cytochrome P450 enzymes play only a small role in progesterone metabolism.{{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 }}

{{Progesterone metabolism||align=center|caption=This diagram illustrates the metabolic pathways involved in the metabolism of progesterone in humans. In addition to the transformations shown in the diagram, conjugation, specifically glucuronidation and sulfation, occurs with metabolites of progesterone that have one or more available hydroxyl (–OH) groups.}}

File:Progesterone levels across the normal menstrual cycle in women.png

Progesterone levels are relatively low during the preovulatory phase of the menstrual cycle, rise after ovulation, and are elevated during the luteal phase, as shown in the diagram above. Progesterone levels tend to be less than 2 ng/mL prior to ovulation and greater than 5 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 7 and 9 weeks, the placenta begins to produce progesterone in place of the corpus luteum in a process called the luteal-placental shift.{{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 }}

After the luteal-placental shift, progesterone levels start to rise further and may reach 100 to 200 ng/mL at term. Whether a decrease in progesterone levels is critical for the initiation of 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.{{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}} Adult males have levels similar to those in women during the follicular phase of the menstrual cycle.

{{clear}}

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.

{{Hidden begin|toggle=left|title=Reference ranges for the blood content of progesterone during the menstrual cycle}}

File:Progesterone during menstrual cycle.png.{{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 }}

• 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.

• 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.]]{{Clear}}

{{Hidden end}}

Progesterone is produced in high amounts in the ovaries (by the corpus luteum) from the onset of puberty to menopause, and is also produced in smaller amounts by the adrenal glands 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 in adipose (fat) tissue, as well.

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 8th week, production of progesterone shifts to the placenta. The placenta 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 mg progesterone per day.

An additional animal source of progesterone is milk products. After consumption of milk products the level of bioavailable progesterone goes up.{{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 }}

In at least one plant, Juglans regia, progesterone has been detected.{{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 | s2cid = 26467578 }} In addition, progesterone-like steroids are found in Dioscorea mexicana. Dioscorea mexicana is a plant that is part of the yam family native to Mexico.{{cite journal | vauthors = Applezweig N | title = Steroids | journal = Chemical Week | volume = 104 | pages = 57–72 | date = May 1969 | pmid = 12255132 }} It contains a steroid called diosgenin that is taken from the plant and is converted into progesterone.{{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 }} 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 saponins — steroids that can be converted to diosgenin and thence to progesterone.{{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 }}

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.{{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 }} Dioscorea polygonoides has been found to contain 2.64% diosgenin as shown by gas chromatography-mass spectrometry.{{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 }} Many of the Dioscorea species that originate from the yam family grow in countries that have tropical and subtropical climates.{{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 }}

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

Progesterone is used as a medication. It is used in combination with estrogens mainly in hormone therapy for menopausal symptoms and low sex hormone levels.{{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 }} 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, which are otherwise referred to as vasomotor symptoms or VMS.{{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 }}

It is also used to support pregnancy and fertility and to treat gynecological disorders.{{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 }}{{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 }}{{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 }}{{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 }} Progesterone has been shown to prevent miscarriage in those with 1) vaginal bleeding early in their current pregnancy and 2) a previous history of miscarriage.{{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 }} Progesterone can be taken by mouth, through the vagina, and by injection into muscle or fat, among other routes.

File:Sample of Progesterone.jpg

{{See also|List of neurosteroids}}

Progesterone is a naturally occurring pregnane steroid and is also known as pregn-4-ene-3,20-dione.{{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–}}{{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–}} It has a double bond (4-ene) between the C4 and C5 positions and two ketone groups (3,20-dione), one at the C3 position and the other at the C20 position.

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 phytosterols 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.{{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 }}

{{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.{{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 }} This synthesis is known as the Marker degradation.

File:Marker snythesis.png of progesterone from diosgenin.]]

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.{{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}}

Progesterone can also be made from the stigmasterol found in soybean oil also. c.f. Percy Julian.

File:Stigmasterol to progesterone synthesis.png to progesterone synthesis.{{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 }}{{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 }}{{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 }}{{cite web | url = https://www.pbs.org/wgbh/nova/transcripts/3402_julian.html | 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 }}{{cite web | url = http://lipidlibrary.aocs.org/history/Julian/index.htm | title = Giants of the Past | publisher = lipidlibrary.aocs.org | url-status = dead | archive-url = https://web.archive.org/web/20120415001340/http://lipidlibrary.aocs.org/history/Julian/index.htm | archive-date = 15 April 2012 }}]]

File:Progesterone Synthesis.png

A total synthesis of progesterone was reported in 1971 by W.S. Johnson.{{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 }} The synthesis begins with reacting the phosphonium salt 7 with phenyl lithium to produce the phosphonium ylide 8. The ylide 8 is reacted with an aldehyde to produce the alkene 9. The ketal protecting groups of 9 are hydrolyzed to produce the diketone 10, which in turn is cyclized to form the cyclopentenone 11. The ketone of 11 is reacted with methyl lithium to yield the tertiary alcohol 12, which in turn is treated with acid to produce the tertiary cation 13. The key step of the synthesis is the π-cation cyclization of 13 in which the B-, C-, and D-rings of the steroid are simultaneously formed to produce 14. 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 15. The cyclopentene A-ring is then opened by oxidizing with ozone to produce 16. Finally, the diketone 17 undergoes an intramolecular aldol condensation by treating with aqueous potassium hydroxide to produce progesterone.

George W. Corner and Willard M. Allen discovered the hormonal action of progesterone in 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}}{{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 }}{{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–}} By 1931–1932, nearly pure crystalline material of high progestational activity had been isolated from the corpus luteum of animals, and by 1934, pure crystalline progesterone had been refined and obtained and the chemical structure of progesterone was determined. This was achieved by Adolf Butenandt at the Chemisches Institut of Technical University in Danzig, who extracted this new compound from several thousand liters of urine.{{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 }}

Chemical synthesis of progesterone from stigmasterol and pregnanediol was accomplished later that year.{{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}} 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.{{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 }} In 1935, at the time of the Second International Conference on the Standardization of Sex Hormones in London, England, a compromise was made between the groups and the name progesterone (progestational steroidal ketone) was created.{{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 }}

The use of progesterone tests in dog breeding to pinpoint ovulation is becoming more widely used. There are several tests available but the most reliable test is a blood test with blood drawn by a veterinarian and sent to a lab for processing. Results can usually be obtained with 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 with a day or two of 9 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.{{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}}

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 currently, 30 capsules of 100 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.{{cite web |title=Progesterone Prices, Coupons & Savings Tips - GoodRx |url=https://www.goodrx.com/progesterone |access-date=1 August 2023 |website=www.goodrx.com |archive-date=30 March 2023 |archive-url=https://web.archive.org/web/20230330054318/https://www.goodrx.com/progesterone |url-status=live }} In comparison, Walgreens offers 30 capsules of 100 mg in the generic version for $51 without insurance or coupons applied. The brand name costs around $431 for 30 capsules of 100 mg.{{Cite web |title=Progesterone Prices, Coupons & Savings Tips - GoodRx |url=https://www.goodrx.com/progesterone |access-date=1 August 2023 |website=www.goodrx.com |archive-date=30 March 2023 |archive-url=https://web.archive.org/web/20230330054318/https://www.goodrx.com/progesterone |url-status=live }} {{Clear}}

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{{reflist|refs=

{{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 }}

{{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 }}

{{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 }}

{{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}}

{{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}}

{{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}}

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• [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 | url-status = dead }}

{{Progesterone}}

{{Hormones}}

{{Endogenous steroids}}

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