Editing Progesterone (section)

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

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

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

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

===Reproductive system===
[[File:Endometrium ocp use3.jpg|thumb|right|[[Micrograph]] showing changes to the [[endometrium]] due to progesterone ([[decidualization]]) [[H&E stain]].]]
Progesterone has key effects via non-genomic signalling on human sperm as they migrate through the female reproductive tract before [[fertilization]] occurs, though the receptor(s) as yet remain unidentified.<ref name="pmid17447210">{{cite journal | vauthors = Correia JN, Conner SJ, Kirkman-Brown JC | title = Non-genomic steroid actions in human spermatozoa. "Persistent tickling from a laden environment" | journal = Seminars in Reproductive Medicine | volume = 25 | issue = 3 | pages = 208–219 | date = May 2007 | pmid = 17447210 | doi = 10.1055/s-2007-973433 | s2cid = 260318879 }}</ref> Detailed characterisation of the events occurring in sperm in response to progesterone has elucidated certain events including intracellular calcium transients and maintained changes,<ref name="pmid10837122">{{cite journal | vauthors = Kirkman-Brown JC, Bray C, Stewart PM, Barratt CL, Publicover SJ | title = Biphasic elevation of [Ca(2+)](i) in individual human spermatozoa exposed to progesterone | journal = Developmental Biology | volume = 222 | issue = 2 | pages = 326–335 | date = June 2000 | pmid = 10837122 | doi = 10.1006/dbio.2000.9729 | doi-access = free }}</ref> slow calcium oscillations,<ref name="pmid14606954">{{cite journal | vauthors = Kirkman-Brown JC, Barratt CL, Publicover SJ | title = Slow calcium oscillations in human spermatozoa | journal = The Biochemical Journal | volume = 378 | issue = Pt 3 | pages = 827–832 | date = March 2004 | pmid = 14606954 | pmc = 1223996 | doi = 10.1042/BJ20031368 }}</ref> now thought to possibly regulate motility.<ref name="pmid15322137">{{cite journal | vauthors = Harper CV, Barratt CL, Publicover SJ | title = Stimulation of human spermatozoa with progesterone gradients to simulate approach to the oocyte. Induction of [Ca(2+)](i) oscillations and cyclical transitions in flagellar beating | journal = The Journal of Biological Chemistry | volume = 279 | issue = 44 | pages = 46315–46325 | date = October 2004 | pmid = 15322137 | doi = 10.1074/jbc.M401194200 | doi-access = free }}</ref> It is produced by the ovaries.<ref name=Marieb>{{cite book | vauthors = Marieb E | title = Anatomy & physiology | publisher = Benjamin-Cummings | page= 903 | year = 2013 | isbn = 9780321887603 }}</ref> Progesterone has also been shown to demonstrate effects on octopus spermatozoa.<ref name="pmid11335951">{{cite journal | vauthors = Tosti E, Di Cosmo A, Cuomo A, Di Cristo C, Gragnaniello G | title = Progesterone induces activation in Octopus vulgaris spermatozoa | journal = Molecular Reproduction and Development | volume = 59 | issue = 1 | pages = 97–105 | date = May 2001 | pmid = 11335951 | doi = 10.1002/mrd.1011 | s2cid = 28390608 }}</ref>

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

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

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

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

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

====Breast cancer risk====
Progesterone also appears to be involved in the [[pathophysiology]] of [[breast cancer]], though its role, and whether it is a promoter or inhibitor of breast cancer risk, has not been fully elucidated.<ref name="pmid23336704">{{cite journal | vauthors = Kuhl H, Schneider HP | title = Progesterone--promoter or inhibitor of breast cancer | journal = Climacteric | volume = 16 | issue = Suppl 1 | pages = 54–68 | date = August 2013 | pmid = 23336704 | doi = 10.3109/13697137.2013.768806 | s2cid = 20808536 }}</ref><ref name="pmid31512725">{{cite journal | vauthors = Trabert B, Sherman ME, Kannan N, Stanczyk FZ | title = Progesterone and Breast Cancer | journal = Endocrine Reviews | volume = 41 | issue = 2 | pages = 320–344 | date = April 2020 | pmid = 31512725 | pmc = 7156851 | doi = 10.1210/endrev/bnz001 }}</ref> Most [[progestin]]s, or [[synthetic compound|synthetic]] progestogens, like [[medroxyprogesterone acetate]], have been found to increase the risk of breast cancer in postmenopausal people in combination with estrogen as a component of [[menopausal hormone therapy]].<ref name="pmid31474332">{{cite journal | title = Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence | journal = Lancet | volume = 394 | issue = 10204 | pages = 1159–1168 | date = September 2019 | pmid = 31474332 | pmc = 6891893 | doi = 10.1016/S0140-6736(19)31709-X | author1 = Collaborative Group on Hormonal Factors in Breast Cancer }}</ref><ref name="pmid31512725" /> The combination of natural oral progesterone or the atypical progestin [[dydrogesterone]] with estrogen has been associated with less risk of breast cancer than progestins plus estrogen.<ref name="pmid29384406">{{cite journal | vauthors = Stute P, Wildt L, Neulen J | title = The impact of micronized progesterone on breast cancer risk: a systematic review | journal = Climacteric | volume = 21 | issue = 2 | pages = 111–122 | date = April 2018 | pmid = 29384406 | doi = 10.1080/13697137.2017.1421925 | s2cid = 3642971 | doi-access = free | url = https://boris.unibe.ch/125894/1/29384406.pdf | access-date = 2 February 2024 | archive-date = 2 February 2024 | archive-url = https://web.archive.org/web/20240202143017/https://boris.unibe.ch/125894/1/29384406.pdf | url-status = live }}</ref><ref name="pmid27456847">{{cite journal | vauthors = Asi N, Mohammed K, Haydour Q, Gionfriddo MR, Vargas OL, Prokop LJ, Faubion SS, Murad MH | display-authors = 6 | title = Progesterone vs. synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis | journal = Systematic Reviews | volume = 5 | issue = 1 | pages = 121 | date = July 2016 | pmid = 27456847 | pmc = 4960754 | doi = 10.1186/s13643-016-0294-5 | doi-access = free }}</ref><ref name="pmid29852797">{{cite journal | vauthors = Gompel A, Plu-Bureau G | title = Progesterone, progestins and the breast in menopause treatment | journal = Climacteric | volume = 21 | issue = 4 | pages = 326–332 | date = August 2018 | pmid = 29852797 | doi = 10.1080/13697137.2018.1476483 | s2cid = 46922084 }}</ref> However, this may simply be an artifact of the low progesterone levels produced with oral progesterone.<ref name="pmid23336704" /><ref name="pmid29526116">{{cite journal | vauthors = Davey DA | title = Menopausal hormone therapy: a better and safer future | journal = Climacteric | volume = 21 | issue = 5 | pages = 454–461 | date = October 2018 | pmid = 29526116 | doi = 10.1080/13697137.2018.1439915 | s2cid = 3850275 }}</ref> More research is needed on the role of progesterone in breast cancer.<ref name="pmid31512725" />

===Skin health===
The [[estrogen receptor]], as well as the [[progesterone receptor]], have been detected in the [[human skin|skin]], including in [[keratinocyte]]s and [[fibroblast]]s.<ref name="pmid12762829">{{cite journal | vauthors = Raine-Fenning NJ, Brincat MP, Muscat-Baron Y | title = Skin aging and menopause : implications for treatment | journal = American Journal of Clinical Dermatology | volume = 4 | issue = 6 | pages = 371–378 | year = 2003 | pmid = 12762829 | doi = 10.2165/00128071-200304060-00001 | s2cid = 20392538 }}</ref><ref name="pmid16120154">{{cite journal | vauthors = Holzer G, Riegler E, Hönigsmann H, Farokhnia S, Schmidt JB | title = Effects and side-effects of 2% progesterone cream on the skin of peri- and postmenopausal women: results from a double-blind, vehicle-controlled, randomized study | journal = The British Journal of Dermatology | volume = 153 | issue = 3 | pages = 626–634 | date = September 2005 | pmid = 16120154 | doi = 10.1111/j.1365-2133.2005.06685.x | s2cid = 6077829 }}</ref> At [[menopause]] and thereafter, decreased levels of female [[sex hormone]]s result in [[atrophy]], thinning, and increased [[wrinkling]] of the skin and a reduction in skin [[elasticity (physics)|elasticity]], firmness, and strength.<ref name="pmid12762829" /><ref name="pmid16120154" /> These skin changes constitute an acceleration in [[Human skin#Aging|skin aging]] and are the result of decreased [[collagen]] content, irregularities in the [[morphology (biology)|morphology]] of [[epidermis (skin)|epidermal]] [[skin cell]]s, decreased [[ground substance]] between [[skin fiber]]s, and reduced [[capillary|capillaries]] and [[blood flow]].<ref name="pmid12762829" /><ref name="pmid16120154" /> The skin also becomes more [[dry skin|dry]] during menopause, which is due to reduced skin [[tissue hydration|hydration]] and [[sebum|surface lipids]] (sebum production).<ref name="pmid12762829" /> Along with chronological aging and photoaging, estrogen deficiency in menopause is one of the three main factors that predominantly influences skin aging.<ref name="pmid12762829" />

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

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

===Sexuality===

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

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

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

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

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

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

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

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

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

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

===Addiction===

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

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

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