Progesterone (medication)

{{Short description|Medication and naturally occurring steroid hormone}} {{About|progesterone as a medication|its role as a hormone|progesterone}} {{Distinguish|text=medroxyprogesterone acetate, a synthetic progestogen}} {{Use dmy dates|date=October 2022}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox drug | Verifiedfields = verified | Watchedfields = verified | drug_name = Progesterone | verifiedrevid = 444066687 | image = Progesterone.svg | image_class = skin-invert-image | width = 225 | alt = | image2 = Progesterone-3D-balls.png | image_class2 = bg-transparent | width2 = 225 | alt2 =

| pronounce = | tradename = Prometrium, Utrogestan, Endometrin, others | Drugs.com = {{drugs.com|monograph|progesterone}} | MedlinePlus = a604017 | DailyMedID =  | pregnancy_AU =  | pregnancy_AU_comment = | pregnancy_category = | routes_of_administration = By mouth, sublingual, topical, vaginal, rectal, intramuscular, subcutaneous, intrauterine | class = Progestogen; Antimineralocorticoid; Neurosteroid | ATC_prefix = G03 | ATC_suffix = DA04 | ATC_supplemental =

| legal_AU = S4 | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00517 | title=Regulatory Decision Summary for pms-Progesterone | work=Drug and Health Product Register | date=23 October 2014 }}</ref><ref>{{cite web | title=Reproductive health | website=Health Canada | date=9 May 2018 | url=https://www.canada.ca/en/services/health/drug-health-products/drug-medical-device-highlights-2017/approved-drugs/reproductive-health.html| access-date=13 April 2024}}</ref><ref>{{cite web | title=Health product highlights 2021: Annexes of products approved in 2021 | website=Health Canada | date=3 August 2022 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-product-highlights-2021/appendices.html | access-date=25 March 2024}}</ref> | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK =  | legal_UK_comment = | legal_US =  | legal_US_comment = | legal_EU = | legal_EU_comment = | legal_UN =  | legal_UN_comment = | legal_status = Rx-only

| bioavailability = Oral: <2.4%<ref name="pmid10689005">{{cite journal | vauthors = Levine H, Watson N | title = Comparison of the pharmacokinetics of crinone 8% administered vaginally versus Prometrium administered orally in postmenopausal women(3) | journal = Fertility and Sterility | volume = 73 | issue = 3 | pages = 516–521 | date = March 2000 | pmid = 10689005 | doi = 10.1016/S0015-0282(99)00553-1 | doi-access = free | title-link = doi }}</ref> Vaginal (micronized insert): 4–8%<ref name="pmid30595525">{{cite journal | vauthors = Griesinger G, Tournaye H, Macklon N, Petraglia F, Arck P, Blockeel C, van Amsterdam P, Pexman-Fieth C, Fauser BC | title = Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction | journal = Reproductive Biomedicine Online | volume = 38 | issue = 2 | pages = 249–259 | date = February 2019 | pmid = 30595525 | doi = 10.1016/j.rbmo.2018.11.017 | doi-access = free | title-link = doi }}</ref><ref name="PandyaGopeenathan2016">{{cite journal| vauthors = Pandya MR, Gopeenathan P, Gopinath PM, Das SK, Sauhta M, Shinde V |title=Evaluating the clinical efficacy and safety of progestogens in the management of threatened and recurrent miscarriage in early pregnancy-A review of the literature|journal=Indian Journal of Obstetrics and Gynecology Research|volume=3|issue=2|year=2016|page=157|issn=2394-2746|doi=10.5958/2394-2754.2016.00043.6|s2cid=36586762}}</ref><ref name="pmid24606090">{{cite journal | vauthors = Paulson RJ, Collins MG, Yankov VI | title = Progesterone pharmacokinetics and pharmacodynamics with 3 dosages and 2 regimens of an effervescent micronized progesterone vaginal insert | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 99 | issue = 11 | pages = 4241–4249 | date = November 2014 | pmid = 24606090 | doi = 10.1210/jc.2013-3937 | doi-access = free | title-link = doi }}</ref> | protein_bound = 98–99%:<ref name="FritzSperoff2012">{{cite book | vauthors = Fritz MA, Speroff L | title = Clinical Gynecologic Endocrinology and Infertility | url = https://books.google.com/books?id=KZLubBxJEwEC&pg=PA44 | date = 28 March 2012 | publisher = Lippincott Williams & Wilkins | isbn = 978-1-4511-4847-3 | pages = 44– }}</ref><ref name="MarshallD.2008">{{cite book | vauthors = Marshall WJ, Bangert SK | title = Clinical Chemistry | url = https://books.google.com/books?id=Gjc704GR5YEC&pg=PA192 | year = 2008 | publisher = Elsevier Health Sciences|isbn=978-0-7234-3455-9|pages=192–}}</ref> • Albumin: 80% • {{abbrlink|CBG|Corticosteroid-binding globulin}}: 18% • {{abbrlink|SHBG|Sex hormone-binding globulin}}: <1% • Free: 1–2% | metabolism = Mainly liver: • 5α- and 5β-reductase • {{abbrlink|3α-|3α-Hydroxysteroid dehydrogenase}} and {{abbrlink|3β-HSD|3β-Hydroxysteroid dehydrogenase}} • {{abbrlink|20α-|20α-Hydroxysteroid dehydrogenase}} and {{abbrlink|20β-HSD|20β-Hydroxysteroid dehydrogenase}} • Conjugation • 17α-Hydroxylase • 21-Hydroxylase • {{abbrlink|CYPs|Cytochrome P450|CYP}} (e.g., CYP3A4) | metabolites = • Dihydroprogesterones • Pregnanolones • Pregnanediols • 20α-Hydroxyprogesterone • 17α-Hydroxyprogesterone • Pregnanetriols • 11-Deoxycorticosterone (and glucuronide/sulfate conjugates) | onset = | elimination_half-life = • Oral: 5 hours (with food)<ref name="pmid25944519">{{cite journal | vauthors = Pickar JH, Bon C, Amadio JM, Mirkin S, Bernick B | title = Pharmacokinetics of the first combination 17β-estradiol/progesterone capsule in clinical development for menopausal hormone therapy | journal = Menopause | volume = 22 | issue = 12 | pages = 1308–1316 | date = December 2015 | pmid = 25944519 | pmc = 4666011 | doi = 10.1097/GME.0000000000000467 }}</ref> * Sublingual: 6–7 hours<ref name="ХомякМамчур2014">{{cite journal | vauthors = Khomyak NV, Mamchur VI, Khomyak EV | date = 2014 | title = Клинико-фармакологические особенности современных лекарственных форм микронизированного прогестерона, применяющихся во время беременности. | trans-title = Clinical and pharmacological features of modern dosage forms of micronized progesterone used during pregnancy. | journal = Доровье | trans-journal = Health | volume = 4 | page = 90 | url = http://health-ua.com/wp-content/uploads/2015/09/MAZG2-2015_28-35.pdf }}</ref> • Vaginal: 14–50 hours<ref name="CrinoneLabel">{{cite web | title = Crinone® 4% and Crinone® 8% (progesterone gel) | work = Watson Pharma, Inc. | publisher = U.S. Food and Drug Administration | date = August 2013 | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020701s026lbl.pdf | archive-url = https://web.archive.org/web/20161221145011/http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020701s026lbl.pdf | archive-date = 21 December 2016 }}</ref><ref name="ХомякМамчур2014" /> • Topical: 30–40 hours<ref name="pmid9842983">{{cite journal | vauthors = Mircioiu C, Perju A, Griu E, Calin G, Neagu A, Enachescu D, Miron DS | title = Pharmacokinetics of progesterone in postmenopausal women: 2. Pharmacokinetics following percutaneous administration | journal = European Journal of Drug Metabolism and Pharmacokinetics | volume = 23 | issue = 3 | pages = 397–402 | year = 1998 | pmid = 9842983 | doi = 10.1007/BF03192300 | s2cid = 32772029 }}</ref> • {{abbr|IM|Intramuscular injection}}: 20–28 hours<ref name="pmid8513955">{{cite journal | vauthors = Simon JA, Robinson DE, Andrews MC, Hildebrand JR, Rocci ML, Blake RE, Hodgen GD | title = The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone | journal = Fertility and Sterility | volume = 60 | issue = 1 | pages = 26–33 | date = July 1993 | pmid = 8513955 | doi = 10.1016/S0015-0282(16)56031-2 | doi-access = free | title-link = doi }}</ref><ref name="CrinoneLabel" /><ref name="pmid26342177">{{cite journal | vauthors = Cometti B | title = Pharmaceutical and clinical development of a novel progesterone formulation | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 94 | issue = Suppl 161 | pages = 28–37 | date = November 2015 | pmid = 26342177 | doi = 10.1111/aogs.12765 | quote = The administration of progesterone in injectable or vaginal form is more efficient than by the oral route, since it avoids the metabolic losses of progesterone encountered with oral administration resulting from the hepatic first-pass effect (32). In addition, the injectable forms avoid the need for higher doses that cause a fairly large number of side-effects, such as somnolence, sedation, anxiety, irritability and depression (33). | s2cid = 31974637 | doi-access = free | title-link = doi }}</ref> • {{abbr|SC|Subcutaneous injection}}: 13–18 hours<ref name="pmid26342177" /> • {{abbrlink|IV|Intravenous injection}}: 3–90 minutes<ref name="pmid945344">{{cite journal | vauthors = Aufrère MB, Benson H | title = Progesterone: an overview and recent advances | journal = Journal of Pharmaceutical Sciences | volume = 65 | issue = 6 | pages = 783–800 | date = June 1976 | pmid = 945344 | doi = 10.1002/jps.2600650602 | bibcode = 1976JPhmS..65..783A }}</ref> | duration_of_action = | excretion = Bile and urine<ref name="PrometriumLabel">{{cite web | title = Prometrium (progesterone, USP) Capsules 100 mg | work = Solvay Pharmaceuticals, Inc. | publisher = U.S. Food and Drug Administration | date = 1998 | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/1998/20843lbl.pdf}}</ref><ref name="ProgesteroneIMLabel">{{cite web | title = Progesterone Injection USP in Sesame Oil for Intramuscular Use Only Rx Only | publisher = U.S. Food and Drug Administration | date = January 2007 | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017362s104lbl.pdf | archive-url = https://web.archive.org/web/20161221145704/http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017362s104lbl.pdf | archive-date = 21 December 2016 }}</ref>

| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 57-83-0 | CAS_supplemental = | PubChem = 5994 | IUPHAR_ligand = 2377 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00396 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 5773 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 4G7DS2Q64Y | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D00066 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 17026 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 103 | NIAID_ChemDB = | PDB_ligand = | synonyms = P4; Pregnenedione; Pregn-4-ene-3,20-dione<ref>{{cite book | vauthors = Adler N, Pfaff D, Goy RW | title = Handbook of Behavioral Neurobiology Volume 7 Reproduction | date = 6 December 2012 | publisher=Plenum Press | location = New York | isbn = 978-1-4684-4834-4 | page = 189 | edition = 1st | url = https://books.google.com/books?id=MoDrBwAAQBAJ&q=pregn-4-ene-3,20-dione;+abbreviated+as+P4&pg=PA189 | access-date = 4 July 2015 }}</ref>

| IUPAC_name = (8''S'',9''S'',10''R'',13''S'',14''S'',17''S'')-17-acetyl-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[''a'']phenanthren-3-one | C=21 | H=30 | O=2 | SMILES = CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CCC4=CC(=O)CC[C@]34C)C | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | StdInChI = 1S/C21H30O2/c1-13(22)17-6-7-18-16-5-4-14-12-15(23)8-10-20(14,2)19(16)9-11-21(17,18)3/h12,16-19H,4-11H2,1-3H3/t16-,17+,18-,19-,20-,21+/m0/s1 | StdInChI_comment = | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = RJKFOVLPORLFTN-LEKSSAKUSA-N | density = | density_notes = | melting_point = 126 | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = [α]D25 = +172 to +182° (2% in dioxane, β-form) }}

'''Progesterone''' ('''P4'''), sold under the brand name '''Prometrium''' among others, is a medication and naturally occurring steroid hormone.<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }}</ref> It is a progestogen and is used in combination with estrogens mainly in hormone therapy for menopausal symptoms and low sex hormone levels in women.<ref name="pmid16112947" /><ref name="pmid28159148" /> It is also used in women to support pregnancy and fertility and to treat gynecological disorders.<ref name="RuanMueck2014" /><ref name="pmid26443945">{{cite journal | vauthors = Filicori M | title = Clinical roles and applications of progesterone in reproductive medicine: an overview | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 94 | issue = Suppl 161 | pages = 3–7 | date = November 2015 | pmid = 26443945 | doi = 10.1111/aogs.12791 | doi-access = free | title-link = doi }}</ref><ref name="pmid26345161">{{cite journal | vauthors = Ciampaglia W, Cognigni GE | title = Clinical use of progesterone in infertility and assisted reproduction | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 94 | issue = Suppl 161 | pages = 17–27 | date = November 2015 | pmid = 26345161 | doi = 10.1111/aogs.12770 | s2cid = 40753277 | doi-access = free | title-link = doi }}</ref><ref name="pmid28989916">{{cite journal | vauthors = Choi SJ | title = Use of progesterone supplement therapy for prevention of preterm birth: review of literatures | journal = Obstetrics & Gynecology Science | volume = 60 | issue = 5 | pages = 405–420 | date = September 2017 | pmid = 28989916 | pmc = 5621069 | doi = 10.5468/ogs.2017.60.5.405 }}</ref> Progesterone can be taken by mouth, vaginally, and by injection into muscle or fat, among other routes.<ref name="pmid16112947" /> A progesterone vaginal ring and progesterone intrauterine device used for birth control also exist in some areas of the world.<ref name=Whit2014>{{cite book | vauthors = Whitaker A, Gilliam M |title=Contraception for Adolescent and Young Adult Women |date=2014 |publisher=Springer |isbn=978-1-4614-6579-9 |page=98 |url=https://books.google.com/books?id=vMQkBAAAQBAJ&pg=PA98 }}</ref><ref name="Chaudhuri2007">{{cite book|author=Chaudhuri|title=Practice of Fertility Control: A Comprehensive Manual |url=https://books.google.com/books?id=pzanxKlcU74C&pg=PA153 |year=2007 |publisher=Elsevier India |isbn=978-81-312-1150-2 |pages=153– |edition=7Th }}</ref>

Progesterone is well tolerated and often produces few or no side effects.<ref name="pmid17924777">{{cite journal | vauthors = Goletiani NV, Keith DR, Gorsky SJ | title = Progesterone: review of safety for clinical studies | journal = Experimental and Clinical Psychopharmacology | volume = 15 | issue = 5 | pages = 427–444 | date = October 2007 | pmid = 17924777 | doi = 10.1037/1064-1297.15.5.427 }}</ref> However, a number of side effects are possible, for instance mood changes.<ref name="pmid17924777" /> If progesterone is taken by mouth or at high doses, certain central side effects including sedation, sleepiness, and cognitive impairment can also occur.<ref name="pmid17924777" /><ref name="pmid16112947" /> The medication is a naturally occurring progestogen and hence is an agonist of the progesterone receptor (PR), the biological target of progestogens like endogenous progesterone.<ref name="pmid16112947" /> It opposes the effects of estrogens in various parts of the body like the uterus and also blocks the effects of the hormone aldosterone.<ref name="pmid16112947" /><ref name="pmid27277331">{{cite journal | vauthors = Stute P, Neulen J, Wildt L | title = The impact of micronized progesterone on the endometrium: a systematic review | journal = Climacteric | volume = 19 | issue = 4 | pages = 316–328 | date = August 2016 | pmid = 27277331 | doi = 10.1080/13697137.2016.1187123 | doi-access = free | title-link = doi | url = https://boris.unibe.ch/94180/1/27277331_13697137.2016.pdf }}</ref> In addition, progesterone has neurosteroid effects in the brain.<ref name="pmid16112947" />

Progesterone was first isolated in pure form in 1934.<ref name="Josimovich2013" /><ref name="CoutinhoSegal1999" /> It first became available as a medication later that year.<ref name="Seaman2011" /><ref name="Simon1995" /> Oral micronized progesterone (OMP), which allowed progesterone to be taken by mouth, was introduced in 1980.<ref name="Simon1995" /><ref name="RuanMueck2014" /><ref name="pmid6925387" /> A large number of synthetic progestogens, or progestins, have been derived from progesterone and are used as medications as well.<ref name="pmid16112947" /> Examples include medroxyprogesterone acetate and norethisterone.<ref name="pmid16112947" /> In 2023, it was the 117th most commonly prescribed medication in the United States, with more than 5{{nbsp}}million prescriptions.<ref name="Top300Drugs">{{cite web | title=Top 300 of 2023 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=12 August 2025 | archive-date=12 August 2025 | archive-url=https://web.archive.org/web/20250812130026/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Progesterone Drug Usage Statistics, United States, 2014 - 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Progesterone | access-date = 18 August 2025 }}</ref> {{TOC limit}}

==Medical uses==

===Menopause=== Progesterone is used in combination with an estrogen as a component of menopausal hormone therapy for the treatment of menopausal symptoms in peri- and postmenopausal women.<ref name="pmid16112947" /><ref name="pmid31282768">{{cite journal | vauthors = Archer DF, Bernick BA, Mirkin S | title = A combined, bioidentical, oral, 17β-estradiol and progesterone capsule for the treatment of moderate to severe vasomotor symptoms due to menopause | journal = Expert Review of Clinical Pharmacology | volume = 12 | issue = 8 | pages = 729–739 | date = August 2019 | pmid = 31282768 | doi = 10.1080/17512433.2019.1637731 | doi-access = free | title-link = doi }}</ref> It is used specifically to provide endometrial protection against unopposed estrogen-induced endometrial hyperplasia and cancer in women with intact uteruses.<ref name="pmid16112947" /><ref name="pmid31282768" /> A 2016 systematic review of endometrial protection with progesterone recommended 100 mg/day continuous oral progesterone, 200 mg/day cyclic oral progesterone, 45 to 100 mg/day cyclic vaginal progesterone, and 100 mg alternate-day vaginal progesterone.<ref name="pmid27277331" /><ref name="pmid28251642" /> Twice-weekly 100 mg vaginal progesterone was also recommended, but more research is needed on this dose and endometrial monitoring may be advised.<ref name="pmid27277331" /><ref name="pmid28251642" /> Transdermal progesterone was not recommended for endometrial protection.<ref name="pmid27277331" /><ref name="pmid28251642" />

The REPLENISH trial was the first adequately powered study to show that continuous 100 mg/day oral progesterone with food provides adequate endometrial protection.<ref name="pmid29630427">{{cite journal | vauthors = Mirkin S | title = Evidence on the use of progesterone in menopausal hormone therapy | journal = Climacteric | volume = 21 | issue = 4 | pages = 346–354 | date = August 2018 | pmid = 29630427 | doi = 10.1080/13697137.2018.1455657 | doi-access = free | title-link = doi }}</ref><ref name="pmid31612748">{{cite journal | vauthors = Mueck AO, Ruan X | title = Will estradiol/progesterone capsules for oral use become the best choice for menopausal hormone therapy? | journal = Climacteric | volume = 22 | issue = 6 | pages = 535–537 | date = December 2019 | pmid = 31612748 | doi = 10.1080/13697137.2019.1663625 | doi-access = free | title-link = doi }}</ref><ref name="pmid31282768" /><ref name="pmid30694918">{{cite journal | vauthors = Lobo RA, Liu J, Stanczyk FZ, Constantine GD, Pickar JH, Shadiack AM, Bernick B, Mirkin S | title = Estradiol and progesterone bioavailability for moderate to severe vasomotor symptom treatment and endometrial protection with the continuous-combined regimen of TX-001HR (oral estradiol and progesterone capsules) | journal = Menopause | volume = 26 | issue = 7 | pages = 720–727 | date = July 2019 | pmid = 30694918 | pmc = 6636803 | doi = 10.1097/GME.0000000000001306 }}</ref> Cyclic 200 mg/day oral progesterone has also been found to be effective in the prevention of endometrial hyperplasia, for instance in the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial.<ref name="pmid29630427" /><ref name="pmid29583028">{{cite journal | vauthors = Gompel A | title = Progesterone, progestins and the endometrium in perimenopause and in menopausal hormone therapy | journal = Climacteric | volume = 21 | issue = 4 | pages = 321–325 | date = August 2018 | pmid = 29583028 | doi = 10.1080/13697137.2018.1446932 | s2cid = 4422872 }}</ref><ref name="pmid28251642">{{cite journal | vauthors = Eden J | title = The endometrial and breast safety of menopausal hormone therapy containing micronised progesterone: A short review | journal = The Australian & New Zealand Journal of Obstetrics & Gynaecology | volume = 57 | issue = 1 | pages = 12–15 | date = February 2017 | pmid = 28251642 | doi = 10.1111/ajo.12583 | s2cid = 206990125 }}</ref> However, the PEPI trial was not adequately powered to fully quantify endometrial hyperplasia or cancer risk.<ref name="pmid29630427" /> No adequately powered studies have assessed endometrial protection with vaginal progesterone.<ref name="pmid29630427" /> In any case, the Early versus Late Intervention Trial with Estradiol (ELITE) found that cyclic 45 mg/day vaginal progesterone gel showed no significant difference from placebo in endometrial cancer rates.<ref name="pmid29630427" /><ref name="pmid27277331" /> Due to the vaginal first-pass effect, low doses of vaginal progesterone may allow for adequate endometrial protection.<ref name="RuanMueck2014"/><ref name="pmid29583019">{{cite journal | vauthors = Warren MP | title = Vaginal progesterone and the vaginal first-pass effect | journal = Climacteric | volume = 21 | issue = 4 | pages = 355–357 | date = August 2018 | pmid = 29583019 | doi = 10.1080/13697137.2018.1450856 | s2cid = 4419927 }}</ref><ref name="pmid16112947" /> Although not sufficiently powered, various other smaller studies have also found endometrial protection with oral or vaginal progesterone.<ref name="pmid29630427" /><ref name="pmid29583028" /><ref name="pmid28251642" /><ref name="Gompel2012">{{cite journal | vauthors = Gompel A | title = Micronized progesterone and its impact on the endometrium and breast vs. progestogens | journal = Climacteric | volume = 15 | issue = Suppl 1 | pages = 18–25 | date = April 2012 | pmid = 22432812 | doi = 10.3109/13697137.2012.669584 | s2cid = 17700754 }}</ref> There is inadequate evidence for endometrial protection with transdermal progesterone cream.<ref name="pmid27277331" /><ref name="RuanMueck2014">{{cite journal | vauthors = Ruan X, Mueck AO | title = Systemic progesterone therapy--oral, vaginal, injections and even transdermal? | journal = Maturitas | volume = 79 | issue = 3 | pages = 248–255 | date = November 2014 | pmid = 25113944 | doi = 10.1016/j.maturitas.2014.07.009 }}</ref><ref name="pmid25196424" /><ref name="pmid15772572" />

Oral progesterone has been found to significantly reduce hot flashes relative to placebo.<ref name="pmid29630427" /><ref name="pmid29962247">{{cite journal | vauthors = Prior JC | title = Progesterone for treatment of symptomatic menopausal women | journal = Climacteric | volume = 21 | issue = 4 | pages = 358–365 | date = August 2018 | pmid = 29962247 | doi = 10.1080/13697137.2018.1472567 | doi-access = free | title-link = doi }}</ref> The combination of an estrogen and oral progesterone likewise reduces hot flashes.<ref name="pmid29630427" /><ref name="pmid31282768" /> Estrogen plus oral progesterone has been found to significantly improve quality of life.<ref name="pmid29630427" /><ref name="pmid31282768" /> The combination of an estrogen and 100 to 300 mg/day oral progesterone has been found to improve sleep outcomes.<ref name="pmid29630427" /><ref name="pmid31282768" /><ref name="pmid29962247" /> Moreover, sleep was improved to a significantly better extent than estrogen plus medroxyprogesterone acetate.<ref name="pmid29630427" /> This may be attributable to the sedative neurosteroid effects of progesterone.<ref name="pmid29630427" /> Reduction of hot flashes may also help to improve sleep outcomes.<ref name="pmid29630427" /> Based on animal research, progesterone may be involved in sexual function in women.<ref name="pmid17431228">{{cite journal | vauthors = Schumacher M, Guennoun R, Ghoumari A, Massaad C, Robert F, El-Etr M, Akwa Y, Rajkowski K, Baulieu EE | title = Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system | journal = Endocrine Reviews | volume = 28 | issue = 4 | pages = 387–439 | date = June 2007 | pmid = 17431228 | doi = 10.1210/er.2006-0050 | doi-access = free | title-link = doi }}</ref><ref name="pmid18374402">{{cite journal | vauthors = Brinton RD, Thompson RF, Foy MR, Baudry M, Wang J, Finch CE, Morgan TE, Pike CJ, Mack WJ, Stanczyk FZ, Nilsen J | title = Progesterone receptors: form and function in brain | journal = Frontiers in Neuroendocrinology | volume = 29 | issue = 2 | pages = 313–339 | date = May 2008 | pmid = 18374402 | pmc = 2398769 | doi = 10.1016/j.yfrne.2008.02.001 }}</ref> However, very limited clinical research suggests that progesterone does not improve sexual desire or function in women.<ref name="pmid26944460">{{cite journal | vauthors = Worsley R, Santoro N, Miller KK, Parish SJ, Davis SR | title = Hormones and Female Sexual Dysfunction: Beyond Estrogens and Androgens--Findings from the Fourth International Consultation on Sexual Medicine | journal = The Journal of Sexual Medicine | volume = 13 | issue = 3 | pages = 283–290 | date = March 2016 | pmid = 26944460 | doi = 10.1016/j.jsxm.2015.12.014 }}</ref>

The combination of an estrogen and oral progesterone has been found to improve bone mineral density (BMD) to a similar extent as an estrogen plus medroxyprogesterone acetate.<ref name="pmid29630427" /> Progestogens, including progesterone, may have beneficial effects on bone independent of those of estrogens, although more research is required to confirm this notion.<ref name="pmid29962257">{{cite journal | vauthors = Prior JC | title = Progesterone for the prevention and treatment of osteoporosis in women | journal = Climacteric | volume = 21 | issue = 4 | pages = 366–374 | date = August 2018 | pmid = 29962257 | doi = 10.1080/13697137.2018.1467400 | doi-access = free | title-link = doi }}</ref> The combination of an estrogen and oral or vaginal progesterone has been found to improve cardiovascular health in women in early menopause but not in women in late menopause.<ref name="pmid29630427" /> Estrogen therapy has a favorable influence on the blood lipid profile, which may translate to improved cardiovascular health.<ref name="pmid29630427" /><ref name="pmid16112947" /> The addition of oral or vaginal progesterone has neutral or beneficial effects on these changes.<ref name="pmid29630427" /><ref name="pmid31282768" /><ref name="pmid29962247" /> This is in contrast to various progestins, which are known to antagonize the beneficial effects of estrogens on blood lipids.<ref name="pmid16112947" /><ref name="pmid29630427" /> Progesterone, both alone and in combination with an estrogen, has been found to have beneficial effects on skin and to slow the rate of skin aging in postmenopausal women.<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>

In the French E3N-EPIC observational study, the risk of diabetes was significantly lower in women on menopausal hormone therapy, including with the combination of an oral or transdermal estrogen and oral progesterone or a progestin.<ref name="MirkinAmadio2015">{{cite journal | vauthors = Mirkin S, Amadio JM, Bernick BA, Pickar JH, Archer DF | title = 17β-Estradiol and natural progesterone for menopausal hormone therapy: REPLENISH phase 3 study design of a combination capsule and evidence review | journal = Maturitas | volume = 81 | issue = 1 | pages = 28–35 | date = May 2015 | pmid = 25835751 | doi = 10.1016/j.maturitas.2015.02.266 | doi-access = free | title-link = doi }}</ref>

===Transgender women=== {{See also|Feminizing hormone therapy#Progestogens}}

Progesterone is used as a component of feminizing hormone therapy for transgender women in combination with estrogens and often antiandrogens.<ref name="WPATH2011">{{citation | author = World Professional Association for Transgender Health | title = Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People, Seventh Version | date = September 2011 | url = http://www.wpath.org/uploaded_files/140/files/IJT%20SOC,%20V7.pdf | archive-url = https://web.archive.org/web/20160106203349/http://www.wpath.org/uploaded_files/140/files/IJT%20SOC%2C%20V7.pdf | archive-date = 6 January 2016| author-link = World Professional Association for Transgender Health }}</ref><ref name="pmid28159148">{{cite journal | vauthors = Wesp LM, Deutsch MB | title = Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons | journal = The Psychiatric Clinics of North America | volume = 40 | issue = 1 | pages = 99–111 | date = March 2017 | pmid = 28159148 | doi = 10.1016/j.psc.2016.10.006 }}</ref><ref name="pmid32599993">{{cite journal | vauthors = Cundill, P | title = Hormone therapy for trans and gender diverse patients in the general practice setting | journal = Australian Journal of General Practice | volume = 49 | issue = 7 | pages = 385–390 | date = July 2020 | doi = 10.31128/AJGP-01-20-5197 | pmid = 32599993 }}</ref> However, the addition of progestogens to HRT for transgender women is controversial and their role is unclear.<ref name="WPATH2011" /><ref name="pmid28159148" /> Some patients and clinicians believe anecdotally that progesterone may enhance breast development, improve mood, regulate sleep, and increase sex drive.<ref name="pmid28159148" /> However, there is a lack of evidence from well-designed studies to support these notions at present.<ref name="pmid28159148" /> In addition, progestogens can produce undesirable side effects, although bioidentical progesterone may be safer and better tolerated than synthetic progestogens like medroxyprogesterone acetate.<ref name="WPATH2011" /><ref name="EttnerMonstrey2016" />

Because some believe that progestogens are necessary for full breast development, progesterone is sometimes used in transgender women with the intention of enhancing breast development.<ref name="WPATH2011" /><ref name="pmid24618412">{{cite journal | vauthors = Wierckx K, Gooren L, T'Sjoen G | title = Clinical review: Breast development in trans women receiving cross-sex hormones | journal = The Journal of Sexual Medicine | volume = 11 | issue = 5 | pages = 1240–1247 | date = May 2014 | pmid = 24618412 | doi = 10.1111/jsm.12487 | url = https://biblio.ugent.be/publication/5775958/file/5776199 | url-access = subscription }}</ref><ref name="EttnerMonstrey2016">{{cite book| vauthors = Ettner R, Monstrey S, Coleman E |title= Principles of Transgender Medicine and Surgery |url= https://books.google.com/books?id=LwszDAAAQBAJ&pg=PA170 |date=20 May 2016 |publisher=Routledge |isbn=978-1-317-51460-2 |pages=170– }}</ref> However, a 2014 review concluded the following on the topic of progesterone for enhancing breast development in transgender women:<ref name="pmid24618412" />

<blockquote>Our knowledge concerning the natural history and effects of different cross-sex hormone therapies on breast development in [transgender] women is extremely sparse and based on low quality of evidence. Current evidence does not provide evidence that progestogens enhance breast development in [transgender] women. Neither do they prove the absence of such an effect. This prevents us from drawing any firm conclusion at this moment and demonstrates the need for further research to clarify these important clinical questions.<ref name="pmid24618412" /></blockquote>

Data on menstruating women shows there is no correlation between water retention, and levels of progesterone or estrogen.<ref name="white2011a">{{cite journal | vauthors = White CP, Hitchcock CL, Vigna YM, Prior JC | title = Fluid Retention over the Menstrual Cycle: 1-Year Data from the Prospective Ovulation Cohort | journal = Obstetrics and Gynecology International | volume = 2011 | article-number = 138451 | date = 2011 | pmid = 21845193 | pmc = 3154522 | doi = 10.1155/2011/138451 | doi-access = free | title-link = doi }}</ref> Despite this, some theorise progesterone might cause temporary breast enlargement due to local fluid retention, and may thus give a misleading appearance of breast growth.<ref name="Copstead-KirkhornBanasik2014">{{cite book | vauthors = Copstead-Kirkhorn EC, Banasik JL |title=Pathophysiology - E-Book|url=https://books.google.com/books?id=i7jwAwAAQBAJ&pg=PA660 |date=25 June 2014 |publisher=Elsevier Health Sciences |isbn=978-0-323-29317-4 |pages=660– |quote=Throughout the reproductive years, some women note swelling of the breast around the latter part of each menstrual cycle before the onset of menstruation. The water retention and subsequent swelling of breast tissue during this phase of the menstrual cycle are thought to be due to high levels of circulating progesterone stimulating the secretory cells of the breast.}}</ref><ref name="pmid19099613">{{cite journal | vauthors = Farage MA, Neill S, MacLean AB | title = Physiological changes associated with the menstrual cycle: a review | journal = Obstetrical & Gynecological Survey | volume = 64 | issue = 1 | pages = 58–72 | date = January 2009 | pmid = 19099613 | doi = 10.1097/OGX.0b013e3181932a37 | s2cid = 22293838 }}</ref> Aside from a hypothetical involvement in breast development, progestogens are not otherwise known to be involved in physical feminization.<ref name="EttnerMonstrey2016" /><ref name="WPATH2011" />

===Pregnancy support=== Vaginally dosed progesterone is being investigated as potentially beneficial in preventing preterm birth in women at risk for preterm birth. The initial study by Fonseca suggested that vaginal progesterone could prevent preterm birth in women with a history of preterm birth.<ref name="pmid12592250">{{cite journal | vauthors = da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M | title = Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study | journal = American Journal of Obstetrics and Gynecology | volume = 188 | issue = 2 | pages = 419–424 | date = February 2003 | pmid = 12592250 | doi = 10.1067/mob.2003.41 | s2cid = 14904733 }}</ref> According to a recent study, women with a short cervix that received hormonal treatment with a progesterone gel had their risk of prematurely giving birth reduced. The hormone treatment was administered vaginally every day during the second half of a pregnancy.<ref>{{cite news| vauthors = Harris G |title=Hormone Is Said to Cut Risk of Premature Birth|url=https://www.nytimes.com/2011/05/03/health/research/03preemie.html|work=The New York Times|access-date=5 May 2011|date=2 May 2011}}</ref> A subsequent and larger study showed that vaginal progesterone was no better than placebo in preventing recurrent preterm birth in women with a history of a previous preterm birth,<ref name="pmid17899572">{{cite journal | vauthors = O'Brien JM, Adair CD, Lewis DF, Hall DR, Defranco EA, Fusey S, Soma-Pillay P, Porter K, How H, Schackis R, Eller D, Trivedi Y, Vanburen G, Khandelwal M, Trofatter K, Vidyadhari D, Vijayaraghavan J, Weeks J, Dattel B, Newton E, Chazotte C, Valenzuela G, Calda P, Bsharat M, Creasy GW | title = Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial | journal = Ultrasound in Obstetrics & Gynecology | volume = 30 | issue = 5 | pages = 687–696 | date = October 2007 | pmid = 17899572 | doi = 10.1002/uog.5158 | s2cid = 31181784 | doi-access = free | title-link = doi }}</ref> but a planned secondary analysis of the data in this trial showed that women with a short cervix at baseline in the trial had benefit in two ways: a reduction in births less than 32 weeks and a reduction in both the frequency and the time their babies were in intensive care.<ref name="pmid17899571">{{cite journal | vauthors = DeFranco EA, O'Brien JM, Adair CD, Lewis DF, Hall DR, Fusey S, Soma-Pillay P, Porter K, How H, Schakis R, Eller D, Trivedi Y, Vanburen G, Khandelwal M, Trofatter K, Vidyadhari D, Vijayaraghavan J, Weeks J, Dattel B, Newton E, Chazotte C, Valenzuela G, Calda P, Bsharat M, Creasy GW | title = Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial | journal = Ultrasound in Obstetrics & Gynecology | volume = 30 | issue = 5 | pages = 697–705 | date = October 2007 | pmid = 17899571 | doi = 10.1002/uog.5159 | s2cid = 15577369 | doi-access = | title-link = doi }}</ref>

In another trial, vaginal progesterone was shown to be better than placebo in reducing preterm birth prior to 34 weeks in women with an extremely short cervix at baseline.<ref name="pmid17671254">{{cite journal | vauthors = Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH | title = Progesterone and the risk of preterm birth among women with a short cervix | journal = The New England Journal of Medicine | volume = 357 | issue = 5 | pages = 462–469 | date = August 2007 | pmid = 17671254 | doi = 10.1056/NEJMoa067815 | s2cid = 14884358 | doi-access = free | title-link = doi }}</ref> An editorial by Roberto Romero discusses the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment.<ref name="pmid17899585">{{cite journal | vauthors = Romero R | title = Prevention of spontaneous preterm birth: the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment | journal = Ultrasound in Obstetrics & Gynecology | volume = 30 | issue = 5 | pages = 675–686 | date = October 2007 | pmid = 17899585 | doi = 10.1002/uog.5174 | s2cid = 46366053 | doi-access = free | title-link = doi }}</ref> A meta-analysis published in 2011 found that vaginal progesterone cut the risk of premature births by 42 percent in women with short cervixes.<ref name="pmid21472815">{{cite journal | vauthors = Hassan SS, Romero R, Vidyadhari D, Fusey S, Baxter JK, Khandelwal M, Vijayaraghavan J, Trivedi Y, Soma-Pillay P, Sambarey P, Dayal A, Potapov V, O'Brien J, Astakhov V, Yuzko O, Kinzler W, Dattel B, Sehdev H, Mazheika L, Manchulenko D, Gervasi MT, Sullivan L, Conde-Agudelo A, Phillips JA, Creasy GW | title = Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial | journal = Ultrasound in Obstetrics & Gynecology | volume = 38 | issue = 1 | pages = 18–31 | date = July 2011 | pmid = 21472815 | pmc = 3482512 | doi = 10.1002/uog.9017 }}</ref><ref name="Doheny 2011">{{cite web | vauthors = Doheny K | title=Hormone Treatment May Drastically Reduce Preterm Births | website=WebMD | date=December 14, 2011 | url=https://www.webmd.com/baby/news/20111214/hormone-treatment-may-drastically-reduce-preterm-births}}</ref> The meta-analysis, which pooled published results of five large clinical trials, also found that the treatment cut the rate of breathing problems and reduced the need for placing a baby on a ventilator.<ref name="urlProgesterone helps cut risk of pre-term birth - Health - Womens health - msnbc.com">{{cite web | url = https://www.nbcnews.com/id/wbna45671241 | archive-url = https://web.archive.org/web/20111215021315/http://www.msnbc.msn.com/id/45671241/ns/health-womens_health/#.TutW95hOERl | url-status = live | archive-date = 15 December 2011 | title = Progesterone helps cut risk of pre-term birth | date = 14 December 2011 | work = Women's health | publisher = msnbc.com | access-date = 14 December 2011 }}</ref>

===Fertility support=== Progesterone is used for luteal support in assisted reproductive technology (ART) cycles such as in vitro fertilization (IVF).<ref name="pmid26345161" /><ref name="pmid25734349">{{cite journal | vauthors = Yanushpolsky EH | title = Luteal phase support in in vitro fertilization | journal = Seminars in Reproductive Medicine | volume = 33 | issue = 2 | pages = 118–127 | date = March 2015 | pmid = 25734349 | doi = 10.1055/s-0035-1545363 | doi-access = free | title-link = doi }}</ref> It is also used to correct luteal phase deficiency to prepare the endometrium for implantation in infertility therapy and is used to support early pregnancy.<ref name="pmid26585269">{{cite journal | vauthors = Palomba S, Santagni S, La Sala GB | title = Progesterone administration for luteal phase deficiency in human reproduction: an old or new issue? | journal = Journal of Ovarian Research | volume = 8 | article-number = 77 | date = November 2015 | pmid = 26585269 | pmc = 4653859 | doi = 10.1186/s13048-015-0205-8 | doi-access = free | title-link = doi }}</ref><ref name="pmid28277122">{{cite journal | vauthors = Czyzyk A, Podfigurna A, Genazzani AR, Meczekalski B | title = The role of progesterone therapy in early pregnancy: from physiological role to therapeutic utility | journal = Gynecological Endocrinology | volume = 33 | issue = 6 | pages = 421–424 | date = June 2017 | pmid = 28277122 | doi = 10.1080/09513590.2017.1291615 | s2cid = 3610323 }}</ref>

===Birth control=== A progesterone vaginal ring is available for birth control when breastfeeding in a number of areas of the world.<ref name=Whit2014/> An intrauterine device containing progesterone has also been marketed under the brand name Progestasert for birth control, including previously in the United States.<ref name="FalconeHurd2007">{{cite book| vauthors = Falcone T, Hurd WW |title=Clinical Reproductive Medicine and Surgery|url=https://books.google.com/books?id=fOPtaEIKvcIC&pg=PA406|year=2007|publisher=Elsevier Health Sciences|isbn=978-0-323-03309-1|pages=406–}}</ref>

===Gynecological disorders=== Progesterone is used to control persistent anovulatory bleeding.<ref name="pmid22230306">{{cite journal | vauthors = Sweet MG, Schmidt-Dalton TA, Weiss PM, Madsen KP | title = Evaluation and management of abnormal uterine bleeding in premenopausal women | journal = American Family Physician | volume = 85 | issue = 1 | pages = 35–43 | date = January 2012 | pmid = 22230306 | url = https://www.aafp.org/afp/2012/0101/p35.pdf }}</ref><ref name="pmid22972055">{{cite journal | vauthors = Hickey M, Higham JM, Fraser I | title = Progestogens with or without oestrogen for irregular uterine bleeding associated with anovulation | journal = The Cochrane Database of Systematic Reviews | volume = 2012 | issue = 9 | article-number = CD001895 | date = September 2012 | pmid = 22972055 | pmc = 7061495 | doi = 10.1002/14651858.CD001895.pub3 }}</ref><ref name="pmid7877394">{{cite journal | vauthors = Wathen PI, Henderson MC, Witz CA | title = Abnormal uterine bleeding | journal = The Medical Clinics of North America | volume = 79 | issue = 2 | pages = 329–344 | date = March 1995 | pmid = 7877394 | doi = 10.1016/S0025-7125(16)30071-2 }}</ref>

===Other uses=== Progesterone is of unclear benefit for the reversal of mifepristone-induced abortion.<ref name="pmid26057457">{{cite journal | vauthors = Grossman D, White K, Harris L, Reeves M, Blumenthal PD, Winikoff B, Grimes DA | title = Continuing pregnancy after mifepristone and "reversal" of first-trimester medical abortion: a systematic review | journal = Contraception | volume = 92 | issue = 3 | pages = 206–211 | date = September 2015 | pmid = 26057457 | doi = 10.1016/j.contraception.2015.06.001 }}</ref> Evidence is insufficient to support use in traumatic brain injury.<ref>{{cite journal | vauthors = Ma J, Huang S, Qin S, You C, Zeng Y | title = Progesterone for acute traumatic brain injury | journal = The Cochrane Database of Systematic Reviews | volume = 12 | issue = 12 | article-number = CD008409 | date = December 2016 | pmid = 28005271 | pmc = 6463867 | doi = 10.1002/14651858.CD008409.pub4 }}</ref>

Progesterone has been used as a topical medication applied to the scalp to treat female and male pattern hair loss.<ref name="Unger1995">{{cite book| vauthors = Unger WP |chapter=Androgenetic alopecia and its treatment. A historical overview|pages=1–33|title=Hair Transplantation | edition = Third |url=https://books.google.com/books?id=_KxsAAAAMAAJ|date=1 February 1995|publisher=Taylor & Francis|isbn=978-0-8247-9363-0}}</ref><ref name="SawayaShapiro2000">{{cite journal | vauthors = Sawaya ME, Shapiro J | title = Androgenetic alopecia. New approved and unapproved treatments | journal = Dermatologic Clinics | volume = 18 | issue = 1 | pages = 47–61, viii | date = January 2000 | pmid = 10626111 | doi = 10.1016/S0733-8635(05)70146-7 }}</ref><ref name="Price1988">{{cite journal | vauthors = Price VH | title = Androgenetic alopecia and hair growth promotion state of the art: present and future | journal = Clinics in Dermatology | volume = 6 | issue = 4 | pages = 218–227 | year = 1988 | pmid = 3063373 | doi = 10.1016/0738-081X(88)90090-9 }}</ref><ref name="Martínez2012">{{cite book| vauthors = Martínez FM |title=Handbook of hair in health and disease|chapter=Hair loss in women|volume=1|year=2012|pages=70–97|issn=2212-375X|doi=10.3920/978-90-8686-728-8_4|series=Human Health Handbooks no. 1|doi-broken-date=12 July 2025 |isbn=978-90-8686-728-8}}</ref><ref name="pmid8435919">{{cite journal | vauthors = Sawaya ME, Hordinsky MK | title = The antiandrogens. When and how they should be used | journal = Dermatologic Clinics | volume = 11 | issue = 1 | pages = 65–72 | date = January 1993 | pmid = 8435919 | doi = 10.1016/S0733-8635(18)30283-3 }}</ref> Variable effectiveness has been reported, but overall its effectiveness for this indication in both sexes has been poor.<ref name="SawayaShapiro2000" /><ref name="Price1988" /><ref name="LourithKanlayavattanakul2013">{{cite journal | vauthors = Lourith N, Kanlayavattanakul M | title = Hair loss and herbs for treatment | journal = Journal of Cosmetic Dermatology | volume = 12 | issue = 3 | pages = 210–222 | date = September 2013 | pmid = 23992163 | doi = 10.1111/jocd.12051 | s2cid = 5094700 }}</ref><ref name="pmid8435919" />

====Breast pain==== Progesterone is approved under the brand name Progestogel as a 1% topical gel for local application to the breasts to treat breast pain in certain countries.<ref name="KeepUtian2012">{{cite book | vauthors = van Keep PA, Utian WH | title = The Premenstrual Syndrome: Proceedings of a workshop held during the Sixth International Congress of Psychosomatic Obstetrics and Gynecology, Berlin, September 1980|url=https://books.google.com/books?id=0IAJBgAAQBAJ&pg=PA51|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-6255-5|pages=51–53}}</ref><ref name="BińkowskaWoroń2015">{{cite journal | vauthors = Bińkowska M, Woroń J | title = Progestogens in menopausal hormone therapy | journal = Przeglad Menopauzalny = Menopause Review | volume = 14 | issue = 2 | pages = 134–143 | date = June 2015 | pmid = 26327902 | pmc = 4498031 | doi = 10.5114/pm.2015.52154 }}</ref><ref name="RuanMueck2014"/> It is not approved for systemic therapy.<ref name="ShawLuesley2010">{{cite book| vauthors = Shaw RW, Luesley D, Monga AK |title=Gynaecology E-Book: Expert Consult: Online and Print|url=https://books.google.com/books?id=Ylqqk9-5zUsC&pg=PA417|date=1 October 2010|publisher=Elsevier Health Sciences|isbn=978-0-7020-4838-8|pages=417–}}</ref><ref name="KeepUtian2012" /> It has been found in clinical studies to inhibit estrogen-induced proliferation of breast epithelial cells and to abolish breast pain and tenderness in women with the condition.<ref name="RuanMueck2014"/> However, in one small study in women with cyclic breast pain it was ineffective.<ref name="SmithPruthi2004">{{cite journal | vauthors = Smith RL, Pruthi S, Fitzpatrick LA | title = Evaluation and management of breast pain | journal = Mayo Clinic Proceedings | volume = 79 | issue = 3 | pages = 353–372 | date = March 2004 | pmid = 15008609 | doi = 10.4065/79.3.353 | doi-access = free | title-link = doi }}</ref> Vaginal progesterone has also been found to be effective in the treatment of breast pain and tenderness.<ref name="SmithPruthi2004" />

====Premenstrual syndrome==== Historically, progesterone has been widely used in the treatment of premenstrual syndrome.<ref name="pmid12725453">{{cite journal | vauthors = Dickerson LM, Mazyck PJ, Hunter MH | title = Premenstrual syndrome | journal = American Family Physician | volume = 67 | issue = 8 | pages = 1743–1752 | date = April 2003 | pmid = 12725453 }}</ref> A 2012 Cochrane review found insufficient evidence for or against the effectiveness of progesterone for this indication.<ref name="pmid22419287">{{cite journal | vauthors = Ford O, Lethaby A, Roberts H, Mol BW | title = Progesterone for premenstrual syndrome | journal = The Cochrane Database of Systematic Reviews | volume = 2012 | issue = 3 | article-number = CD003415 | date = March 2012 | pmid = 22419287 | pmc = 7154383 | doi = 10.1002/14651858.CD003415.pub4 }}</ref> Another review of 10 studies found that progesterone was not effective for this condition, although it stated that insufficient evidence is available currently to make a definitive statement on progesterone in premenstrual syndrome.<ref name="pmid12725453" /><ref name="pmid11588078">{{cite journal | vauthors = Wyatt K, Dimmock P, Jones P, Obhrai M, O'Brien S | title = Efficacy of progesterone and progestogens in management of premenstrual syndrome: systematic review | journal = BMJ | volume = 323 | issue = 7316 | pages = 776–780 | date = October 2001 | pmid = 11588078 | pmc = 57352 | doi = 10.1136/bmj.323.7316.776 }}</ref>

====Catamenial epilepsy==== Progesterone can be used to treat catamenial epilepsy by supplementation during certain periods of the menstrual cycle.<ref name="DevinskySchachter2005">{{cite book | vauthors = Devinsky O, Schachter S, Pacia S | title = Complementary and Alternative Therapies for Epilepsy | url = https://books.google.com/books?id=WVUE-6Xdny4C&pg=PT378 | date = 1 January 2005 | publisher = Demos Medical Publishing | isbn = 978-1-934559-08-6 | pages = 378–}}</ref>

===Available forms=== {{See also|Estradiol/progesterone|Estradiol benzoate/progesterone|Estradiol hemisuccinate/progesterone}}

Progesterone is available in a variety of different forms, including oral capsules; sublingual tablets; vaginal capsules, tablets, gels, suppositories, and rings; rectal suppositories; oil solutions for intramuscular injection; and aqueous solutions for subcutaneous injection.<ref name="Drugs@FDA1" /><ref name="pmid16112947" /> A 1% topical progesterone gel is approved for local application to the breasts to treat breast pain, but is not indicated for systemic therapy.<ref name="ShawLuesley2010" /><ref name="KeepUtian2012" /> Progesterone was previously available as an intrauterine device for use in hormonal contraception, but this formulation was discontinued.<ref name="Drugs@FDA1" /> Progesterone is also limitedly available in combination with estrogens such as estradiol and estradiol benzoate for use by intramuscular injection.<ref name="Drugs.com" /><ref name="Micromedex" />

In addition to approved pharmaceutical products, progesterone is available in unregulated custom compounded and over-the-counter formulations like systemic transdermal creams and other preparations.<ref name="pmid26035149" /><ref name="pmid26418479" /><ref name="pmid25196424" /><ref name="pmid15772572" /><ref name="pmid15901742" /> The systemic efficacy of transdermal progesterone is controversial and has not been demonstrated.<ref name="pmid25196424" /><ref name="pmid15772572" /><ref name="pmid15901742" />

==Contraindications== Contraindications of progesterone include hypersensitivity to progesterone or progestogens, prevention of cardiovascular disease (a Black Box warning), thrombophlebitis, thromboembolic disorder, cerebral hemorrhage, impaired liver function or disease, breast cancer, reproductive organ cancers, undiagnosed vaginal bleeding, missed menstruations, miscarriage, or a history of these conditions.<ref name="AschenbrennerVenable2009">{{cite book | vauthors = Aschenbrenner DS, Venable SJ |title=Drug Therapy in Nursing|url=https://books.google.com/books?id=5zd_W_PUwvYC&pg=PA1150|year=2009|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6587-9|pages=1150–}}</ref><ref name="Moini2008">{{cite book| vauthors = Moini J |title=Fundamental Pharmacology for Pharmacy Technicians|url=https://books.google.com/books?id=bXkGAAAAQBAJ&pg=PA322|date=29 October 2008|publisher=Cengage Learning|isbn=978-1-111-80040-6|pages=322–}}</ref> Progesterone should be used with caution in people with conditions that may be adversely affected by fluid retention such as epilepsy, migraine headaches, asthma, cardiac dysfunction, and renal dysfunction.<ref name="AschenbrennerVenable2009" /><ref name="Moini2008" /> It should also be used with caution in patients with anemia, diabetes mellitus, a history of depression, previous ectopic pregnancy, and unresolved abnormal Pap smear.<ref name="AschenbrennerVenable2009" /><ref name="Moini2008" /> Use of progesterone is not recommended during pregnancy and breastfeeding.<ref name="Moini2008" /> However, the medication has been deemed usually safe in breastfeeding by the American Academy of Pediatrics, but should not be used during the first four months of pregnancy.<ref name="AschenbrennerVenable2009" /> Some progesterone formulations contain benzyl alcohol, and this may cause a potentially fatal "gasping syndrome" if given to premature infants.<ref name="AschenbrennerVenable2009" />

==Side effects== Progesterone is well tolerated, and many clinical studies have reported no side effects.<ref name="pmid17924777" /> Side effects of progesterone may include abdominal cramps, back pain, breast tenderness, constipation, nausea, dizziness, edema, vaginal bleeding, hypotension, fatigue, dysphoria, depression, and irritability, among others.<ref name="pmid17924777" /> Central nervous system depression, such as sedation and cognitive/memory impairment, can also occur.<ref name="pmid17924777" /><ref name="pmid16112947" />

Vaginal progesterone may be associated with vaginal irritation, itchiness, and discharge, decreased libido, painful sexual intercourse, vaginal bleeding or spotting in association with cramps, and local warmth or a "feeling of coolness" without discharge.<ref name="pmid17924777" /> Intramuscular injection may cause mild-to-moderate pain at the site of injection.<ref name="pmid17924777" /> High intramuscular doses of progesterone have been associated with increased body temperature, which may be alleviated with paracetamol treatment.<ref name="pmid17924777" />

Progesterone lacks undesirable off-target hormonal activity, in contrast to various progestins.<ref name="pmid16112947" /> As a result, it is not associated with androgenic, antiandrogenic, estrogenic, or glucocorticoid effects.<ref name="pmid16112947" /> Conversely, progesterone can still produce side effects related to its antimineralocorticoid and neurosteroid activity.<ref name="pmid16112947" /> Compared to the progestin medroxyprogesterone acetate, there are fewer reports of breast tenderness with progesterone.<ref name="pmid17924777" /> In addition, the magnitude and duration of vaginal bleeding with progesterone are reported to be lower than with medroxyprogesterone acetate.<ref name="pmid17924777" />

===Central depression=== Progesterone can produce central nervous system depression as an adverse effect, particularly with oral administration or with high doses of progesterone.<ref name="pmid16112947" /><ref name="pmid17924777" /> These side effects may include drowsiness, sedation, sleepiness, fatigue, sluggishness, reduced vigor, dizziness, lightheadedness, confusion, and cognitive, memory, and/or motor impairment.<ref name="pmid17924777" /><ref name="Wang-ChengNeuner2007">{{cite book | vauthors = Wang-Cheng R, Neuner JM, Barnabei VM | title = Menopause | url = https://books.google.com/books?id=mPs5Ly71OCQC&pg=PA97 | year = 2007 | publisher = ACP Press | isbn = 978-1-930513-83-9 | page = 97}}</ref><ref name="BergemannRiecher-Rössler2005">{{cite book | vauthors = Bergemann N, Ariecher-Rössler A | title = Estrogen Effects in Psychiatric Disorders | url = https://books.google.com/books?id=L4YQ50SbBnsC&pg=PA179 | date = 27 December 2005 | publisher = Springer Science & Business Media | isbn = 978-3-211-27063-9 | page = 179}}</ref> Limited available evidence has shown minimal or no adverse influence on cognition with oral progesterone (100–600 mg), vaginal progesterone (45 mg gel), or progesterone by intramuscular injection (25–200 mg).<ref name="pmid29852783" /><ref name="pmid29630427" /><ref name="pmid17924777" /><ref name="pmid16024758">{{cite journal | vauthors = Stein DG | title = The case for progesterone | journal = Annals of the New York Academy of Sciences | volume = 1052 | pages = 152–169 | date = June 2005 | issue = 1 | pmid = 16024758 | doi = 10.1196/annals.1347.011 | s2cid = 34913189 | bibcode = 2005NYASA1052..152S }}</ref><ref name="pmid1576050">{{cite journal | vauthors = Freeman EW, Weinstock L, Rickels K, Sondheimer SJ, Coutifaris C | title = A placebo-controlled study of effects of oral progesterone on performance and mood | journal = British Journal of Clinical Pharmacology | volume = 33 | issue = 3 | pages = 293–298 | date = March 1992 | pmid = 1576050 | pmc = 1381278 | doi = 10.1111/j.1365-2125.1992.tb04038.x }}</ref> However, high doses of oral progesterone (300–1200 mg), vaginal progesterone (100–200 mg), and intramuscular progesterone (100–200 mg) have been found to result in dose-dependent fatigue, drowsiness, and decreased vigor.<ref name="pmid17924777" /><ref name="pmid16024758" /><ref name="pmid29852783">{{cite journal | vauthors = Henderson VW | title = Progesterone and human cognition | journal = Climacteric | volume = 21 | issue = 4 | pages = 333–340 | date = August 2018 | pmid = 29852783 | pmc = 6309195 | doi = 10.1080/13697137.2018.1476484 }}</ref><ref name="pmid16112947" /><ref name="pmid12627037" /><ref name="pmid1576050" /><ref name="pmid14644065">{{cite journal | vauthors = Söderpalm AH, Lindsey S, Purdy RH, Hauger R, de Harriet W | title = Administration of progesterone produces mild sedative-like effects in men and women | journal = Psychoneuroendocrinology | volume = 29 | issue = 3 | pages = 339–354 | date = April 2004 | pmid = 14644065 | doi = 10.1016/s0306-4530(03)00033-7 | s2cid = 21796848 }}</ref> Moreover, high single doses of oral progesterone (1200 mg) produced significant cognitive and memory impairment.<ref name="pmid17924777" /><ref name="pmid12627037">{{cite journal | title = Role of progestogen in hormone therapy for postmenopausal women: position statement of The North American Menopause Society | journal = Menopause | volume = 10 | issue = 2 | pages = 113–132 | date = 2003 | pmid = 12627037 | doi = 10.1097/00042192-200310020-00003 | author1 = North American Menopause Society }}</ref><ref name="pmid1576050" /><ref name="pmid16112947" /> Intravenous infusion of high doses of progesterone (e.g., 500 mg) has been found to induce deep sleep in humans.<ref name="Tausk1971">{{cite book | vauthors = Tausk M | chapter = Various Other Effects of Progesterone | pages = 375–387 | veditors = Bengtsson LP, Tausk M | title = Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents | url = https://books.google.com/books?id=lf1sAAAAMAAJ | date = 30 January 1971 | publisher = Pergamon Press| isbn = 978-0-08-015745-0 }}</ref><ref name="pmid945344" /><ref name="Kopell1969">{{cite book| vauthors = Kopell BS |title=Metabolic Effects of Gonadal Hormones and Contraceptive Steroids|chapter=The Role of Progestins and Progesterone in Brain Function and Behavior|year=1969|pages=649–667|publisher=Springer |doi=10.1007/978-1-4684-1782-1_48|isbn=978-1-4684-1784-5}}</ref><ref name="pmid13211793" /> Some individuals are more sensitive and can experience considerable sedative and hypnotic effects at lower doses of oral progesterone (e.g., 400 mg).<ref name="pmid16112947" /><ref name="pmid3189454">{{cite journal | vauthors = Arafat ES, Hargrove JT, Maxson WS, Desiderio DM, Wentz AC, Andersen RN | title = Sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites | journal = American Journal of Obstetrics and Gynecology | volume = 159 | issue = 5 | pages = 1203–1209 | date = November 1988 | pmid = 3189454 | doi = 10.1016/0002-9378(88)90448-6 }}</ref>

Sedation and cognitive and memory impairment with progesterone are attributable to its inhibitory neurosteroid metabolites.<ref name="pmid16112947" /> These metabolites occur to a greater extent with oral progesterone, and may be minimized by switching to a parenteral route.<ref name="pmid16112947" /><ref name="pmid26342177" /><ref name="pmid11108875">{{cite journal | vauthors = de Ziegler D, Fanchin R | title = Progesterone and progestins: applications in gynecology | journal = Steroids | volume = 65 | issue = 10–11 | pages = 671–679 | year = 2000 | pmid = 11108875 | doi = 10.1016/s0039-128x(00)00123-9 | s2cid = 5867301 }}</ref> Progesterone can also be taken before bed to avoid these side effects and to help with sleep.<ref name="Wang-ChengNeuner2007" /> The neurosteroid effects of progesterone are unique to progesterone and are not shared with progestins.<ref name="pmid16112947" />

===Breast cancer=== Breast cell proliferation has been found to be significantly increased by the combination of an oral estrogen plus cyclic medroxyprogesterone acetate in postmenopausal women but not by the combination of transdermal estradiol plus oral progesterone.<ref name="pmid29630427" /> Studies of topical estradiol and progesterone applied to the breasts for 2 weeks have been found to result in highly pharmacological local levels of estradiol and progesterone.<ref name="pmid29630427" /><ref name="pmid8612843">{{cite journal | vauthors = Spicer DV, Ursin G, Pike MC | title = Progesterone concentrations--physiologic or pharmacologic? | journal = Fertility and Sterility | volume = 65 | issue = 5 | pages = 1077–1078 | date = May 1996 | pmid = 8612843 | doi = 10.1016/s0015-0282(16)58295-8 | doi-access = free | title-link = doi }}</ref> These studies have assessed breast proliferation markers and have found increased proliferation with estradiol alone, decreased proliferation with progesterone, and no change in proliferation with estradiol and progesterone combined.<ref name="pmid29630427" /> In the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, the combination of estrogen and cyclic oral progesterone resulted in a higher mammographic breast density than estrogen alone (3.1% vs. 0.9%) but a non-significantly lower breast density than the combination of estrogen and cyclic or continuous medroxyprogesterone acetate (3.1% vs. 4.4–4.6%).<ref name="pmid29630427" /> Higher breast density is a strong known risk factor for breast cancer.<ref name="pmid19709825">{{cite journal | vauthors = Martin LJ, Minkin S, Boyd NF | title = Hormone therapy, mammographic density, and breast cancer risk | journal = Maturitas | volume = 64 | issue = 1 | pages = 20–26 | date = September 2009 | pmid = 19709825 | doi = 10.1016/j.maturitas.2009.07.009 }}</ref> Other studies have had mixed findings however.<ref name="StuteWildt2018">{{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 | doi-access = free | title-link = doi | url = https://boris.unibe.ch/125894/1/29384406.pdf }}</ref> A 2018 systematic review reported that breast density with an estrogen plus oral progesterone was significantly increased in three studies and unchanged in two studies.<ref name="StuteWildt2018" /> Changes in breast density with progesterone appear to be less than with the compared progestins.<ref name="StuteWildt2018" />

In large short-term observational studies, estrogen alone and the combination of estrogen and oral progesterone have generally not been associated with an increased risk of breast cancer.<ref name="pmid29630427" /><ref name="pmid27898258">{{cite journal | vauthors = Yang Z, Hu Y, Zhang J, Xu L, Zeng R, Kang D | title = Estradiol therapy and breast cancer risk in perimenopausal and postmenopausal women: a systematic review and meta-analysis | journal = Gynecological Endocrinology | volume = 33 | issue = 2 | pages = 87–92 | date = February 2017 | pmid = 27898258 | doi = 10.1080/09513590.2016.1248932 | s2cid = 205631264 }}</ref><ref name="pmid24485796">{{cite journal | vauthors = Lambrinoudaki I | title = Progestogens in postmenopausal hormone therapy and the risk of breast cancer | journal = Maturitas | volume = 77 | issue = 4 | pages = 311–317 | date = April 2014 | pmid = 24485796 | doi = 10.1016/j.maturitas.2014.01.001 }}</ref><ref name="pmid28251642" /> Conversely, the combination of estrogen and almost any progestin, such as medroxyprogesterone acetate or norethisterone acetate, has been associated with an increased risk of breast cancer.<ref name="pmid29630427" /><ref name="pmid27898258" /><ref name="pmid28251642" /><ref name="pmid24485796" /><ref name="pmid23336704" /> The only exception among progestins is dydrogesterone, which has shown similar risk to that of oral progesterone.<ref name="pmid29630427" /> Breast cancer risk with estrogen and progestin therapy is duration-dependent, with the risk being significantly greater with more than 5 years of exposure relative to less than 5 years.<ref name="pmid27898258" /> In contrast to shorter-term studies, the longer-term observations (>5 years) of the French E3N study showed significant associations of both estrogen plus oral progesterone and estrogen plus dydrogesterone with higher breast cancer risk, similarly to estrogen plus other progestogens.<ref name="pmid29630427" /> Oral progesterone has very low bioavailability and has relatively weak progestogenic effects.<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> The delayed onset of breast cancer risk with estrogen plus oral progesterone is potentially consistent with a weak proliferative effect of oral progesterone on the breasts.<ref name="pmid23336704" /><ref name="pmid29526116" /> As such, a longer duration of exposure may be necessary for a detectable increase in breast cancer risk to occur.<ref name="pmid23336704" /><ref name="pmid29526116" /> In any case, the risk remains lower than that with most progestins.<ref name="pmid29630427" /><ref name="pmid24485796" /> A 2018 systematic review of progesterone and breast cancer concluded that short-term use (<5 years) of an estrogen plus progesterone is not associated with a significant increase in risk of breast cancer but that long-term use (>5 years) is associated with greater risk.<ref name="StuteWildt2018" /> The conclusions for progesterone were the same in a 2019 meta-analysis of the worldwide epidemiological evidence by the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC).<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>

Most data on breast density changes and breast cancer risk are with oral progesterone.<ref name="StuteWildt2018" /> Data on breast safety with vaginal progesterone are scarce.<ref name="StuteWildt2018" /> The Early versus Late Intervention Trial with Estradiol (ELITE) was a randomized controlled trial of about 650 postmenopausal women who used estradiol and 45 mg/day cyclic vaginal progesterone.<ref name="StuteWildt2018" /><ref name="HodisMack2016">{{cite journal | vauthors = Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N, Stanczyk FZ, Selzer RH, Azen SP | title = Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol | journal = The New England Journal of Medicine | volume = 374 | issue = 13 | pages = 1221–1231 | date = March 2016 | pmid = 27028912 | pmc = 4921205 | doi = 10.1056/NEJMoa1505241 }}</ref> Incidence of breast cancer was reported as an adverse effect.<ref name="StuteWildt2018" /><ref name="HodisMack2016" /> The absolute incidences were 10 cases in the estradiol plus vaginal progesterone group and 8 cases in the control group.<ref name="StuteWildt2018" /><ref name="HodisMack2016" /> However, the study was not adequately powered for quantifying breast cancer risk.<ref name="StuteWildt2018" /><ref name="HodisMack2016" />

{{Worldwide epidemiological evidence on breast cancer risk with menopausal hormone therapy}}

{{Risk of breast cancer with menopausal hormone therapy in large observational studies}}

{{Risk of breast cancer with menopausal hormone therapy by duration in large observational studies}}

===Blood clots=== Whereas the combination of estrogen and a progestin is associated with increased risk of venous thromboembolism (VTE) relative to estrogen alone, there is no difference in risk of VTE with the combination of estrogen and oral progesterone relative to estrogen alone.<ref name="pmid29526116" /><ref name="pmid29570359">{{cite journal | vauthors = Scarabin PY | title = Progestogens and venous thromboembolism in menopausal women: an updated oral versus transdermal estrogen meta-analysis | journal = Climacteric | volume = 21 | issue = 4 | pages = 341–345 | date = August 2018 | pmid = 29570359 | doi = 10.1080/13697137.2018.1446931 | s2cid = 4229701 }}</ref> Hence, in contrast to progestins, oral progesterone added to estrogen does not appear to increase coagulation or VTE risk.<ref name="pmid29526116" /><ref name="pmid29570359" /> The reason for the differences between progesterone and progestins in terms of VTE risk are unclear.<ref name="pmid23238854">{{cite journal | vauthors = Stanczyk FZ, Hapgood JP, Winer S, Mishell DR | title = Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects | journal = Endocrine Reviews | volume = 34 | issue = 2 | pages = 171–208 | date = April 2013 | pmid = 23238854 | pmc = 3610676 | doi = 10.1210/er.2012-1008 }}</ref><ref name="pmid29526116" /><ref name="pmid23336704" /> However, they may be due to very low progesterone levels and relatively weak progestogenic effects produced by oral progesterone.<ref name="pmid29526116" /><ref name="pmid23336704" /> In contrast to oral progesterone, non-oral progesterone—which can achieve much higher progesterone levels—has not been assessed in terms of VTE risk.<ref name="pmid29526116" /><ref name="pmid23336704" />

==Overdose== Progesterone is likely to be relatively safe in overdose. Levels of progesterone during pregnancy are up to 100-fold higher than during normal menstrual cycling, although levels increase gradually over the course of pregnancy.<ref name="PlantZeleznik2014">{{cite book| vauthors = Plant TM, Zeleznik AJ |title=Knobil and Neill's Physiology of Reproduction|url=https://books.google.com/books?id=I1ACBAAAQBAJ&pg=PA2386|date=15 November 2014|publisher=Academic Press|isbn=978-0-12-397769-4|pages=2289, 2386}}</ref> Oral dosages of progesterone of as high as 3,600 mg/day have been assessed in clinical trials, with the main side effect being sedation.<ref name="pmid7604143">{{cite journal | vauthors = Schweizer E, Case WG, Garcia-Espana F, Greenblatt DJ, Rickels K | title = Progesterone co-administration in patients discontinuing long-term benzodiazepine therapy: effects on withdrawal severity and taper outcome | journal = Psychopharmacology | volume = 117 | issue = 4 | pages = 424–429 | date = February 1995 | pmid = 7604143 | doi = 10.1007/bf02246214 | s2cid = 8221132 }}</ref> There is a case report of progesterone misuse with an oral dosage of 6,400 mg per day.<ref name="pmid8609776">{{cite journal | vauthors = Keefe DL, Sarrel P | title = Dependency on progesterone in woman with self-diagnosed premenstrual syndrome | journal = Lancet | volume = 347 | issue = 9009 | page = 1182 | date = April 1996 | pmid = 8609776 | doi = 10.1016/s0140-6736(96)90639-x | s2cid = 5446017 }}</ref> Administration of as much as 500 mg progesterone by intravenous infusion in humans was uneventful in terms of toxicity, but did induce deep sleep, though the individuals were still able to be awakened with sufficient stimulation.<ref name="Tausk1971" /><ref name="pmid945344" /><ref name="Kopell1969" /><ref name="pmid13211793">{{cite journal | vauthors = Merryman W, Boiman R, Barnes L, Rothchild I | title = Progesterone anesthesia in human subjects | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 14 | issue = 12 | pages = 1567–1569 | date = December 1954 | pmid = 13211793 | doi = 10.1210/jcem-14-12-1567 }}</ref>

== Interactions ==

There are several notable drug interactions with progesterone. Certain selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, and sertraline may increase the GABAA receptor-related central depressant effects of progesterone by enhancing its conversion into 5α-dihydroprogesterone and allopregnanolone via activation of 3α-HSD.<ref name="pmid18473173">{{cite journal | vauthors = Pinna G, Agis-Balboa RC, Pibiri F, Nelson M, Guidotti A, Costa E | title = Neurosteroid biosynthesis regulates sexually dimorphic fear and aggressive behavior in mice | journal = Neurochemical Research | volume = 33 | issue = 10 | pages = 1990–2007 | date = October 2008 | pmid = 18473173 | doi = 10.1007/s11064-008-9718-5 | s2cid = 19338424 }}</ref> Progesterone potentiates the sedative effects of benzodiazepines and alcohol.<ref name="BabalonisLile2011">{{cite journal | vauthors = Babalonis S, Lile JA, Martin CA, Kelly TH | title = Physiological doses of progesterone potentiate the effects of triazolam in healthy, premenopausal women | journal = Psychopharmacology | volume = 215 | issue = 3 | pages = 429–439 | date = June 2011 | pmid = 21350928 | pmc = 3137367 | doi = 10.1007/s00213-011-2206-7 }}</ref> Notably, there is a case report of progesterone abuse alone with very high doses.<ref>{{cite journal | title = Progesterone abuse | year = 1996 | issn = 1179-2051 | doi = 10.2165/00128415-199605990-00031 | volume = 599 | issue = 1 | page = 9 | journal=Reactions Weekly | s2cid = 195107326 }}</ref> 5α-Reductase inhibitors such as finasteride and dutasteride inhibit the conversion of progesterone into the inhibitory neurosteroid allopregnanolone, and for this reason, may have the potential to reduce the sedative and related effects of progesterone.<ref name="pmid24955220">{{cite journal | vauthors = Traish AM, Mulgaonkar A, Giordano N | title = The dark side of 5α-reductase inhibitors' therapy: sexual dysfunction, high Gleason grade prostate cancer and depression | journal = Korean Journal of Urology | volume = 55 | issue = 6 | pages = 367–379 | date = June 2014 | pmid = 24955220 | pmc = 4064044 | doi = 10.4111/kju.2014.55.6.367 }}</ref><ref name="pmid18291663">{{cite journal | vauthors = Meyer L, Venard C, Schaeffer V, Patte-Mensah C, Mensah-Nyagan AG | title = The biological activity of 3alpha-hydroxysteroid oxido-reductase in the spinal cord regulates thermal and mechanical pain thresholds after sciatic nerve injury | journal = Neurobiology of Disease | volume = 30 | issue = 1 | pages = 30–41 | date = April 2008 | pmid = 18291663 | doi = 10.1016/j.nbd.2007.12.001 | s2cid = 5830825 }}</ref><ref name="pmid15181090">{{cite journal | vauthors = Pazol K, Wilson ME, Wallen K | title = Medroxyprogesterone acetate antagonizes the effects of estrogen treatment on social and sexual behavior in female macaques | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 89 | issue = 6 | pages = 2998–3006 | date = June 2004 | pmid = 15181090 | pmc = 1440328 | doi = 10.1210/jc.2003-032086 }}</ref>

Progesterone is a weak but significant agonist of the pregnane X receptor (PXR), and has been found to induce several hepatic cytochrome P450 enzymes, such as CYP3A4, especially when concentrations are high, such as with pregnancy range levels.<ref name="pmid22837389">{{cite journal | vauthors = Choi SY, Koh KH, Jeong H | title = Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone | journal = Drug Metabolism and Disposition | volume = 41 | issue = 2 | pages = 263–269 | date = February 2013 | pmid = 22837389 | pmc = 3558868 | doi = 10.1124/dmd.112.046276 }}</ref><ref name="Meanwell2014">{{cite book| vauthors = Meanwell NA | title = Tactics in Contemporary Drug Design|url=https://books.google.com/books?id=j2HEBQAAQBAJ&pg=PA161|date=8 December 2014|publisher=Springer|isbn=978-3-642-55041-6|pages=161–}}</ref><ref name="LegatoBilezikian2004">{{cite book | vauthors = Legato MJ, Bilezikian JP | title=Principles of Gender-specific Medicine|url=https://books.google.com/books?id=TiLxa8nPbLkC&pg=PA146 |year=2004 |publisher= Gulf Professional Publishing |isbn=978-0-12-440906-4 |pages=146–}}</ref><ref name="LemkeWilliams2012">{{cite book | vauthors = Lemke TL, Williams DA | title = Foye's Principles of Medicinal Chemistry | 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|pages=164–}}</ref> As such, progesterone may have the potential to accelerate the metabolism of various medications.<ref name="pmid22837389" /><ref name="Meanwell2014" /><ref name="LegatoBilezikian2004" /><ref name="LemkeWilliams2012" />

==Pharmacology==

===Pharmacodynamics=== {{Main|Pharmacodynamics of progesterone}}

Progesterone is a progestogen, or an agonist of the nuclear progesterone receptors (PRs), the PR-A, PR-B, and PR-C.<ref name="pmid16112947" /> In addition, progesterone is an agonist of the membrane progesterone receptors (mPRs), including the mPRα, mPRβ, mPRγ, mPRδ, and mPRϵ.<ref name="pmid23756388">{{cite journal | vauthors = Soltysik K, Czekaj P | title = Membrane estrogen receptors - is it an alternative way of estrogen action? | journal = Journal of Physiology and Pharmacology | volume = 64 | issue = 2 | pages = 129–142 | date = April 2013 | pmid = 23756388 }}</ref><ref name="pmid24530924">{{cite journal | vauthors = Prossnitz ER, Barton M | title = Estrogen biology: new insights into GPER function and clinical opportunities | journal = Molecular and Cellular Endocrinology | volume = 389 | issue = 1–2 | pages = 71–83 | date = May 2014 | pmid = 24530924 | pmc = 4040308 | doi = 10.1016/j.mce.2014.02.002 | bibcode = 2014MolCE.389...71P }}</ref> Aside from the PRs and mPRs, progesterone is a potent antimineralocorticoid, or antagonist of the mineralocorticoid receptor, the biological target of the mineralocorticoid aldosterone.<ref name="pmid8282004">{{cite journal | vauthors = Rupprecht R, Reul JM, van Steensel B, Spengler D, Söder M, Berning B, Holsboer F, Damm K | title = Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands | journal = European Journal of Pharmacology | volume = 247 | issue = 2 | pages = 145–154 | date = October 1993 | pmid = 8282004 | doi = 10.1016/0922-4106(93)90072-H }}</ref><ref name="pmid14667981">{{cite journal | vauthors = Elger W, Beier S, Pollow K, Garfield R, Shi SQ, Hillisch A | title = Conception and pharmacodynamic profile of drospirenone | journal = Steroids | volume = 68 | issue = 10–13 | pages = 891–905 | date = November 2003 | pmid = 14667981 | doi = 10.1016/j.steroids.2003.08.008 | s2cid = 41756726 }}</ref> In addition to its activity as a steroid hormone, progesterone is a neurosteroid.<ref name="pmid11108866">{{cite journal | vauthors = Baulieu E, Schumacher M | title = Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination | journal = Steroids | volume = 65 | issue = 10–11 | pages = 605–612 | year = 2000 | pmid = 11108866 | doi = 10.1016/s0039-128x(00)00173-2 | s2cid = 14952168 }}</ref> Among other neurosteroid activities, and via its active metabolites allopregnanolone and pregnanolone, progesterone is a potent positive allosteric modulator of the GABAA receptor, the major signaling receptor of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).<ref name="pmid1347506">{{cite journal | vauthors = Paul SM, Purdy RH | title = Neuroactive steroids | journal = FASEB Journal | volume = 6 | issue = 6 | pages = 2311–2322 | date = March 1992 | pmid = 1347506 | doi = 10.1096/fasebj.6.6.1347506 | s2cid = 221753076 | doi-access = free | title-link = doi | bibcode = 1992FASEJ...6.2311P }}</ref>

The PRs are expressed widely throughout the body, including in the uterus, cervix, vagina, fallopian tubes, breasts, fat, skin, pituitary gland, hypothalamus, and in other areas of the brain.<ref name="pmid16112947" /><ref name="Bentley1980">{{cite book| vauthors = Bentley PJ |title=Endocrine Pharmacology: Physiological Basis and Therapeutic Applications|url=https://books.google.com/books?id=W6M9AAAAIAAJ&pg=PA264|year=1980|publisher=CUP Archive|isbn=978-0-521-22673-8|pages=264, 274}}</ref> In accordance, progesterone has numerous effects throughout the body.<ref name="pmid16112947" /> Among other effects, progesterone produces changes in the female reproductive system, the breasts, and the brain.<ref name="pmid16112947" /><ref name="Bentley1980" /> Progesterone has functional antiestrogenic effects due to its progestogenic activity, including in the uterus, cervix, and vagina.<ref name="pmid16112947" /> The effects of progesterone may influence health in both positive and negative ways.<ref name="pmid16112947" /> In addition to the aforementioned effects, progesterone has antigonadotropic effects due to its progestogenic activity, and can inhibit ovulation and suppress gonadal sex hormone production.<ref name="pmid16112947" />

The activities of progesterone besides those mediated by the PRs and mPRs are also of significance.<ref name="pmid16112947" /> Progesterone lowers blood pressure and reduces water and salt retention among other effects via its antimineralocorticoid activity.<ref name="pmid16112947" /><ref name="pmid11246598">{{cite journal | vauthors = Oelkers W | title = Drospirenone--a new progestogen with antimineralocorticoid activity, resembling natural progesterone | journal = The European Journal of Contraception & Reproductive Health Care | volume = 5 | issue = Suppl 3 | pages = 17–24 | date = December 2000 | doi = 10.1080/14730782.2000.12288986 | pmid = 11246598 | s2cid = 35051390 }}</ref> In addition, progesterone can produce sedative, hypnotic, anxiolytic, euphoric, amnestic, cognitive-impairing, motor-impairing, anticonvulsant, and even anesthetic effects via formation of sufficiently high concentrations of its neurosteroid metabolites and consequent GABAA receptor potentiation in the brain.<ref name="pmid17924777" /><ref name="Wang-ChengNeuner2007" /><ref name="BergemannRiecher-Rössler2005" /><ref name="pmid23978486">{{cite journal | vauthors = Bäckström T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G, Savic I, Strömberg J, Timby E, van Broekhoven F, van Wingen G | title = Allopregnanolone and mood disorders | journal = Progress in Neurobiology | volume = 113 | pages = 88–94 | date = February 2014 | pmid = 23978486 | doi = 10.1016/j.pneurobio.2013.07.005 | s2cid = 207407084 }}</ref>

There are differences between progesterones and progestins, such as medroxyprogesterone acetate and norethisterone, with implications for pharmacodynamics and pharmacokinetics, as well as for efficacy, tolerability, and safety.<ref name="pmid16112947" />

===Pharmacokinetics=== {{Main|Pharmacokinetics of progesterone}}

The pharmacokinetics of progesterone are dependent on its route of administration. The medications is approved in the form of oil-filled capsules containing micronized progesterone for oral administration, termed ''oral micronized progesterone'' or ''OMP''.<ref name="Zutshi2005">{{cite book|author=Zutshi|title=Hormones in Obstetrics and Gynaecology|url=https://books.google.com/books?id=IBxBbaDjXw0C&pg=PA75|year=2005|publisher=Jaypee Brothers, Medical Publishers|isbn=978-81-8061-427-9|pages=74–75|quote=It has been observed that micronized progesterone has no suppressive effects on high-density lipoprotein-cholesterol (HDL-C). Jensen et al have proved that oral micronized progesterone has no adverse effect on serum lipids. These preparations have the same antiestrogenic and antimineralocorticoid effect but no androgenic action. It does not affect aldosterone synthesis, blood pressure, carbohydrate metabolism or mood changes. No side effects have been reported as far as lipid profile, coagulation factors and blood pressure are concerned.}}{{Dead link|date=January 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> It is also available in the form of vaginal or rectal suppositories or pessaries, topical creams and gels,<ref name=Lark1999>{{cite book |title=Making the Estrogen Decision | vauthors = Lark S |author-link=Susan Lark |year=1999 |publisher=McGraw-Hill Professional |isbn=978-0-87983-696-2 |page=22 |url=https://books.google.com/books?id=d3IP-dmpoNsC&q=progesterone+%22skin+cream%22+liver&pg=PA22}}</ref> oil solutions for intramuscular injection, and aqueous solutions for subcutaneous injection.<ref name="Zutshi2005" /><ref name="pmid26342177" /><ref name="Drugs.com2">{{citation | url = https://www.drugs.com/pro/progesterone.html | title = Progesterone - Drugs.com | access-date = 23 August 2015}}</ref>

Routes of administration that progesterone has been used by include oral, intranasal, transdermal/topical, vaginal, rectal, intramuscular, subcutaneous, and intravenous injection.<ref name="pmid26342177" /> Vaginal progesterone is available in the form of progesterone capsules, tablets or inserts, gels, suppositories or pessaries, and rings.<ref name="pmid26342177" />

The bioavailability of progesterone was commonly overestimated due to the immunoassay method of analysis failing to distinguish between progesterone itself and its metabolites.<ref name="Kuhl2011">{{cite journal | vauthors = Kuhl H | title = Pharmacology of Progestogens | journal = Journal für Reproduktionsmedizin und Endokrinologie-Journal of Reproductive Medicine and Endocrinology | year = 2011 | volume = 8 | issue = 1 | pages = 157–177 | url = http://www.kup.at/kup/pdf/10168.pdf}}</ref><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="pmid29526116"/> Newer methods have adjusted the oral bioavailbility estimate from 6.2 to 8.6%<ref name="pmid10090424"/> down to less than 2.4%.<ref name="pmid10689005" />

==Chemistry== [[File:Steroidogenesis.svg|thumb|upright=1.6|class=skin-invert-image|Steroidogenesis.]]

Progesterone is a naturally occurring pregnane steroid and is also known as pregn-4-ene-3,20-dione.<ref name="Elks2014" /><ref name="IndexNominum2000" /> 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.<ref name="Elks2014" /><ref name="IndexNominum2000" /> Due to its pregnane core and C4(5) double bond, progesterone is often abbreviated as P4. It is contrasted with pregnenolone, which has a C5(6) double bond and is often abbreviated as P5.

===Derivatives=== {{See also|Progestogen ester|List of progestogens#Progesterone derivatives|List of progestogen esters#Esters of progesterone derivatives|List of neurosteroids}}

A large number of progestins, or synthetic progestogens, have been derived from progesterone.<ref name="Elks2014" /><ref name="pmid16112947" /> They can be categorized into several structural groups, including derivatives of retroprogesterone, 17α-hydroxyprogesterone, 17α-methylprogesterone, and 19-norprogesterone, with a respective example from each group including dydrogesterone, medroxyprogesterone acetate, medrogestone, and promegestone.<ref name="pmid16112947" /> The progesterone ethers quingestrone (progesterone 3-cyclopentyl enol ether) and progesterone 3-acetyl enol ether are among the only examples that do not belong to any of these groups.<ref name="Bentley1980" /><ref name="pmid13480263">{{cite journal | vauthors = Pincus G, Miyake T, Merrill AP, Longo P | title = The bioassay of progesterone | journal = Endocrinology | volume = 61 | issue = 5 | pages = 528–533 | date = November 1957 | pmid = 13480263 | doi = 10.1210/endo-61-5-528 | doi-access = free | title-link = doi }}</ref> Another major group of progestins, the 19-nortestosterone derivatives, exemplified by norethisterone (norethindrone) and levonorgestrel, are not derived from progesterone but rather from testosterone.<ref name="pmid16112947" />

A variety of synthetic inhibitory neurosteroids have been derived from progesterone and its neurosteroid metabolites, allopregnanolone and pregnanolone.<ref name="Elks2014" /> Examples include alfadolone, alfaxolone, ganaxolone, hydroxydione, minaxolone, and renanolone.<ref name="Elks2014" /> In addition, C3 and C20 conjugates of progesterone, such as progesterone carboxymethyloxime (progesterone 3-(''O''-carboxymethyl)oxime; P4-3-CMO), P1-185 (progesterone 3-''O''-(L-valine)-''E''-oxime), EIDD-1723 (progesterone 20''E''-[''O''-[(phosphonooxy)methyl]oxime] sodium salt), EIDD-036 (progesterone 20-oxime; P4-20-O), and VOLT-02 (chemical structure unreleased), have been developed as water-soluble prodrugs of progesterone and its neurosteroid metabolites.<ref name="BasuMitra1990">{{cite journal| vauthors = Basu K, Mitra AK |title=Effects of 3-hydrazone modification on the metabolism and protein binding of progesterone|journal=International Journal of Pharmaceutics|volume=65|issue=1–2|year=1990|pages=109–114|issn=0378-5173|doi=10.1016/0378-5173(90)90015-V}}</ref><ref name="pmid27267687">{{cite journal | vauthors = Wali B, Sayeed I, Guthrie DB, Natchus MG, Turan N, Liotta DC, Stein DG | title = Evaluating the neurotherapeutic potential of a water-soluble progesterone analog after traumatic brain injury in rats | journal = Neuropharmacology | volume = 109 | pages = 148–158 | date = October 2016 | pmid = 27267687 | doi = 10.1016/j.neuropharm.2016.05.017 | s2cid = 19906601 }}</ref><ref name="US9802978B2">{{cite patent | title = Progesterone phosphate analogs and uses related thereto | inventor = Guthrie DA, Lockwood MA, Natchus MG, Liotta DC, Stein DG, Sayeed I | country = US | number = 9802978 | url = https://patents.google.com/patent/US9802978B2/en | assign1 = Emory University | gdate = 31 October 2017 | postscript = . }}</ref><ref name="pmid19791804">{{cite journal | vauthors = MacNevin CJ, Atif F, Sayeed I, Stein DG, Liotta DC | title = Development and screening of water-soluble analogues of progesterone and allopregnanolone in models of brain injury | journal = Journal of Medicinal Chemistry | volume = 52 | issue = 19 | pages = 6012–6023 | date = October 2009 | pmid = 19791804 | doi = 10.1021/jm900712n | s2cid = 23608386 }}</ref><ref name="pmid24900479">{{cite journal | vauthors = Guthrie DB, Stein DG, Liotta DC, Lockwood MA, Sayeed I, Atif F, Arrendale RF, Reddy GP, Evers TJ, Marengo JR, Howard RB, Culver DG, Natchus MG | title = Water-soluble progesterone analogues are effective, injectable treatments in animal models of traumatic brain injury | journal = ACS Medicinal Chemistry Letters | volume = 3 | issue = 5 | pages = 362–366 | date = May 2012 | pmid = 24900479 | pmc = 4025794 | doi = 10.1021/ml200303r }}</ref><ref name="AdisInsight-VOLT-02">{{Cite web | url=https://adisinsight.springer.com/drugs/800041522 | title=Progesterone conjugate - Levolta Pharmaceuticals | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref>

===Synthesis=== Chemical syntheses of progesterone have been published.<ref name="Springer2013">{{cite book|title=Die Gestagene|url=https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA5|date=27 November 2013|publisher=Springer-Verlag|isbn=978-3-642-99941-3|pages=5–}}</ref>

==History==

===Discovery and synthesis=== The hormonal action of progesterone was discovered in 1929.<ref name="Josimovich2013">{{cite book | vauthors = Josimovich JB | title = Gynecologic Endocrinology | url = https://books.google.com/books?id=9vv2BwAAQBAJ&pg=PA25|date=11 November 2013|publisher=Springer Science & Business Media|isbn=978-1-4613-2157-6|pages=9, 25–29, 139}}</ref><ref name="CoutinhoSegal1999">{{cite book | vauthors = Coutinho EM, Segal SJ | title = Is Menstruation Obsolete? | url = https://books.google.com/books?id=1ZzmCwAAQBAJ&pg=PA31 | year = 1999 | publisher = Oxford University Press | isbn=978-0-19-513021-8|pages=31–}}</ref><ref name="Walker2008">{{cite book | vauthors = Walker A | title = The Menstrual Cycle | url = https://books.google.com/books?id=7HQBAwAAQBAJ&pg=PA49|date=7 March 2008|publisher=Routledge|isbn=978-1-134-71411-7|pages=49–}}</ref> Pure crystalline progesterone was isolated in 1934 and its chemical structure was determined.<ref name="Josimovich2013" /><ref name="CoutinhoSegal1999" /> Later that year, chemical synthesis of progesterone was accomplished.<ref name="CoutinhoSegal1999"/><ref name="Ginsburg2012">{{cite book | vauthors = Ginsburg B | title = Premenstrual Syndrome: Ethical and Legal Implications in a Biomedical Perspective|url=https://books.google.com/books?id=HTLoBwAAQBAJ&pg=PA274|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4684-5275-4|pages=274–}}</ref> Shortly following its chemical synthesis, progesterone began being tested clinically in women.<ref name="CoutinhoSegal1999" /><ref name="MVJain2018" />

===Injections and implants=== In 1933 or 1934, Schering introduced progesterone in oil solution as a medication by intramuscular injection under the brand name Proluton.<ref name="EichlerFarah1968">{{cite book|title=Die Gestagene|url=https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA1027|date=27 November 2013|publisher=Springer-Verlag|isbn=978-3-642-99941-3|pages=1027–}}</ref><ref name="Seaman2011">{{cite book | vauthors = Seaman B | title=The Greatest Experiment Ever Performed on Women: Exploding the Estrogen Myth|url=https://books.google.com/books?id=HHm1qkcgFSUC&pg=PA27|date=4 January 2011|publisher=Seven Stories Press|isbn=978-1-60980-062-8|pages=27–}}</ref><ref name="Simon1995">{{cite journal | vauthors = Simon JA | title = Micronized progesterone: vaginal and oral uses | journal = Clinical Obstetrics and Gynecology | volume = 38 | issue = 4 | pages = 902–914 | date = December 1995 | pmid = 8616985 | doi = 10.1097/00003081-199538040-00024 }}</ref><ref name="RuanMueck2014" /><ref name="Gerald2013">{{Cite book|title = The Drug Book| vauthors = Gerald M |publisher = Sterling Publishing|year = 2013|isbn = 978-1-4027-8264-0|location = New York, New York|page = 186}}</ref> This was the first pharmaceutical formulation of progesterone to be marketed for medical use.<ref name="MVJain2018B">{{cite book| vauthors = Anita MV, Jain S, Goel N |title=Use of Progestogens in Clinical Practice of Obstetrics and Gynecology|url=https://books.google.com/books?id=VrpEDwAAQBAJ&pg=PA3|date=31 July 2018|publisher=JP Medical Ltd|isbn=978-93-5270-218-3|pages=3–}}</ref> It was initially a corpus luteum extract, becoming pure synthesized progesterone only subsequently.<ref name="pmid29648134" /><ref name="Kaufmann1934" /><ref name="EichlerFarah1968" /><ref name="Reifenstein1944">{{cite journal| vauthors = Reifenstein EC |title=Endocrinology: A Synopsis of Normal and Pathologic Physiology, Diagnostic Procedures, and Therapy|journal=Medical Clinics of North America|volume=28|issue=5|year=1944|pages=1232–1276|issn=0025-7125|doi=10.1016/S0025-7125(16)36180-6}}</ref> A clinical study of the formulation was published in 1933.<ref name="EichlerFarah1968" /><ref name="Kaufman1933">{{cite journal| vauthors = Kaufman C | title = Die Behandlung der Amenorrhöe mit Hohen Dosen der Ovarialhormone|trans-title=Treatment of Amenorrhea with High Doses of Ovarian Hormones|journal=Klinische Wochenschrift|volume=12|issue=40|year=1933|pages=1557–1562|issn=0023-2173|doi=10.1007/BF01765673|s2cid=25856898}}</ref><ref name="Kaufmann1934">{{cite journal| vauthors = Kaufmann C |title=Therapeutics with Hormones of the Ovary|journal=Proceedings of the Royal Society of Medicine|volume=27|issue=7|year=1934|pages=849–863|issn=0035-9157|doi=10.1177/003591573402700711| doi-access = free | title-link = doi |pmid=19989793 |pmc=2205019}}</ref> Multiple formulations of progesterone in oil solution for intramuscular injection, under the brand names Proluton, Progestin, and Gestone, were available by 1936.<ref name="pmid29648134">{{cite journal | vauthors = Johnstone RW | title = Sex Hormone Therapy in Gynæcology | journal = Edinburgh Medical Journal | volume = 43 | issue = 11 | pages = 680–695 | date = November 1936 | pmid = 29648134 | pmc = 5303355 }}</ref><ref name="pmid20780598">{{cite journal | vauthors = Bishop PM | title = Hormones in the Treatment of Menstrual Disturbances | journal = British Medical Journal | volume = 1 | issue = 3979 | pages = 763–765 | date = April 1937 | pmid = 20780598 | pmc = 2088583 | doi = 10.1136/bmj.1.3979.763 }}</ref> A parenteral route was used because oral progesterone had very low activity and was thought to be inactive.<ref name="RuanMueck2014" /><ref name="Gerald2013" /><ref name="Reifenstein1944" /> Progesterone was initially very expensive due to the large doses required.<ref name="pmid21313067">{{cite journal | vauthors = Beattie J | title = The Use of Hormones in Obstetrics and Gynæcology | journal = Postgraduate Medical Journal | volume = 13 | issue = 141 | pages = 234–240 | date = July 1937 | pmid = 21313067 | pmc = 2476623 | doi = 10.1136/pgmj.13.141.234 }}</ref> However, with the start of steroid manufacturing from diosgenin in the 1940s, costs greatly decreased.<ref name="Djerassi2003">{{cite book| vauthors = Djerassi C |title=This Man's Pill: Reflections on the 50th Birthday of the Pill|url=https://books.google.com/books?id=J4VSAwAAQBAJ&pg=PA21|year=2003|publisher=Oxford University Press|isbn=978-0-19-860695-6|pages=21–}}</ref>

Subcutaneous pellet implants of progesterone were first studied in women in the late 1930s.<ref name="Mishell1941">{{cite journal| vauthors = Mishell DR |title=A clinical study of progesterone therapy by pellet implantation|journal=American Journal of Obstetrics and Gynecology|volume=41|issue=4|year=1941|pages=687–693|issn=0002-9378|doi=10.1016/S0002-9378(41)90665-8}}</ref><ref name="Foss1943">{{cite journal| vauthors = Foss GL |title=Implantation of Sex Hormone Tablets in Man|journal=British Medical Bulletin|volume=1|issue=2|year=1943|pages=21–22|issn=1471-8391|doi=10.1093/oxfordjournals.bmb.a070135}}</ref><ref name="GreenblattHair1945">{{cite journal| vauthors = Greenblatt RB, Hair LQ |title=Absorption of Pellets of Progesterone|journal=The Journal of Clinical Endocrinology & Metabolism|volume=5|issue=1|year=1945|pages=38–39|issn=0021-972X|doi=10.1210/jcem-5-1-38|s2cid=71161306 }}</ref><ref name="pmid18123090">{{cite journal | vauthors = Greenblatt RB, Suran RR | title = Indications for hormonal pellets in the therapy of endocrine and gynecic disorders | journal = American Journal of Obstetrics and Gynecology | volume = 57 | issue = 2 | pages = 294–301 | date = February 1949 | pmid = 18123090 | doi = 10.1016/0002-9378(49)90429-9 }}</ref><ref name="pmid14862159">{{cite journal | vauthors = Bishop PM, Folley SJ | title = Absorption of hormone implants in man | journal = Lancet | volume = 2 | issue = 6676 | pages = 229–232 | date = August 1951 | pmid = 14862159 | doi = 10.1016/S0140-6736(51)93237-0 }}</ref> They were the first long-acting progestogen formulation.<ref name="Rauscher1960">{{cite book| vauthors = Rauscher H |title=Moderne Entwicklungen auf dem Gestagengebiet|chapter=Therapie mit Depotgestagenen|series=Symposion der Deutschen Gesellschaft für Endokrinologie |year=1960|pages=87–92|publisher=Springer |doi=10.1007/978-3-662-25301-4_11|isbn=978-3-662-23272-9}}</ref> Pellets were reported to be extruded out of the skin within a few weeks at high rates, even when implanted beneath the deep fascia, and also produced frequent inflammatory reactions at the site of implantation.<ref name="Schering1962" /><ref name="GreenblattHair1945" /><ref name="pmid13407238" /> In addition, they were absorbed too slowly and achieved unsatisfactorily low progesterone levels.<ref name="Schering1962" /> Consequently, they were soon abandoned, in favor of other preparations such as aqueous suspensions.<ref name="Schering1962" /><ref name="pmid13407238" /><ref name="Bishop1944">{{cite journal| vauthors = Bishop PM |title=Endocrine Therapy in Gynaecology and Obstetrics|journal=BJOG: An International Journal of Obstetrics and Gynaecology|volume=51|issue=1|year=1944|pages=51–63|issn=1470-0328|doi=10.1111/j.1471-0528.1944.tb07317.x|s2cid=71319436}}</ref><ref name="Rauscher1960" /> However, subcutaneous pellet implants of progesterone were later studied as a form of birth control in women in the 1980s and early 1990s, though no preparations were ultimately marketed.<ref name="pmid3320572">{{cite journal | vauthors = Croxatto HB, Díaz S | title = The place of progesterone in human contraception | journal = Journal of Steroid Biochemistry | volume = 27 | issue = 4–6 | pages = 991–994 | date = 1987 | pmid = 3320572 | doi = 10.1016/0022-4731(87)90179-8 }}</ref><ref name="pmid1835650">{{cite journal | vauthors = Shaaban MM | title = Contraception with progestogens and progesterone during lactation | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 40 | issue = 4–6 | pages = 705–710 | date = 1991 | pmid = 1835650 | doi = 10.1016/0960-0760(91)90294-F | s2cid = 25152238 }}</ref><ref name="pmid7114130">{{cite journal | vauthors = Croxatto HB, Díaz S, Peralta O, Juez G, Casado ME, Salvatierra AM, Durán E | title = Fertility regulation in nursing women. II. Comparative performance of progesterone implants versus placebo and copper T | journal = American Journal of Obstetrics and Gynecology | volume = 144 | issue = 2 | pages = 201–208 | date = September 1982 | pmid = 7114130 | doi = 10.1016/0002-9378(82)90628-7 }}</ref><ref name="pmid6509984">{{cite journal | vauthors = Díaz S, Peralta O, Juez G, Herreros C, Casado ME, Salvatierra AM, Miranda P, Croxatto HB | title = Fertility regulation in nursing women. VI. Contraceptive effectiveness of a subdermal progesterone implant | journal = Contraception | volume = 30 | issue = 4 | pages = 311–325 | date = October 1984 | pmid = 6509984 | doi = 10.1016/S0010-7824(84)80023-2 }}</ref>

Aqueous suspensions of progesterone crystals for intramuscular injection were first described in 1944.<ref name="Rauscher1960" /><ref name="pmid12999984">{{cite journal | vauthors = Masters WH, Grody MH, Magallon DT | title = Progesterone in aqueous crystalline suspension versus progesterone in oil; comparison by withdrawal bleeding tests in the human female | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 12 | issue = 11 | pages = 1445–1453 | date = November 1952 | pmid = 12999984 | doi = 10.1210/jcem-12-11-1445 | doi-access = free | title-link = doi }}</ref><ref name="Miescher1944">{{cite journal | vauthors = Miescher K, Gasche P, Frey H | title = Depotwirkung von Kristallsuspensionen weiblicher Sexualhormone (Ovocyclin- und Lutocyclin-Kristallampullen). Experimentelle und theoretische Grundlagen | journal = Helvetica Physiologica et Pharmacologica Acta | year = 1944 | volume = 2 | pages = 515–532 | issn = 0367-6242 | oclc = 499306481 | url = https://scholar.google.com/scholar?cluster=9741975641705488663}}</ref><ref name="KorefEngel1946">{{cite journal | vauthors = Koref O, Engel P | title = Administration of progesterone in the form of microcrystals | journal = Endocrinology | volume = 38 | issue = 3 | pages = 214–215 | date = March 1946 | pmid = 21025113 | doi = 10.1210/endo-38-3-214 }}</ref> These preparations were on the market in the 1950s under a variety of brand names including Flavolutan, Luteosan, Lutocyclin M, and Lutren, among others.<ref name="Kahr1956">{{cite book| vauthors = Kahr H |title=Konservative Therapie der Frauenkrankheiten: Anzeigen, Grenzen und Methoden Einschliesslich der Rezeptur|url=https://books.google.com/books?id=Hte1BgAAQBAJ&pg=PA20|date=8 March 2013|publisher=Springer-Verlag|isbn=978-3-7091-5694-0|pages=20–21}}</ref> Aqueous suspensions of steroids were developed because they showed much longer durations than intramuscular injection of steroids in oil solution.<ref name="Edkins1959">{{cite journal| vauthors = Edkins RP |title=The Modification of the Duration of Drug Action|journal=Journal of Pharmacy and Pharmacology|volume=11|issue=S1|year=1959|pages=54T–66T|issn=0022-3573|doi=10.1111/j.2042-7158.1959.tb10412.x|s2cid=78850713}}</ref> However, local injection site reactions, which do not occur with oil solutions, have limited the clinical use of aqueous suspensions of progesterone and other steroids.<ref name="pmid14905411">{{cite journal | vauthors = Gordon D, Horwitt BN, Segaloff A, Murison PJ, Schlosser JV | title = Hormonal therapy in cancer of the breast. III. Effect of progesterone on clinical course and hormonal excretion | journal = Cancer | volume = 5 | issue = 2 | pages = 275–277 | date = March 1952 | pmid = 14905411 | doi = 10.1002/1097-0142(195203)5:2<275::aid-cncr2820050213>3.0.co;2-h | doi-access = free | title-link = doi }}</ref><ref name="pmid13021207">{{cite journal | vauthors = Bradbury JT, Long RC, Durham WC | title = Progesterone and estrogen requirements to induce and maintain decidua | journal = Fertility and Sterility | volume = 4 | issue = 1 | pages = 63–75 | date = 1953 | pmid = 13021207 | doi = 10.1016/s0015-0282(16)31145-1 }}</ref><ref name="Fraser1998">{{cite book| vauthors = Fraser IS |title=Estrogens and Progestogens in Clinical Practice|url=https://books.google.com/books?id=eO5qAAAAMAAJ|year=1998|publisher=Churchill Livingstone|isbn=978-0-443-04706-0|page=13}}</ref> Today, a preparation with the brand name Agolutin Depot remains on the market in the Czech Republic and Slovakia.<ref name="Drugs.com-Agolutin">{{Cite web|url=https://www.drugs.com/international/agolutin.html|title = Progesterone: Uses, Dosage & Side Effects}}</ref><ref name="Agolutin-Depot-Label">{{cite web |url=http://www.sukl.cz/download/spc/SPC14550.pdf |title=Agolutin Depot Label |website=www.sukl.cz |access-date=15 January 2022 |archive-url=https://web.archive.org/web/20190519061250/http://www.sukl.cz/download/spc/SPC14550.pdf |archive-date=19 May 2019 }}</ref> A combined preparation of progesterone, estradiol benzoate, and lidocaine remains available with the brand name Clinomin Forte in Paraguay as well.<ref name="Clinomin Forte-Label">{{cite web |url=http://www.indufar.com.py/files/shares/prospectos/400000154.pdf |title=Clinomin Forte Label |website=www.indufar.com.py |access-date=15 January 2022 |archive-url=https://web.archive.org/web/20200818223302/http://www.indufar.com.py/files/shares/prospectos/400000154.pdf |archive-date=18 August 2020 }}</ref> In addition to aqueous suspensions, water-in-oil emulsions of steroids were studied by 1949,<ref name="pmid18140399">{{cite journal | vauthors = Lens J, Overbeek GA, Polderman J | title = The effect of sex hormones in some organic solvents; emulsified in water | journal = Acta Endocrinologica | volume = 2 | issue = 4 | pages = 396–404 | date = 1949 | pmid = 18140399 | doi = 10.1530/acta.0.0020396 }}</ref><ref name="pmid14907837">{{cite journal | vauthors = Ferin J | title = Relative duration of action of natural and synthetic estrogens administered parenterally in women with estrogen deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 12 | issue = 1 | pages = 28–35 | date = January 1952 | pmid = 14907837 | doi = 10.1210/jcem-12-1-28 }}</ref><ref name="Overbeek1952">{{cite book| vauthors = Overbeek CA |title=Ciba Foundation Symposium - Steroid Hormone Administration (Book II of Colloquia on Endocrinology, Vol. 3)|chapter=Some Data on Emulsions of Steroid Hormones|series=Novartis Foundation Symposia|year=1952|pages=254–262|publisher=John Wiley & Sons |issn=1935-4657|doi=10.1002/9780470715154.ch2|isbn=978-0-470-71515-4}}</ref> and long-acting emulsions of progesterone were introduced for use by intramuscular injection under the brand names Progestin and Di-Pro-Emulsion (with estradiol benzoate) by the 1950s.<ref name="Kahr1956" /><ref name="Kimmig2013">{{cite book| vauthors = Kimmig J |title=Therapie der Haut- und Geschlechtskrankheiten|url=https://books.google.com/books?id=txrUBgAAQBAJ&pg=PA508|date=14 March 2013|publisher=Springer-Verlag|isbn=978-3-642-94850-3|pages=508–}}</ref><ref name="JoresNowakowski1960">{{cite book| vauthors = Jores A, Nowakowski H |title=Praktische Endokrinologie|url=https://books.google.com/books?id=QhdsAAAAMAAJ|year=1960|publisher=G. Thieme|page=295}}</ref><ref name="pmid14810456">{{cite journal | vauthors = Von Numers C | title = Simultaneous treatment of secondary amenorrhoea with oestrogen and progesterone | journal = Acta Endocrinologica | volume = 6 | issue = 1 | pages = 67–89 | date = 1951 | pmid = 14810456 | doi = 10.1530/acta.0.0060067 }}</ref><ref name="NeueSpezialitäten1958">{{cite journal|title=Neue Spezialitäten|journal=Klinische Wochenschrift|volume=36|issue=17|year=1958|page=833|issn=0023-2173|doi=10.1007/BF01481957|s2cid=42166026}}</ref> Due to lack of standardization of crystal sizes, crystalline suspensions of steroids had marked variations in effect.<ref name="Schering1962" /> Emulsions were said to be even more unreliable.<ref name="Schering1962" />

Macrocrystalline aqueous suspensions of progesterone as well as microspheres of progesterone were investigated as potential progestogen-only injectable contraceptives and combined injectable contraceptives (with estradiol) by the late 1980s and early 1990s but were never marketed.<ref name="Garza-FloresCravioto1992" /><ref name="Alvarez-SanchezBrache1993" /><ref name="Cullins1992" /><ref name="Garza-Flores1994">{{cite journal | vauthors = Garza-Flores J | title = Pharmacokinetics of once-a-month injectable contraceptives | journal = Contraception | volume = 49 | issue = 4 | pages = 347–359 | date = April 1994 | pmid = 8013219 | doi = 10.1016/0010-7824(94)90032-9 }}</ref><ref name="pmid1893701">{{cite journal | vauthors = Garza-Flores J, Fatinikun T, Hernandez L, Ramos I, Cardenas M, Menjivar M | title = A pilot study on the assessment of a progesterone/estradiol sustained release as once-a-month-injectable contraceptive | journal = Contraception | volume = 44 | issue = 1 | pages = 45–59 | date = July 1991 | pmid = 1893701 | doi = 10.1016/0010-7824(91)90105-o }}</ref>

Aqueous solutions of water-insoluble steroids were first developed via association with colloid solubility enhancers in the 1940s.<ref name="pmid15432051">{{cite journal | vauthors = Ekwall P, Sjoblom L | title = Aqueous solutions of steroid hormones | journal = Acta Endocrinologica | volume = 4 | issue = 2 | pages = 179–191 | date = 1950 | pmid = 15432051 | doi = 10.1530/acta.0.0040179 }}</ref> An aqueous solution of progesterone for use by intravenous injection was marketed by Schering AG under the brand name Primolut Intravenous by 1962.<ref name="Schering1962B">{{cite book|title=Basic Sex Hormone Therapy|url=https://books.google.com/books?id=uJrIvQEACAAJ|year=1962|publisher=Schering A.G.|page=93,96|quote=Intravenous: The intravenous injection of sex hormones is restricted mainly to specific circumstances where a speedy elevation of hormone levels is required, for example, in treatment of threatened abortion. [...] Crystalline Suspension: With crystalline suspensions the crystalline size governs the rate of absorption and therefore the duration of action. The lack of standardisation of crystalline size in commercial products plus the limits imposed by needle bore, introduces marked variations in effect. The results from emulsified forms are even more unreliable. [...] Hormone Pellets for Implantation: The subcutaneous implantation of sterile tablets was the first means of achieving prolonged action. Such possible factors as encapsulation or extrusion and diminished absorption as the surface area of the pellet is reduced, may be a drawback. Implantation of testosterone (about eight 100 mg. pellets), repeated 6-monthly, is a satisfactory treatment for eunuchoidism and implantation of oestradiol (a 50 mg. pellet remains active for about a year or more) is sometimes a useful procedure. The implantation of progesterone is best discarded altogether; extrusion of pellets (even when placed beneath the deep fascia) and slowness of absorption, in relation to metabolic requirements, make it unsatisfactory and the new depot hormones should be given preference. [...] Sex Hormone Preparations of Schering A.G. Berlin [...] Trade Name: Primolut intravenous. Chemical Description: Progesterone in aqueous solution. Packing: Ampoules of 1 c. c. = 20 mg.}}</ref><ref name="CurrMedDrugs1962"/> One of its intended uses was the treatment of threatened abortion, in which rapid-acting effect was desirable.<ref name="Schering1962" /> An aqueous solution of progesterone complexed with cyclodextrin to increase its water solubility was introduced for use by once-daily subcutaneous injection in Europe under the brand name Prolutex in the mid-2010s.<ref name="Prolutex-AdisInsight">{{Cite web | url=https://adisinsight.springer.com/drugs/800048238 | title=Progesterone - IBSA | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref><ref name="pmid26342177" />

In the 1950s, long-acting parenteral progestins such as hydroxyprogesterone caproate, medroxyprogesterone acetate, and norethisterone enanthate were developed and introduced for use by intramuscular injection.<ref name="Rauscher1960" /><ref name="pmid14164973">{{cite journal | vauthors = Greenblatt RB, Mahesh VB, Shapiro ST | title = Physiologic and Clinical Aspects of Ovarian Hormones | journal = Archives of Dermatology | volume = 89 | issue = 6 | pages = 846–857 | date = June 1964 | pmid = 14164973 | doi = 10.1001/archderm.1964.01590300074022 }}</ref><ref name="Babcock1964">{{cite book| vauthors = Babcock JC |title=Molecular Modification in ''Drug'' Design|chapter=Synthetic Progestational Agents|series=Advances in Chemistry|volume=45|year=1964|pages=190–203|publisher=American Chemical Society |issn=0065-2393|doi=10.1021/ba-1964-0045.ch016|isbn=0-8412-0046-7}}</ref> They lacked the need for frequent injections and the injection site reactions associated with progesterone by intramuscular injection and soon supplanted progesterone for parenteral therapy in most cases.<ref name="Babcock1964" /><ref name="pmid14164973" /><ref name="pmid4307936">{{cite book| vauthors = Tausk M | chapter=Practically Applicable Results of Twenty Years of Research in Endocrinology | title=Progress in Drug Research / Fortschritte der Arzneimittelforschung / Progrès des recherches pharmaceutiques | journal = Progress in Drug Research. Fortschritte der Arzneimittelforschung. Progres des Recherches Pharmaceutiques | volume = 12 | pages = 137–164 | date = 1968 | publisher = Birkhäuser | location = Basel | pmid = 4307936 | doi = 10.1007/978-3-0348-7065-8_3 | isbn = 978-3-0348-7067-2 | veditors = Jucker E }}</ref>

===Oral and sublingual=== The first study of oral progesterone in humans was published in 1949.<ref name="pmid18133494">{{cite journal | vauthors = Bickers W | title = Progesterone; a comparison of intramuscular, oral and sublingual routes of administration | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 9 | issue = 8 | pages = 736–742 | date = August 1949 | pmid = 18133494 | doi = 10.1210/jcem-9-8-736 }}</ref><ref name="pmid15436649">{{cite journal | vauthors = Greenblatt RB, Barfield WE, Clark S, Brown N | title = Physiologic effectiveness of oral progesterone | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 10 | issue = 8 | pages = 886–896 | date = August 1950 | pmid = 15436649 | doi = 10.1210/jcem-10-8-886 }}</ref> It found that oral progesterone produced significant progestational effects in the endometrium in women.<ref name="pmid18133494" /> Prior to this study, animal research had suggested that oral progesterone was inactive, and for this reason, oral progesterone had never been evaluated in humans.<ref name="pmid18133494" /><ref name="pmid15436649" /> A variety of other early studies of oral progesterone in humans were also published in the 1950s and 1960s.<ref name="pmid15436649" /><ref name="pmid14933526">{{cite journal | vauthors = Bickers W | title = Menstrual arrhythmias; oral estrogen and progesterone therapy | journal = American Journal of Obstetrics and Gynecology | volume = 64 | issue = 1 | pages = 148–154 | date = July 1952 | pmid = 14933526 | doi = 10.1016/s0002-9378(16)38745-2 }}</ref><ref name="pmid12980155">{{cite journal | vauthors = Mulligan WJ, Horne HW, Rock J | title = Cyclic oral therapy of menstrual disorders | journal = Fertility and Sterility | volume = 3 | issue = 4 | pages = 328–333 | date = 1952 | pmid = 12980155 | doi = 10.1016/S0015-0282(16)30965-7 }}</ref><ref name="pmid13084722">{{cite journal | vauthors = Fischer RH, McCOLGAN SP | title = Progesterone metabolism. II. Pregnanediol excretion following oral, sublingual and parenteral administration of progesterone | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 13 | issue = 9 | pages = 1043–1053 | date = September 1953 | pmid = 13084722 | doi = 10.1210/jcem-13-9-1043 }}</ref><ref name="pmid13183192">{{cite journal | vauthors = Frank R, Guterman HS | title = Comparison of progesterone preparations in secondary amenorrhea | journal = Fertility and Sterility | volume = 5 | issue = 4 | pages = 374–381 | date = 1954 | pmid = 13183192 | doi = 10.1016/S0015-0282(16)31687-9 }}</ref><ref name="pmid13405054">{{cite journal | vauthors = Kupperman HS, Lefkovics SC | title = Progesterone in problems of sterility; diagnostic and therapeutic use | journal = Fertility and Sterility | volume = 8 | issue = 2 | pages = 131–46; discussion, 146–8 | date = 1957 | pmid = 13405054 | doi = 10.1016/S0015-0282(16)32642-5 }}</ref><ref name="pmid13477811">{{cite journal | vauthors = Rock J, Garcia CR, Pincus G | title = Synthetic progestins in the normal human menstrual cycle | journal = Recent Progress in Hormone Research | volume = 13 | pages = 323–39; discussion 339–46 | date = 1957 | pmid = 13477811 | url = https://www.popline.org/node/476326 | access-date = 2 May 2019 | archive-url = https://web.archive.org/web/20190502051339/https://www.popline.org/node/476326 | archive-date = 2 May 2019 }}</ref><ref name="pmid13504644">{{cite journal | vauthors = Birnberg CH, Livingston S, Davis JG | title = Large-dose oral progesterone therapy in menstrual disorders | journal = Obstetrics and Gynecology | volume = 11 | issue = 1 | pages = 115–118 | date = January 1958 | pmid = 13504644 | url = https://journals.lww.com/greenjournal/Citation/1958/01000/Large_Dose_Oral_Progesterone_Therapy_in_Menstrual.23.aspx }}</ref><ref name="VolkEscher1960">{{cite journal| vauthors = Volk H, Escher GC, Huseby RA, Tyler FH, Cheda J |title=Hormonal therapy in carcinoma of the breast.I. Effect of oral progesterone on clinical course and metabolism of nitrogen and selected electrolytes and steroids|journal=Cancer|volume=13|issue=4|year=1960|pages=757–763|issn=0008-543X|doi=10.1002/1097-0142(196007/08)13:4<757::AID-CNCR2820130417>3.0.CO;2-9| doi-access = free | title-link = doi }}</ref><ref name="Takeuchi-Demirci2018" /> These studies generally reported oral progesterone to be only very weakly active.<ref name="pmid15436649" /><ref name="pmid13405054" /><ref name="pmid13183192" /> Oral non-micronized progesterone was introduced as a pharmaceutical medication around 1953, for instance as ''Cyclogesterin'' (1 mg estrogenic substances and 30 mg progesterone tablets) for menstrual disturbances by Upjohn, though it saw limited use.<ref name="pmid13030701">{{cite journal | vauthors = Abrams RE | title = Modern medicinals in review | journal = American Journal of Pharmacy and the Sciences Supporting Public Health | volume = 125 | issue = 2 | pages = 49–69 | date = February 1953 | pmid = 13030701 | quote = Cyclogesterin. A relatively new approach to progesterone therapy, Cyclogesterin establishes that this hormone can be effective by the oral route. Primarily indicated to induce menstruation in secondary amenorrhea by oral therapy, it contains 30 mg. of progesterone and 1 mg. of mixed natural estrogens per tablet. One tablet is given three times daily for five consecutive days and therapy is stopped. Menstruation follows in one to six days in the non-pregnant patient. The product is manufactured by the Upjohn Company. }}</ref><ref name="Gutman1958">{{cite book| vauthors = Gutman J |title=Modern Drug Encyclopedia and Therapeutic Index|url=https://books.google.com/books?id=a83GAAAAIAAJ|year=1958|publisher=Yorke Medical Group|page=299}}</ref> Another preparation, which contained progesterone alone, was ''Synderone'' (trademark registered by Chemical Specialties in 1952).<ref name="pmid13901505">{{cite journal | vauthors = Greenblatt RB, Rose FD | title = Delay of menses: test of progestational efficacy in induction of pseudopregnancy | journal = Obstetrics and Gynecology | volume = 19 | pages = 730–735 | date = June 1962 | pmid = 13901505 }}</ref><ref name="pmid14216475">{{cite journal | vauthors = Puebla RA, Greenblatt RB | title = Clomiphene Citrate in the Management of Anovulatory Uterine Bleeding1 | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 24 | pages = 863–866 | date = September 1964 | issue = 9 | pmid = 14216475 | doi = 10.1210/jcem-24-9-863 | doi-access = free | title-link = doi }}</ref><ref name="Office1955">{{cite book|author=United States. Patent Office|title=Official Gazette of the United States Patent Office|url=https://books.google.com/books?id=FKnNAAAAMAAJ&pg=RA2-PA80|year=1955|publisher=U.S. Patent Office.|pages=2–}}</ref>

Sublingual progesterone in women was first studied in 1944 by Robert Greenblatt.<ref name="Greenblatt1944a">{{cite journal| vauthors = Greenblatt RB |title=Sublingual Absorption of Progesterone and Anhydrohydroxyprogesterone|journal=The Journal of Clinical Endocrinology & Metabolism|volume=4|issue=4|year=1944|pages=156–158|issn=0021-972X|doi=10.1210/jcem-4-4-156}}</ref><ref name="Greenblatt1944b">{{cite journal| vauthors = Greenblatt RB |title=Perlingual Absorption of Progesterone and Anhydrohydroxyprogesterone1,2|journal=The Journal of Clinical Endocrinology & Metabolism|volume=4|issue=7|year=1944|pages=321–325|issn=0021-972X|doi=10.1210/jcem-4-7-321}}</ref><ref name="pmid13407238" /><ref name="pmid18133494" /><ref name="pmid13073082">{{cite journal | vauthors = Soule SD, Yanow M | title = Recovery of pregnanediol from urine following administration of oral anhydrohydroxyprogesterone, buccal progesterone, and intramuscular progesterone | journal = Obstetrics and Gynecology | volume = 2 | issue = 1 | pages = 68–72 | date = July 1953 | pmid = 13073082 }}</ref><ref name="pmid13084722"/> Buccal progesterone tablets were marketed by Schering under the brand name ''Proluton Buccal Tablets'' by 1949.<ref name="JAPA1949">{{cite journal|title=New Prescription Products|journal=Journal of the American Pharmaceutical Association (Practical Pharmacy Ed.)|volume=10|issue=4|year=1949|pages=198–206|issn=0095-9561|doi=10.1016/S0095-9561(16)31795-9}}</ref> Sublingual progesterone tablets were marketed under the brand names ''Progesterone Lingusorbs'' and ''Progesterone Membrettes'' by 1951.<ref name="RemingtonCook1951">{{cite book| vauthors = Remington JP, Cook EF, Martin EW |title=Remington's Practice of Pharmacy: A Treatise on the Preparing, Standardizing, and Dispensing of Official and Extemporaneous Pharmaceutical Products, with Descriptions of Medicinal Substances, Their Properties, Uses and Doses. Also a Guide to Other Professional Services Rendered by the Pharmacist in Connection with Community Health. Intended for the Use of Pharmacists and Physicians and as a Textbook for Students|url=https://books.google.com/books?id=2u8jAQAAMAAJ|year=1951|publisher=Mack Publishing Company|pages=936–937}}</ref><ref name="Welsh1951">{{cite book| vauthors = Welsh AL |title=Dermatological Formulary: A Guide for Medical Students and Resident Physicians in Dermatology|url=https://books.google.com/books?id=1m-C5uGARQEC|year=1951|publisher=Educational Publishers|page=155}}</ref><ref name="HagerKern1969">{{cite book| vauthors = Hager HH, Kern W, List PH, Roth HJ |title=Hagers Handbuch der Pharmazeutischen Praxis: Für Apotheker, Arzneimittelhersteller, Ärzte und Medizinalbeamte: Wirkstoffgruppen II Chemikalien und Drogen (A-AL)|url=https://books.google.com/books?id=a2a0BgAAQBAJ&pg=PA178|date=1969|publisher=Springer-Verlag|isbn=978-3-662-25655-8|pages=178–}}</ref> A sublingual tablet formulation of progesterone has been approved under the brand name ''Luteina'' in Poland and Ukraine and remains marketed today.<ref name="Drugs.com" /><ref name="Micromedex" />

Progesterone was the first progestogen that was found to inhibit ovulation, both in animals and in women.<ref name="pmid14232795">{{cite book | vauthors = Pincus G, Bialy G | title = Drugs Used in Control of Reproduction | volume = 3 | pages = 285–313 | date = 1964 | pmid = 14232795 | doi = 10.1016/S1054-3589(08)61115-1 | quote = The original observation of Makepeace et al. (1937) that progesterone inhibited ovulation in the rabbit was substantiated by Pincus and Chang (1953). In women, 300 mg of progesterone per day taken orally resulted in ovulation inhibition in 80% of cases (Pincus, 1956). The high dosage and frequent incidence of breakthrough bleeding limited the practical application of the method. Subsequently, the utilization of potent 19-norsteroids, which could be given orally, opened the field to practical oral contraception.| series = Advances in Pharmacology | publisher = Academic Press | isbn = 978-0-12-032903-8 }}</ref> Injections of progesterone were first shown to inhibit ovulation in animals between 1937 and 1939.<ref name="pmid356615">{{cite journal | vauthors = Chang MC | title = Development of the oral contraceptives | journal = American Journal of Obstetrics and Gynecology | volume = 132 | issue = 2 | pages = 217–219 | date = September 1978 | pmid = 356615 | doi = 10.1016/0002-9378(78)90928-6 }}</ref><ref name="pmid14232795" /><ref name="MakepeaceWeinstein1937">{{cite journal| vauthors = Makepeace AW, Weinstein GL, Friedman MH |title=The effect of progestin and progesterone on ovulation in the rabbit|journal=American Journal of Physiology. Legacy Content|volume=119|issue=3|year=1937|pages=512–516|issn=0002-9513|doi=10.1152/ajplegacy.1937.119.3.512}}</ref><ref name="AstwoodFevold1939">{{cite journal| vauthors = Astwood EB, Fevold HL |title=Action of progesterone on the gonadotropic activity of the pituitary|journal=American Journal of Physiology. Legacy Content|volume=127|issue=1|year=1939|pages=192–198|issn=0002-9513|doi=10.1152/ajplegacy.1939.127.1.192| doi-access = | title-link = doi }}</ref> Inhibition of fertilization by administration of progesterone during the luteal phase was also demonstrated in animals between 1947 and 1949.<ref name="pmid356615" /> Ovulation inhibition by progesterone in animals was subsequently re-confirmed and expanded on by Gregory Pincus and colleagues in 1953 and 1954.<ref name="pmid14232795" /><ref name="pmid13138262">{{cite journal | vauthors = Pincus G, Chang MC | title = The effects of progesterone and related compounds on ovulation and early development in the rabbit | journal = Acta Physiologica Latino Americana | volume = 3 | issue = 2–3 | pages = 177–183 | date = 1953 | pmid = 13138262 }}</ref><ref name="pmid13162007">{{cite journal | vauthors = Slechta RF, Chang MC, Pincus G | title = Effects of progesterone and related compounds on mating and pregnancy in the rat | journal = Fertility and Sterility | volume = 5 | issue = 3 | pages = 282–293 | date = 1954 | pmid = 13162007 | doi = 10.1016/S0015-0282(16)31628-4 }}</ref> Findings on inhibition of ovulation by progesterone in women were first presented at the Fifth International Conference on Planned Parenthood in Tokyo, Japan in October 1955.<ref name="Takeuchi-Demirci2018">{{cite book| vauthors = Takeuchi-Demirci A |title=Contraceptive Diplomacy: Reproductive Politics and Imperial Ambitions in the United States and Japan|url=https://books.google.com/books?id=FvJFDwAAQBAJ&pg=PT188|date=9 January 2018|publisher=Stanford University Press|isbn=978-1-5036-0441-4|pages=188–191, 243}}</ref><ref name="pmid5848673">{{cite journal | vauthors = Diczfalusy E | title = Probable mode of action of oral contraceptives | journal = British Medical Journal | volume = 2 | issue = 5475 | pages = 1394–1399 | date = December 1965 | pmid = 5848673 | pmc = 1847181 | doi = 10.1136/bmj.2.5475.1394 | quote = At the Fifth International Conference on Planned Parenthood in Tokyo, Pincus (1955) reported an ovulation inhibition by progesterone or norethynodrel1 taken orally by women. This report indicated the beginning of a new era in the history of contraception. [...] That the cervical mucus might be one of the principal sites of action was suggested by the first studies of Pincus (1956, 1959) and of Ishikawa et al. (1957). These investigators found that no pregnancies occurred in women treated orally with large doses of progesterone, though ovulation was inhibited only in some 70% of the cases studied. [...] The mechanism of protection in this method—and probably in that of Pincus (1956) and of Ishikawa et al. (1957)—must involve an effect on the cervical mucus and/or endometrium and Fallopian tubes. }}</ref> Three different research groups presented their findings on this topic at the conference.<ref name="Takeuchi-Demirci2018" /><ref name="pmid5848673" /> They included Pincus (in conjunction with John Rock, who did not attend the conference); a nine-member Japanese group led by Masaomi Ishikawa; and the two-member team of Abraham Stone and Herbert Kupperman.<ref name="Takeuchi-Demirci2018" /><ref name="pmid5848673" /><ref name="Pincus1955">{{cite book| vauthors = Pincus G |chapter=Some Effects of Progesterone and Related Compounds upon Reproduction and Early Development in Mammals|pages=175–184|title=The Fifth International Conference on Planned Parenthood: Theme, Overpopulation and Family Planning: Report of the Proceedings, 24-29 October, 1955, Tokyo, Japan|year=1955|publisher=International Planned Parenthood Federation|url=https://books.google.com/books?id=d5oTAQAAMAAJ}}</ref><ref name="StoneKupperman1955">{{cite book| vauthors = Stone A, Kupperman HS |chapter=The Effects of Progesterone on Ovulation: A Preliminary Report|title=The Fifth International Conference on Planned Parenthood: Theme, Overpopulation and Family Planning: Report of the Proceedings, 24-29 October, 1955, Tokyo, Japan|year=1955|volume=33 |pages=202 |publisher=International Planned Parenthood Federation|doi=10.1016/0093-691x(90)90626-5 |chapter-url=https://www.popline.org/node/472171|quote=The results of testing the effects of progesterone on ovulation in 13 patients at the Margaret Sanger Research Bureau are presented. The patients had normal menstrual cycles and showed clear evidence of ovulation. Each patient was given 1000 [mg] of [oral] progesterone daily during the midperiod for 10 or 12 days during 16 cycles. Ovulation was inhibited in 6 cycles. No disturbance in menstrual rhythm was observed. 3 of 12 patients with longstanding infertility histories became pregnant within 2–4 months after the cessation of progesterone therapy.|access-date=2 May 2019|archive-date=2 May 2019|archive-url=https://web.archive.org/web/20190502082734/https://www.popline.org/node/472171}}</ref><ref name="Ishikawa1955">{{cite book| vauthors = Ishikawa M, Kyushiro F, Yoshio F, Takashi K, Masanao M, Michio M, Seiichi M, Tatsuo T, Sigeki T |chapter=Some Effects of Progesterone and Related Compounds upon Reproduction and Early Development in Mammals |pages=186–187|title=The Fifth International Conference on Planned Parenthood: Theme, Overpopulation and Family Planning: Report of the Proceedings, 24-29 October, 1955, Tokyo, Japan|year=1955|publisher=International Planned Parenthood Federation|url=https://books.google.com/books?id=d5oTAQAAMAAJ}}</ref> The conference marked the beginning of a new era in the history of birth control.<ref name="pmid5848673" /> The results were subsequently published in scientific journals in 1956 in the case of Pincus and in 1957 in the case of Ishikawa and colleagues.<ref name="pmid13394044">{{cite journal | vauthors = Pincus G | title = Some effects of progesterone and related compounds upon reproduction and early development in mammals | journal = Acta Endocrinologica. Supplementum | volume = 23 | issue = Suppl 28 | pages = 18–36 | date = 1956 | pmid = 13394044 | doi = 10.1530/acta.0.023S018 | s2cid = 33729147 }}</ref><ref name="IshikawaFujii1957">{{cite journal | vauthors = Ishikawa M, Fujii K, Furusawa Y, Kobayashi T, Makino T, Matsumoto S, Takashima T, Takeuchi S | title = Unknown | journal = J. Jap. Family Plann. Ass. | volume = 2 | pages = 51–56 }}</ref><ref name="Pincus1959">{{cite book| vauthors = Pincus G |chapter=Progestational Agents and the Control of Fertility|title=Vitamins and Hormones: Advances in Research and Applications|volume=17|year=1959|pages=307–324|issn=0083-6729|doi=10.1016/S0083-6729(08)60274-5|quote=Ishikawa et al. (1957) employing the same regime of progesterone administration also observed suppression of ovulation in a proportion of the cases taken to laparotomy. Although sexual intercourse was practised freely by the subjects of our experiments and those of Ishikawa el al., no pregnancies occurred. Since ovulation presumably took place in a proportion of cycles, the lack of any pregnancies may be due to chance, but Ishikawa et al. (1957) have presented data indicating that in women receiving oral progesterone the cervical mucus becomes impenetrable to sperm.|series=Vitamins & Hormones|publisher=Academic Press |isbn=978-0-12-709817-3}}</ref> Rock and Pincus also subsequently described findings from 1952 that "pseudopregnancy" therapy with a combination of high doses of diethylstilbestrol and oral progesterone prevented ovulation and pregnancy in women.<ref name="pmid13477811" /><ref name="pmid8506121">{{cite journal | vauthors = Perone N | title = The history of steroidal contraceptive development: the progestins | journal = Perspectives in Biology and Medicine | volume = 36 | issue = 3 | pages = 347–362 | date = 1993 | pmid = 8506121 | doi = 10.1353/pbm.1993.0054 | s2cid = 46312750 }}</ref><ref name="pmid21091163">{{cite journal | vauthors = Dhont M | title = History of oral contraception | journal = The European Journal of Contraception & Reproductive Health Care | volume = 15 | issue = Suppl 2 | pages = S12–S18 | date = December 2010 | pmid = 21091163 | doi = 10.3109/13625187.2010.513071 | s2cid = 22706524 | doi-access = free | title-link = doi }}</ref><ref name="ArellanoSeipp2017" /><ref name="MarshRonner2008">{{cite book | vauthors = Marsh M, Ronner W | title=The Fertility Doctor: John Rock and the Reproductive Revolution|url=https://archive.org/details/fertilitydoctorj0000mars|url-access=registration|date=31 October 2008|publisher=JHU Press|isbn=978-1-4214-0208-6|pages=[https://archive.org/details/fertilitydoctorj0000mars/page/333 333]–|quote=43. The first study used progesterone continuously rather than cyclically. Women began by taking 5 mg of stilbestrol and 50 mg of progesterone, increasing the dose of stilbestrol by 5 mg and of progesterone by 50 mg every two weeks. By the end of twelve weeks, women were taking 30 mg stilbestrol and 300 mg of progesterone. If they had vaginal bleeding at any time, the doses were increased. "Pseudopregnancy," typescript, 15 July 1954, GP-LC. Rock also summarizes his early studies in John Rock, Celso-Ramon Garcia, and Gregory Pincus, "Synthetic Progestins in the Normal Human Menstrual Cycle," Recent Progress in Hormone Research, vol. 13 (New York: Academic Press, 1957), 323-24.}}</ref><ref name="Watkins2001">{{cite book| vauthors = Watkins ES |title=On the Pill: A Social History of Oral Contraceptives, 1950-1970|url=https://books.google.com/books?id=jqbmtSPMfXYC|date=14 September 2001|publisher=Johns Hopkins University Press|isbn=978-1-4214-0371-7|quote=In the early 1950s, independent of Pincus's work in Worcester, Rock successfully induced pregnancy in previously infertile women by treating them for several months with estrogen and progesterone. Although the steroids prevented pregnancy during the course of therapy, some of the women conceived when the treatment ended; this phenomenon became known as the "Rock rebound effect."58 When Pincus learned of Rock's work, he asked the physician to join forces in the hunt for an ovulation inhibitor, and Rock agreed. Pincus suggested two changes in the experimental regimen: use only progesterone (estrogen promoted cancer in laboratory animals) and administer the hormone for twenty days each month (to allow a period of menstruation). Rock achieved the same rate of success in curing infertility (about 15%), but a significant problem remained: tests indicated that about 15 percent of the women ovulated while taking the progesterone.59 Pincus and Rock needed to find an orally active compound that would completely inhibit ovulation. It was time to test the 19-nor steroids in humans. [...]}}</ref>

Unfortunately, the use of oral progesterone as a hormonal contraceptive was plagued by problems.<ref name="pmid14232795" /><ref name="ArellanoSeipp2017" /> These included the large and by extension expensive doses required, incomplete inhibition of ovulation even at high doses, and a frequent incidence of breakthrough bleeding.<ref name="pmid14232795" /><ref name="ArellanoSeipp2017" /> At the 1955 Tokyo conference, Pincus had also presented the first findings of ovulation inhibition by oral progestins in animals, specifically 19-nortestosterone derivatives like noretynodrel and norethisterone.<ref name="ArellanoSeipp2017" /><ref name="Takeuchi-Demirci2018" /> These progestins were far more potent than progesterone, requiring much smaller doses orally.<ref name="ArellanoSeipp2017" /><ref name="Takeuchi-Demirci2018" /> By December 1955, inhibition of ovulation by oral noretynodrel and norethisterone had been demonstrated in women.<ref name="ArellanoSeipp2017" /> These findings as well as results in animals were published in 1956.<ref name="pmid13380400">{{cite journal | vauthors = Pincus G, Chang MC, Hafez ES, Zarrow MX, Merrill A | title = Effects of certain 19-nor steroids on reproductive processes in animals | journal = Science | volume = 124 | issue = 3227 | pages = 890–891 | date = November 1956 | pmid = 13380400 | doi = 10.1126/science.124.3227.890-a | s2cid = 31577493 | bibcode = 1956Sci...124..890P }}</ref><ref name="pmid13380401">{{cite journal | vauthors = Garcia CR, Pincus G, Rock J | title = Effects of certain 19-nor steroids on the normal human menstrual cycle | journal = Science | volume = 124 | issue = 3227 | pages = 891–893 | date = November 1956 | pmid = 13380401 | doi = 10.1126/science.124.3227.891 | bibcode = 1956Sci...124..891R }}</ref> Noretynodrel and norethisterone did not show the problems associated with oral progesterone—in the studies, they fully inhibited ovulation and did not produce menstruation-related side effects.<ref name="ArellanoSeipp2017" /> Consequently, oral progesterone was abandoned as a hormonal contraceptive in women.<ref name="pmid14232795"/><ref name="ArellanoSeipp2017">{{cite book| vauthors = Ramírez de Arellano AB, Seipp C |title=Colonialism, Catholicism, and Contraception: A History of Birth Control in Puerto Rico|url=https://books.google.com/books?id=0fs4DwAAQBAJ&pg=PT106|date=10 October 2017|publisher=University of North Carolina Press|isbn=978-1-4696-4001-3|pages=106–112|quote=[...] Still, neither of the two researchers was completely satisfied with the results. Progesterone tended to cause "premature menses," or breakthrough bleeding, in approximately 20 percent of the cycles, an occurrence that disturbed the patients and worried Rock.17 in addition, Pincus was concerned about the failure to inhibit ovulation in all the cases. Only large doses of orally administered progesterone could insure the suppression of ovulation, and these doses were expensive. The mass use of this regimen as a birth control method was thus seriously imperiled.18 [...]}}</ref> The first birth control pills to be introduced were a noretynodrel-containing product in 1957 and a norethisterone-containing product in 1963, followed by numerous others containing a diversity of progestins.<ref name="Marks2010">{{cite book| vauthors = Marks L |title=Sexual Chemistry: A History of the Contraceptive Pill|url=https://books.google.com/books?id=_i-s4biQs7MC&pg=PA75|year=2010|publisher=Yale University Press|isbn=978-0-300-16791-7|pages=75–}}</ref> Progesterone itself has never been introduced for use in birth control pills.<ref name="pmid23384741">{{cite journal | vauthors = Christin-Maitre S | title = History of oral contraceptive drugs and their use worldwide | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 27 | issue = 1 | pages = 3–12 | date = February 2013 | pmid = 23384741 | doi = 10.1016/j.beem.2012.11.004 }}</ref>

More modern clinical studies of oral progesterone demonstrating elevated levels of progesterone and end-organ responses in women, specifically progestational endometrial changes, were published between 1980 and 1983.<ref name="pmid7370683">{{cite journal | vauthors = Whitehead MI, Townsend PT, Gill DK, Collins WP, Campbell S | title = Absorption and metabolism of oral progesterone | journal = British Medical Journal | volume = 280 | issue = 6217 | pages = 825–827 | date = March 1980 | pmid = 7370683 | pmc = 1600943 | doi = 10.1136/bmj.280.6217.825 }}</ref><ref name="pmid6784875">{{cite journal | vauthors = Whitehead M, Lane G, Townsend P, Siddle N, Pryse-Davies J, King RJ | title = Oral progesterone | journal = British Medical Journal | volume = 282 | issue = 6274 | page = 1476 | date = May 1981 | pmid = 6784875 | pmc = 1505208 | doi = 10.1136/bmj.282.6274.1476-a }}</ref><ref name="pmid7119381">{{cite journal | vauthors = Morville R, Dray F, Reynier J, Barrat J | title = [The bioavailability of natural progesterone given by mouth. Measurement of steroid concentrations in plasma, endometrium and breast tissue] | language = fr | journal = Journal de Gynécologie, Obstétrique et Biologie de la Reproduction | volume = 11 | issue = 3 | pages = 355–363 | date = 1982 | pmid = 7119381 | trans-title = The bioavailability of natural progesterone given by mouth. Measurement of steroid concentrations in plasma, endometrium and breast tissue }}</ref><ref name="pmid6315123">{{cite journal | vauthors = Lane G, Siddle NC, Ryder TA, Pryse-Davies J, King RJ, Whitehead MI | title = Dose dependent effects of oral progesterone on the oestrogenised postmenopausal endometrium | journal = British Medical Journal | volume = 287 | issue = 6401 | pages = 1241–1245 | date = October 1983 | pmid = 6315123 | pmc = 1549751 | doi = 10.1136/bmj.287.6401.1241 }}</ref> Up to this point, many clinicians and researchers apparently still thought that oral progesterone was inactive.<ref name="pmid6315123" /><ref name="pmid6991820">{{cite journal | vauthors = Adlercreutz H, Martin F | title = Biliary excretion and intestinal metabolism of progesterone and estrogens in man | journal = Journal of Steroid Biochemistry | volume = 13 | issue = 2 | pages = 231–244 | date = February 1980 | pmid = 6991820 | doi = 10.1016/0022-4731(80)90196-X | quote = It is generally accepted that orally administered progesterone has little biological effect. }}</ref><ref name="pmid7193749">{{cite journal | vauthors = González ER | title = Even oral progesterone may be effective | journal = JAMA | volume = 245 | issue = 14 | page = 1394 | date = April 1981 | pmid = 7193749 | doi = 10.1001/jama.1981.03310390003001 }}</ref> It was not until almost half a century after the introduction of progesterone in medicine that a reasonably effective oral formulation of progesterone was marketed.<ref name="Sauer2013"/> Micronization of progesterone and suspension in oil-filled capsules, which allowed progesterone to be absorbed several-fold more efficiently by the oral route, was first studied in the late 1970s and described in the literature in 1982.<ref name="pmid29806794">{{cite journal | vauthors = Piette P | title = The history of natural progesterone, the never-ending story | journal = Climacteric | volume = 21 | issue = 4 | pages = 308–314 | date = August 2018 | pmid = 29806794 | doi = 10.1080/13697137.2018.1462792 | s2cid = 44066213 }}</ref><ref name="pmid7119381" /><ref name="pmid2801843">{{cite journal | vauthors = Hargrove JT, Maxson WS, Wentz AC | title = Absorption of oral progesterone is influenced by vehicle and particle size | journal = American Journal of Obstetrics and Gynecology | volume = 161 | issue = 4 | pages = 948–951 | date = October 1989 | pmid = 2801843 | doi = 10.1016/0002-9378(89)90759-X }}</ref> This formulation, known as oral micronized progesterone (OMP), was then introduced for medical use under the brand name Utrogestan in France in 1982.<ref name="pmid7119381" /><ref name="pmid6925387">{{cite journal | vauthors = Csech J, Gervais C | title = [Utrogestan] | language = fr | journal = Soins. Gynécologie, Obstétrique, Puériculture, Pédiatrie | issue = 16 | pages = 45–46 | date = September 1982 | pmid = 6925387 | trans-title = Utrogestan }}</ref><ref name="Simon1995"/><ref name="RuanMueck2014"/> Subsequently, oral micronized progesterone was introduced under the brand name Prometrium in the United States in 1998.<ref name="pmid10090424">{{cite journal | vauthors = de Lignières B | title = Oral micronized progesterone | journal = Clinical Therapeutics | volume = 21 | issue = 1 | pages = 41–60; discussion 1–2 | date = January 1999 | pmid = 10090424 | doi = 10.1016/S0149-2918(00)88267-3 }}</ref><ref>{{cite web | url = http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019781&TABLE1=OB_Rx | archive-url = https://web.archive.org/web/20100502150241/http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019781&TABLE1=OB_Rx | archive-date = 2 May 2010 | title = Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations: 019781 | access-date = 7 July 2010 | date = 2 July 2010 | publisher = Food and Drug Administration }}</ref> By 1999, oral micronized progesterone had been marketed in more than 35 countries.<ref name="pmid10090424" /> In 2019, the first combination of oral estradiol and progesterone was introduced under the brand name Bijuva in the United States.<ref name="pmid25944519" /><ref name="TherapeuticsMD2018">{{Cite web | url=https://ir.therapeuticsmd.com/news-releases/news-release-details/therapeuticsmd-announces-fda-approval-tx-001hr-bijuvatm | title=TherapeuticsMD Announces FDA Approval of TX-001HR: BIJUVA™ (Estradiol and Progesterone) Capsules for the Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause | access-date=2 May 2019 | archive-date=5 May 2019 | archive-url=https://web.archive.org/web/20190505224657/https://ir.therapeuticsmd.com/news-releases/news-release-details/therapeuticsmd-announces-fda-approval-tx-001hr-bijuvatm }}</ref>

A sustained-release (SR) formulation of oral micronized progesterone, also known as "oral natural micronized progesterone sustained release" or "oral NMP SR", was marketed in India in 2012 under the brand name Gestofit SR.<ref name="pmid27042538" /><ref name="HaleemKhan2015" /><ref name="KirkSerat1997" /><ref name="Drugs.com" /> Many additional brand names followed.<ref name="HaleemKhan2015" /><ref name="Drugs.com" /> The preparation was originally developed in 1986 by a compounding pharmacy called Madison Pharmacy Associates in Madison, Wisconsin in the United States.<ref name="pmid27042538" /><ref name="KirkSerat1997" />

===Vaginal, rectal, and uterine=== Vaginal progesterone suppositories were first studied in women by Robert Greenblatt in 1954.<ref name="pmid13211792">{{cite journal | vauthors = Greenblatt RB | title = The physiologic effectiveness of progesterone vaginal suppositories | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 14 | issue = 12 | pages = 1564–1567 | date = December 1954 | pmid = 13211792 | doi = 10.1210/jcem-14-12-1564 }}</ref><ref name="pmid13407238">{{cite journal | vauthors = Greenblatt RB, Clark SL | title = The use of newer progestational preparations in clinical practice | journal = The Medical Clinics of North America | volume = 41 | issue = 2 | pages = 587–603 | date = March 1957 | pmid = 13407238 | doi = 10.1016/S0025-7125(16)34457-1 }}</ref><ref name="pmid6301793">{{cite journal | vauthors = Benziger DP, Edelson J | title = Absorption from the vagina | journal = Drug Metabolism Reviews | volume = 14 | issue = 2 | pages = 137–168 | date = 1983 | pmid = 6301793 | doi = 10.3109/03602538308991387 }}</ref> Shortly thereafter, vaginal progesterone suppositories were introduced for medical use under the brand name Colprosterone in 1955.<ref name="JAPA1955">{{cite journal|title=NEW Prescription Products|journal=Journal of the American Pharmaceutical Association (Practical Pharmacy Ed.)|volume=16|issue=3|year=1955|pages=193–200|issn=0095-9561|doi=10.1016/S0095-9561(16)33664-7}}</ref><ref name="pmid13407238" /> Rectal progesterone suppositories were first studied in men and women by Christian Hamburger in 1965.<ref name="Hamburger1965">{{cite journal| vauthors = Hamburger C |title=Administration of Progesterone in the Form of Suppositories|journal=Acta Endocrinologica|volume=49|issue=3_Suppl|year=1965|pages=S101|issn=0804-4643|doi=10.1530/acta.0.049S101}}</ref><ref name="pmid6301793" /> Vaginal and rectal progesterone suppositories were introduced for use under the brand name Cyclogest by 1976.<ref name="UnlistedDrugs1976">{{cite book|title=Unlisted Drugs|url=https://books.google.com/books?id=nxdtAAAAMAAJ|year=1976|publisher=Unlisted Drugs|page=360}}</ref><ref name="Belfast1977">{{cite book|title=The Belfast Gazette|url=https://books.google.com/books?id=YoNw_AGBEH8C|date=January 1977|publisher=H.M. Stationery Office|page=158}}</ref><ref name="Negwer1978">{{cite book| vauthors = Negwer M |title=Organic-chemical Drugs and Their Synonyms|url=https://books.google.com/books?id=4QMkAQAAMAAJ|year=1978|publisher=Akademie-Verlag|page=872}}</ref> Vaginal micronized progesterone gels and capsules were introduced for medical use under brand names such as Utrogestan and Crinone in the early 1990s.<ref name="Sauer2013" /><ref name="RacowskySchlegel2011">{{cite book|vauthors=Racowsky C, Schlegel PN, Fauser BC, Carrell D|title=Biennial Review of Infertility|url=https://books.google.com/books?id=4LgOGlCK_FMC&pg=PA84|date=7 June 2011|publisher=Springer Science & Business Media|isbn=978-1-4419-8456-2|pages=84–85}}</ref> Progesterone was approved in the United States as a vaginal gel in 1997 and as a vaginal insert in 2007.<ref>{{cite web | url = http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=020701&TABLE1=OB_Rx | archive-url = https://web.archive.org/web/20121017065419/http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=020701&TABLE1=OB_Rx | archive-date = 17 October 2012 | title = Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations: 020701 | access-date = 7 July 2010 | date = 2 July 2010 | publisher = Food and Drug Administration }}</ref><ref>{{cite web | url = http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=022057&TABLE1=OB_Rx | archive-url = https://web.archive.org/web/20110916221258/http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=022057&TABLE1=OB_Rx | archive-date = 16 September 2011 | title = Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations: 022057 | access-date = 7 July 2010 | date = 2 July 2010 | publisher = Food and Drug Administration }}</ref> A progesterone contraceptive vaginal ring known as Progering was first studied in women in 1985 and continued to be researched through the 1990s.<ref name="FaundesBrache2004">{{cite journal| vauthors = Faundes A, Brache V, Alvarez F |title=Pros and Cons of Vaginal Rings for Contraceptive Hormone Delivery|journal=American Journal of Drug Delivery|volume=2|issue=4|year=2004|pages=241–250|issn=1175-9038|doi=10.2165/00137696-200402040-00004|s2cid=72093345}}</ref><ref name="pmid26732558">{{cite journal | vauthors = Friend DR | title = Development of controlled release systems over the past 50years in the area of contraception | journal = Journal of Controlled Release | volume = 240 | pages = 235–241 | date = October 2016 | pmid = 26732558 | doi = 10.1016/j.jconrel.2015.12.043 }}</ref> It was approved for use as a contraceptive in lactating mothers in Latin America by 2004.<ref name="FaundesBrache2004" /> A second progesterone vaginal ring known as Fertiring was developed as a progesterone supplement for use during assisted reproduction and was approved in Latin America by 2007.<ref name="Rabe2007">{{cite journal | vauthors = Rabe T | title = Contraception – Update and Trends | journal = J. Reproduktionsmed. Endokrinol | year = 2007 | volume = 4 | issue = 6 | pages = 337–357 | issn = 1810-2107 | url = https://www.kup.at/kup/pdf/6827.pdf}}</ref><ref name="HilleryPark2016">{{cite book| vauthors = Hillery AM, Park K |title=Drug Delivery: Fundamentals and Applications, Second Edition|url=https://books.google.com/books?id=TERnDwAAQBAJ&pg=PA294|date=15 September 2016|publisher=CRC Press|isbn=978-1-4822-1772-8|pages=294–}}</ref>

Development of a progesterone-containing intrauterine device (IUD) for contraception began in the 1960s.<ref name="pmid19445984">{{cite journal | vauthors = Rose S, Chaudhari A, Peterson CM | title = Mirena (Levonorgestrel intrauterine system): a successful novel drug delivery option in contraception | journal = Advanced Drug Delivery Reviews | volume = 61 | issue = 10 | pages = 808–812 | date = August 2009 | pmid = 19445984 | doi = 10.1016/j.addr.2009.04.022 }}</ref> Incorporation of progesterone into IUDs was initially studied to help reduce the risk of IUD expulsion.<ref name="pmid19445984" /> However, while addition of progesterone to IUDs showed no benefit on expulsion rates, it was unexpectedly found to induce endometrial atrophy.<ref name="pmid19445984" /> This led in 1976 to the development and introduction of Progestasert, a progesterone-containing product and the first progestogen-containing IUD.<ref name="FalconeHurd2007" /><ref name="pmid19445984" /><ref name="Chaudhuri2007" /> Unfortunately, the product had various problems that limited its use.<ref name="pmid19445984" /><ref name="Chaudhuri2007" /><ref name="FalconeHurd2007" /> These included a short duration of efficacy of only one year, a high cost, a relatively high 2.9% failure rate, a lack of protection against ectopic pregnancy, and difficult and sometimes painful insertions that could necessitate use of a local anesthetic or analgesic.<ref name="pmid19445984" /><ref name="Chaudhuri2007" /><ref name="FalconeHurd2007" /> As a result of these issues, Progestasert never became widely used, and was discontinued in 2001.<ref name="pmid19445984" /><ref name="Chaudhuri2007" /><ref name="FalconeHurd2007" /> It was used mostly in the United States and France while it was marketed.<ref name="Chaudhuri2007" />

===Transdermal and topical=== A topical gel formulation of progesterone, for direct application to the breasts as a local therapy for breast disorders such as breast pain, was introduced under the brand name ''Progestogel'' in Europe by 1972.<ref name="Masson1972">{{cite journal|journal=Journal de Gynécologie, Obstétrique et Biologie de la Reproduction|url=https://books.google.com/books?id=NjH9dmzFBfsC|year=1972|publisher=Masson|pages=198, 214, 327}}</ref> No transdermal formulations of progesterone for systemic use have been successfully marketed, in spite of efforts of pharmaceutical companies towards this goal.<ref name="pmid25196424">{{cite journal | vauthors = Stanczyk FZ | title = Treatment of postmenopausal women with topical progesterone creams and gels: are they effective? | journal = Climacteric | volume = 17 | issue = Suppl 2 | pages = 8–11 | date = December 2014 | pmid = 25196424 | doi = 10.3109/13697137.2014.944496 | s2cid = 20019151 }}</ref><ref name="RuanMueck2014"/><ref name="pmid2642780">{{cite journal | vauthors = Sitruk-Ware R | title = Transdermal delivery of steroids | journal = Contraception | volume = 39 | issue = 1 | pages = 1–20 | date = January 1989 | pmid = 2642780 | doi = 10.1016/0010-7824(89)90012-7 }}</ref> The low potency of transdermal progesterone has thus far precluded it as a possibility.<ref name="pmid15863530">{{cite journal | vauthors = Potts RO, Lobo RA | title = Transdermal drug delivery: clinical considerations for the obstetrician-gynecologist | journal = Obstetrics and Gynecology | volume = 105 | issue = 5 Pt 1 | pages = 953–961 | date = May 2005 | pmid = 15863530 | doi = 10.1097/01.AOG.0000161958.70059.db | s2cid = 23411589 }}</ref><ref name="UnferdiRenzo2006">{{cite journal| vauthors = Unfer V, di Renzo GC, Gerli S, Casini ML |title=The Use of Progesterone in Clinical Practice: Evaluation of its Efficacy in Diverse Indications Using Different Routes of Administration|journal=Current Drug Therapy |volume=1 |issue=2 |year=2006 |pages=211–219 |doi=10.2174/157488506776930923}}</ref><ref name="pmid16109599">{{cite journal | vauthors = Unfer V, Casini ML, Marelli G, Costabile L, Gerli S, Di Renzo GC | title = Different routes of progesterone administration and polycystic ovary syndrome: a review of the literature | journal = Gynecological Endocrinology | volume = 21 | issue = 2 | pages = 119–127 | date = August 2005 | pmid = 16109599 | doi = 10.1080/09513590500170049 | s2cid = 24890723 }}</ref><ref name="pmid11108875"/> Although no formulations of transdermal progesterone are approved for systemic use, transdermal progesterone is available in the form of creams and gels from custom compounding pharmacies in some countries, and is also available over-the-counter without a prescription in the United States.<ref name="pmid25196424" /><ref name="pmid15772572"/><ref name="pmid15901742"/> However, these preparations are unregulated and have not been adequately characterized, with low and unsubstantiated effectiveness.<ref name="pmid25196424" /><ref name="RuanMueck2014"/>

==Society and culture==

===Generic names=== ''Progesterone'' is the generic name of the drug in English and its {{abbrlink|INN|International Nonproprietary Name|INN}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|USP|United States Pharmacopeia}}, {{abbrlink|BAN|British Approved Name}}, {{abbrlink|DCIT|Denominazione Comune Italiana}}, and {{abbrlink|JAN|Japanese Accepted Name}}, while ''progestérone'' is its name in French and its {{abbrlink|DCF|Dénomination Commune Française}}.<ref name="Drugs.com">{{Cite web | url=https://www.drugs.com/international/progesterone.html | title=Progesterone}}</ref><ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1024|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=1024–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA880|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=880–}}</ref><ref name="MortonHall1999">{{cite book | vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=mqaOMOtk61IC&pg=PA232|date=31 October 1999|publisher=Springer Science & Business Media|isbn=978-0-7514-0499-9|pages=232–}}</ref> It is also referred to as ''progesteronum'' in Latin, ''progesterona'' in Spanish and Portuguese, and ''progesteron'' in German.<ref name="Drugs.com" /><ref name="IndexNominum2000" />

===Brand names=== {{redirect|Prometrium|the chemical element|Promethium}} right|thumb|Prometrium 100 mg oral capsule.

Progesterone is marketed under a large number of brand names throughout the world.<ref name="Drugs.com"/><ref name="IndexNominum2000" /> Examples of major brand names under which progesterone has been marketed include Crinone, Crinone 8%, Cyclogest, Endogest, Endometrin, Estima, Geslutin, Gesterol, Gestone, Luteina, Luteinol, Lutigest, Lutinus, Microgest, Progeffik, Progelan, Progendo, Progering, Progest, Progestaject, Progestan, Progesterone, Progestin, Progestogel, Prolutex, Proluton, Prometrium, Prontogest, Strone, Susten, Utrogest, and Utrogestan.<ref name="Drugs.com" /><ref name="IndexNominum2000" />

===Availability=== Progesterone is widely available in countries throughout the world in a variety of formulations.<ref name="Drugs.com" /><ref name="Micromedex">{{Cite web | url=http://www.micromedexsolutions.com/micromedex2/librarian | title=Micromedex Products: Please Login}}</ref> Progesterone in the form of oral capsules; vaginal capsules, tablets/inserts, and gels; and intramuscular oil have widespread availability.<ref name="Drugs.com" /><ref name="Micromedex" /> The following formulations/routes of progesterone have selective or more limited availability:<ref name="Drugs.com" /><ref name="Micromedex" /> * A tablet of micronized progesterone which is marketed under the brand name Luteina is indicated for sublingual administration in addition to vaginal administration and is available in Poland and Ukraine.<ref name="Drugs.com" /><ref name="Micromedex" /> * A progesterone suppository which is marketed under the brand name Cyclogest is indicated for rectal administration in addition to vaginal administration and is available in Cyprus, Hong Kong, India, Malaysia, Malta, Oman, Singapore, South Africa, Thailand, Tunisia, Turkey, the United Kingdom, and Vietnam.<ref name="Drugs.com" /><ref name="Micromedex" /> * An aqueous solution of progesterone complexed with β-cyclodextrin for subcutaneous injection is marketed under the brand name Prolutex in the Czech Republic, Hungary, Italy, Poland, Portugal, Slovakia, Spain, and Switzerland.<ref name="Drugs.com" /><ref name="Micromedex" /> * A non-systemic topical gel formulation of progesterone for local application to the breasts to treat breast pain is marketed under the brand name Progestogel and is available in Belgium, Bulgaria, Colombia, Ecuador, France, Georgia, Germany, Hong Kong, Lebanon, Peru, Romania, Russia, Serbia, Switzerland, Tunisia, Venezuela, and Vietnam.<ref name="Drugs.com" /><ref name="Micromedex" /> It was also formerly available in Italy, Portugal, and Spain, but was discontinued in these countries.<ref name="Micromedex" /> * A progesterone intrauterine device was previously marketed under the brand name Progestasert and was available in Canada, France, the United States, and possibly other countries, but was discontinued.<ref name="Micromedex" /><ref name="Gelijns1991">{{cite book| vauthors = Gelijns A |title=Innovation in Clinical Practice: The Dynamics of Medical Technology Development |url= https://books.google.com/books?id=MZkrAAAAYAAJ&pg=PA195 |year=1991 |publisher=National Academies |pages=195– |id=NAP:13513 }}</ref> * Progesterone vaginal rings are marketed under the brand names Fertiring and Progering and are available in Chile, Ecuador, and Peru.<ref name="Drugs.com" /><ref name="Micromedex" /> * A sustained-release tablet formulation of oral micronized progesterone (also known as "oral natural micronized progesterone sustained release" or "oral NMP SR") is marketed in India under the brand names Lutefix Pro (CROSMAT Technology), Dubagest SR, Gestofit SR, and Susten SR, among many others.<ref name="pmid27042538">{{cite journal | vauthors = Malik S, Krishnaprasad K | title = Natural Micronized Progesterone Sustained Release (SR) and Luteal Phase: Role Redefined!! | journal = Journal of Clinical and Diagnostic Research | volume = 10 | issue = 2 | pages = QE01–QE04 | date = February 2016 | pmid = 27042538 | pmc = 4800604 | doi = 10.7860/JCDR/2016/17278.7212 }}</ref><ref name="PurandareHajare2014">{{cite journal| vauthors = Purandare AC, Hajare A, Krishnaprasad K, Bhargava A |title=Prescription event monitoring study to assess the safety profile of oral natural micronized progesterone sustained release in India|journal=International Journal of Medical Research & Health Sciences|volume=3|issue=4|year=2014|page=975|issn=2319-5886|doi=10.5958/2319-5886.2014.00034.4|doi-access=free}}</ref><ref name="HaleemKhan2015B">{{cite journal | vauthors = Haleem S, Khan MI | title = Changing Indian Market Trends of NMP: A Review | journal = International Journal of Pharma Research & Review | volume = 4 | issue = 3 | pages = 28–30 | date = March 2015 }}</ref><ref name="Nigam2018">{{cite journal | vauthors = Nigam A | title = Luteal Phase Support: Why, When and How | journal = Pan Asian Journal of Obstetrics & Gynecology | volume = 1 | issue = 2 | pages = 79–83 | date = 2018 | url = https://pajog.com/prints/Luteal%20Phase%20Support%20Why%20When%20and%20How.pdf| archive-url = https://web.archive.org/web/20200819051545/https://pajog.com/prints/Luteal%20Phase%20Support%20Why%20When%20and%20How.pdf | archive-date = 19 August 2020 }}</ref><ref name="pmid26894126">{{cite journal | vauthors = Malhotra J, Krishnaprasad K | title = Open-label, Prospective, Investigator Initiated Study to Assess the Clinical Role of Oral Natural or Synthetic Progesterone During Stimulated IUI Cycles for Unexplained Infertility | journal = Journal of Clinical and Diagnostic Research | volume = 10 | issue = 1 | pages = QC08–QC10 | date = January 2016 | pmid = 26894126 | pmc = 4740654 | doi = 10.7860/JCDR/2016/17058.7106 }}</ref><ref name="PrabhatKorukonda2018">{{cite journal| vauthors = Prabhat P, Korukonda K |title= A Drug Utilisation Surveillance Study to Assess the Clinical Utility and Safety of Oral Natural Micronized Progesterone SR in High Risk Pregnancies: NAP-DELAY Study|journal=Journal of Clinical and Diagnostic Research|year=2018|issn=2249-782X|doi=10.7860/JCDR/2018/34886.12118| doi-access = free | title-link = doi }}</ref><ref name="SinghReddy2015">{{cite journal | vauthors = Singh N, Reddy A | title = Current Concepts in Management of Preterm Labour - A Review Article | journal = Indian Obstetrics and Gynaecology | volume = 5 | issue = 2 | date = April–June 2015 | url = https://iog.org.in/index.php/iog/article/view/192 | access-date = 19 August 2020 | archive-date = 29 August 2021 | archive-url = https://web.archive.org/web/20210829012204/https://iog.org.in/index.php/iog/article/view/192 }}</ref><ref name="KirkSerat1997">{{cite journal | vauthors = Kirk EP, Serat S, Burrows LJ, Mott LA, Yeo KJ, Fitzmaurice T, Lewis LD | title = A pharmacokinetic study of micronized natural progesterone extended release tablets | journal = Restore Health | date = 1997 | url = https://pharmacysolutionsonline.com/progesterone-even-release-tablets.php| archive-url = https://web.archive.org/web/20190304112338/https://pharmacysolutionsonline.com/progesterone-even-release-tablets.php | archive-date = 4 March 2019 }}</ref><ref name="Drugs.com" />

In addition to single-drug formulations, the following progesterone combination formulations are or have been marketed, albeit with limited availability:<ref name="Drugs.com" /><ref name="Micromedex" /> * A combination pack of progesterone capsules for oral use and estradiol gel for transdermal use is marketed under the brand name Estrogel Propak in Canada.<ref name="Drugs.com" /><ref name="Micromedex" /> * A combination pack of progesterone capsules and estradiol tablets for oral use is marketed in an under the brand name Duogestan in Belgium.<ref name="Drugs.com" /><ref name="Micromedex" /> * Progesterone and estradiol in an aqueous suspension for use by intramuscular injection is marketed under the brand name Cristerona FP in Argentina.<ref name="Drugs.com" /><ref name="Micromedex" /> * Progesterone and estradiol in microspheres in an oil solution for use by intramuscular injection is marketed under the brand name Juvenum in Mexico.<ref name="Drugs.com" /><ref name="Micromedex" /><ref name="AdisInsight-Juvenum">{{Cite web | url=https://adisinsight.springer.com/drugs/800044558 | title=Estradiol/progesterone injection - Laboratorios Carnot | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref> * Progesterone and estradiol benzoate in an oil solution for use by intramuscular injection is marketed under the brand names Duogynon, Duoton Fort T P, Emmenovis, Gestrygen, Lutofolone, Menovis, Mestrolar, Metrigen Fuerte, Nomestrol, Phenokinon-F, Prodiol, Pro-Estramon-S, Proger F, Progestediol, and Vermagest and is available in Belize, Egypt, El Salvador, Ethiopia, Guatemala, Honduras, Italy, Lebanon, Malaysia, Mexico, Nicaragua, Taiwan, Thailand, and Turkey.<ref name="Drugs.com" /><ref name="Micromedex" /> * Progesterone and estradiol hemisuccinate in an oil solution for use by intramuscular injection is marketed under the brand name Hosterona in Argentina.<ref name="Drugs.com" /><ref name="Micromedex" /> * Progesterone and estrone for use by intramuscular injection is marketed under the brand name Synergon in Monaco.<ref name="Drugs.com" />

====United States==== {{See also|List of progestogens available in the United States}}

{{As of|2016|11}}, progesterone is available in the United States in the following formulations:<ref name="Drugs@FDA1">{{cite web | title = Drugs@FDA: FDA Approved Drug Products | publisher = United States Food and Drug Administration | access-date = 29 November 2016 | url = http://www.accessdata.fda.gov/scripts/cder/daf/| archive-url = https://web.archive.org/web/20161104020628/http://www.accessdata.fda.gov/scripts/cder/daf/| archive-date = 4 November 2016}}</ref> * Oral: Capsules: Prometrium (100 mg, 200 mg, 300 mg) * Vaginal: Tablets: Endometrin (100 mg); Gels: Crinone (4%, 8%) * Intramuscular injection: Oil: Progesterone (50 mg/mL)

A 25 mg/mL concentration of progesterone oil for intramuscular injection and a 38 mg/device progesterone intrauterine device (Progestasert) have been discontinued.<ref name="Drugs@FDA1" />

An oral combination formulation of micronized progesterone and estradiol in oil-filled capsules (brand name Bijuva) is marketed in the United States for the treatment of menopausal symptoms and endometrial hyperplasia.<ref name="AdisInsight-TX-001-HR">{{Cite web | url=http://adisinsight.springer.com/drugs/800038089 | title=Estradiol/progesterone - TherapeuticsMD | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref><ref name="pmid25944519" />

Progesterone is also available in unregulated custom preparations from compounding pharmacies in the United States.<ref name="pmid26035149">{{cite journal | vauthors = Kaunitz AM, Kaunitz JD | title = Compounded bioidentical hormone therapy: time for a reality check? | journal = Menopause | volume = 22 | issue = 9 | pages = 919–920 | date = September 2015 | pmid = 26035149 | doi = 10.1097/GME.0000000000000484 }}</ref><ref name="pmid26418479">{{cite journal | vauthors = Pinkerton JV, Pickar JH | title = Update on medical and regulatory issues pertaining to compounded and FDA-approved drugs, including hormone therapy | journal = Menopause | volume = 23 | issue = 2 | pages = 215–223 | date = February 2016 | pmid = 26418479 | pmc = 4927324 | doi = 10.1097/GME.0000000000000523 }}</ref> In addition, transdermal progesterone is available over-the-counter in the United States, although the clinical efficacy of transdermal progesterone is controversial.<ref name="pmid25196424" /><ref name="pmid15772572">{{cite journal | vauthors = Stanczyk FZ, Paulson RJ, Roy S | title = Percutaneous administration of progesterone: blood levels and endometrial protection | journal = Menopause | volume = 12 | issue = 2 | pages = 232–237 | date = March 2005 | pmid = 15772572 | doi = 10.1097/00042192-200512020-00019 | s2cid = 10982395 }}</ref><ref name="pmid15901742">{{cite journal | vauthors = Hermann AC, Nafziger AN, Victory J, Kulawy R, Rocci ML, Bertino JS | title = Over-the-counter progesterone cream produces significant drug exposure compared to a food and drug administration-approved oral progesterone product | journal = Journal of Clinical Pharmacology | volume = 45 | issue = 6 | pages = 614–619 | date = June 2005 | pmid = 15901742 | doi = 10.1177/0091270005276621 | s2cid = 28399314 }}</ref>

==Research== Progesterone was studied as a progestogen-only injectable contraceptive, but was never marketed.<ref name="Garza-FloresCravioto1992">{{cite book|vauthors=Garza-Flores J, Cravioto MC, Pérez-Palacios G|chapter=Steroid Injectable Contraception: Current Concepts and Perspectives|pages=41–70|editor1=L. R. Sitruk-Ware|editor2=C. Wayne Bardin|title=Contraception: newer pharmacological agents, devices, and delivery systems|url=https://books.google.com/books?id=L5NsAAAAMAAJ|year=1992|publisher=M. Dekker|isbn=978-0-8247-8700-4}}</ref><ref name="Alvarez-SanchezBrache1993">{{cite journal | vauthors = Alvarez-Sanchez F, Brache V, Faundes A | title = Recent experience with and future directions of contraceptive implants and injectable contraceptives | journal = Current Opinion in Obstetrics & Gynecology | volume = 5 | issue = 6 | pages = 805–814 | date = December 1993 | pmid = 8286694 | doi = 10.1097/00001703-199312000-00016 }}</ref><ref name="Cullins1992">{{cite journal | vauthors = Cullins VE | title = Injectable and implantable contraceptives | journal = Current Opinion in Obstetrics & Gynecology | volume = 4 | issue = 4 | pages = 536–543 | date = August 1992 | pmid = 1387011 | doi = 10.1097/00001703-199208000-00008 | s2cid = 39442952 }}</ref> Combinations of estradiol and progesterone as a macrocrystalline aqueous suspension and as an aqueous suspension of microspheres have been studied as once-a-month combined injectable contraceptives, but were likewise never marketed.<ref name="Alvarez-SanchezBrache1993" /><ref name="Garza-Flores1994"/>

Progesterone has been assessed for the suppression of sex drive and spermatogenesis in men.<ref name="Brotherton1976">{{cite book| vauthors = Brotherton J |title=Sex Hormone Pharmacology|url=https://books.google.com/books?id=zt5sAAAAMAAJ|year=1976|publisher=Academic Press|isbn=978-0-12-137250-7|pages=341–342}}</ref><ref name="NeumannDiallo1976">{{cite journal | vauthors = Neumann F, Diallo FA, Hasan SH, Schenck B, Traore I | title = The influence of pharmaceutical compounds on male fertility | journal = Andrologia | volume = 8 | issue = 3 | pages = 203–235 | year = 1976 | pmid = 793446 | doi = 10.1111/j.1439-0272.1976.tb02137.x | s2cid = 24859886 | doi-access = free | title-link = doi }}</ref> In one study, 100 mg rectal suppositories of progesterone given five times per day for 9 days resulted in progesterone levels of 5.5 to 29 ng/mL and suppressed circulating testosterone and growth hormone levels by about 50% in men, but did not affect libido or erectile potency in this short treatment period.<ref name="Brotherton1976" /><ref name="pmid5558416">{{cite journal | vauthors = Sundsfjord JA, Aakvaag A, Norman N | title = Reduced plasma testosterone and LH in young men during progesterone administration | journal = Journal of Reproduction and Fertility | volume = 26 | issue = 2 | pages = 263–265 | date = August 1971 | pmid = 5558416 | doi = 10.1530/jrf.0.0260263 | doi-access = free | title-link = doi }}</ref> In other studies, 50 mg/day progesterone by intramuscular injection for 10 weeks in men produced azoospermia, decreased testicular size, markedly suppressed libido and erectile potency, and resulted in minimal semen volume upon ejaculation.<ref name="Brotherton1976" /><ref name="NeumannDiallo1976" /><ref name="pmid13583821">{{cite journal | vauthors = Heller CG, Laidlaw WM, Harvey HT, Nelson WO | title = Effects of progestational compounds on the reproductive processes of the human male | journal = Annals of the New York Academy of Sciences | volume = 71 | issue = 5 | pages = 649–665 | date = July 1958 | pmid = 13583821 | doi = 10.1111/j.1749-6632.1958.tb54641.x | s2cid = 32637425 }}</ref><ref name="pmid14400846">{{cite journal | vauthors = Heller CG, Moore DJ, Paulsen CA, Nelson WO, Laidlaw WM | title = Effects of progesterone and synthetic progestins on the reproductive physiology of normal men | journal = Federation Proceedings | volume = 18 | pages = 1057–1065 | date = December 1959 | pmid = 14400846 }}</ref>

An oil and water nanoemulsion of progesterone (particles of <1 mm in diameter) using micellar nanoparticle technology for transdermal administration known as Progestsorb NE was under development by Novavax for use in menopausal hormone therapy in the 2000s.<ref name="Progestsorb NE-AdisInsight">{{Cite web|url=https://adisinsight.springer.com/drugs/800017094|title=Progesterone topical - Novavax | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref><ref name="Plunkett2004">{{cite book| vauthors = Plunkett JW |title=Plunkett's Nanotechnology & MEMS Industry Almanac|url=https://books.google.com/books?id=Bu8MFtGR_iEC&pg=PT265|date=March 2004|publisher=Plunkett Research, Ltd.|isbn=978-1-59392-004-3|pages=265–}}</ref><ref name="Novavax2002">{{cite web |url=https://ir.novavax.com/static-files/af4f0b93-c3f2-442b-9da5-f3ee0c63f844 |title= Form 10-K Novavax, inc. |website=ir.novavax.com |access-date=15 January 2022 |archive-url=https://web.archive.org/web/20191222045252/https://ir.novavax.com/static-files/af4f0b93-c3f2-442b-9da5-f3ee0c63f844 |archive-date=22 December 2019 }}</ref> However, development was discontinued in 2007 and the formulation was never marketed.<ref name="Progestsorb NE-AdisInsight" />

== References == {{Reflist}}

== Further reading == {{refbegin}} * {{cite journal | vauthors = Sitruk-Ware R, Bricaire C, De Lignieres B, Yaneva H, Mauvais-Jarvis P | title = Oral micronized progesterone. Bioavailability pharmacokinetics, pharmacological and therapeutic implications--a review | journal = Contraception | volume = 36 | issue = 4 | pages = 373–402 | date = October 1987 | pmid = 3327648 | doi = 10.1016/0010-7824(87)90088-6 }} * {{cite journal | vauthors = 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 }} {{refend}}

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