Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Hydroxyprogesterone caproate: Difference between pages

{{Short description|Chemical compound}}

{{Distinguish|17α-Hydroxyprogesterone|Medroxyprogesterone acetate}}

{{Use dmy dates|date=December 2023}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

{{Infobox drug

| Verifiedfields = verified

| verifiedrevid = 477198932

| width = 250

| image2 = Hydroxyprogesterone caproate molecule ball.png

| width2 = 250

| caption =

<!-- Clinical data -->

| pronounce =

| tradename = Delalutin, Proluton, Makena, others

| Drugs.com =

| MedlinePlus =

| DailyMedID = <!-- DailyMed may use generic or brand name (generic name preferred) -->

| pregnancy_AU_comment =

| pregnancy_category =

| routes_of_administration = [[Intramuscular injection]],<ref name="pmid21888448" /> [[Subcutaneous injection|subcutaneous]] [[autoinjector|autoinjection]]<ref name="pmid29191450" /><ref name="Makena FDA label" />

| class = [[Progestogen (medication)|Progestogen]]; [[Progestin]]; [[Progestogen ester]]; [[Antigonadotropin]]

| ATC_prefix = G03

| ATC_suffix = DA03

| ATC_supplemental = <br />{{ATC|G03|FA02}}

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment =

| legal_US = withdrawn

| legal_EU =

| legal_EU_comment =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->

| bioavailability = [[Oral administration|Oral]]: Very low (~3% in rats)<ref name="pmid26153441" /><br />[[Intramuscular injection|Intramuscular]]: 100% (in rats)<ref name="pmid26153441" />

| protein_bound = Extensive (to [[human serum albumin|albumin]], not to {{abbrlink|CBG|corticosteroid-binding globulin}} or (likely) {{abbrlink|SHBG|sex hormone-binding globulin}})<ref name="pmid21888448" /><ref name="pmid7306509" /><ref name="pmid7195404" />

| metabolism = [[Redox|Reduction]] and [[hydroxylation]] (via [[CYP3A4]], [[CYP3A5]], [[CYP3A7]]) and [[conjugation (biochemistry)|conjugation]] ([[glucuronidation]], [[sulfation]], [[acetylation]])<ref name="pmid21888448" />

| metabolites =

| >

| elimination_half-life = Non-pregnant: 7.8 days<ref name="pmid2932883">{{cite journal | vauthors = Onsrud M, Paus E, Haug E, Kjørstad K | title = Intramuscular administration of hydroxyprogesterone caproate in patients with endometrial carcinoma. Pharmacokinetics and effects on adrenal function | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 64 | issue = 6 | pages = 519–23 | date = 1985 | pmid = 2932883 | doi = 10.3109/00016348509156732 | s2cid = 12007439 }}</ref><ref name="pmid23413110" /><br />Singlet: 16–17 days<ref name="pmid21888448" /><ref name="pmid25256193" /><br />Twins: 10 days<ref name="pmid25256193" />

| duration_of_action =

| excretion = [[Feces]]: 50%<ref name="pmid21888448" /><br />[[Urine]]: 30%<ref name="pmid21888448" />

<!-- Identifiers -->

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 630-56-8

| CAS_supplemental =

| IUPHAR_ligand =

| DrugBank = DB06789

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 276F2O42F5

| KEGG = D00949

| ChEBI = 5812

| ChEMBL = 1200848

| NIAID_ChemDB =

| PDB_ligand =

| synonyms = OHPC; Hydroxyprogesterone capronate; Hydroxyprogesterone hexanoate; 17α-Hydroxyprogesterone caproate; 17α-OHPC; 17-Hydroxyprogesterone caproate; 17-OHPC; 17-HPC; 17α-HPC; HPC; LPCN-1107; 17α-Hydroxypregn-4-ene-3,20-dione 17α-hexanoate

<!-- Chemical and physical data -->

| IUPAC_name = [(8''R'',9''S'',10''R'',13''S'',14''S'',17''R'')-17-acetyl-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1''H''-cyclopenta[''a'']phenanthren-17-yl] hexanoate

| C=27 | H=40 | O=4

| SMILES = O=C4\C=C2/[C@]([C@H]1CC[C@@]3([C@@](OC(=O)CCCCC)(C(=O)C)CC[C@H]3[C@@H]1CC2)C)(C)CC4

| StdInChI_comment =

| density =

| density_notes =

| melting_point =

| melting_high =

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility =

| sol_units =

| specific_rotation =

<!-- Definition and medical uses -->

'''Hydroxyprogesterone caproate''', sold under the brand name '''Delalutin''' among others, is a [[medication]] used to reduce the risk of preterm birth in women pregnant with one baby who have a history of spontaneous preterm birth.<ref name="FDA PR 20230406" /> In March 2023, the manufacturer, Covis Pharma, agreed to withdraw the drug from the US market.<ref name="Jewett-2023">{{Cite news | vauthors = Jewett C |date=8 March 2023 |title=Preterm Birth Drug Withdrawn After 12 Years |work=The New York Times |url=https://www.nytimes.com/2023/03/07/health/preterm-birth-drug-makena-fda.html |access-date=10 March 2023 |archive-date=10 March 2023 |archive-url=https://web.archive.org/web/20230310001041/https://www.nytimes.com/2023/03/07/health/preterm-birth-drug-makena-fda.html |url-status=live }}</ref><ref name="Dillinger-2023">{{Cite web | vauthors = Dillinger K |date=8 March 2023 |title=Maker of preterm birth drug Makena to withdraw it from market |url=https://www.cnn.com/2023/03/08/health/makena-preterm-birth-withdrawn-covis/index.html |access-date=10 March 2023 |website=CNN |archive-date=10 March 2023 |archive-url=https://web.archive.org/web/20230310093637/https://www.cnn.com/2023/03/08/health/makena-preterm-birth-withdrawn-covis/index.html |url-status=live }}</ref><ref name="Covis Pharma-2023">{{cite press release | title=Covis Pharma Responds to Presiding Officer's Report Summarizing FDA Advisory Committee Hearing | publisher=Covis Pharma | via=GlobeNewswire | date=7 March 2023 | url=https://www.globenewswire.com/news-release/2023/03/07/2622609/0/en/Covis-Pharma-Responds-to-Presiding-Officer-s-Report-Summarizing-FDA-Advisory-Committee-Hearing.html | access-date=13 March 2023 | archive-date=13 March 2023 | archive-url=https://web.archive.org/web/20230313233616/https://www.globenewswire.com/news-release/2023/03/07/2622609/0/en/Covis-Pharma-Responds-to-Presiding-Officer-s-Report-Summarizing-FDA-Advisory-Committee-Hearing.html | url-status=live }}</ref> The approval of this drug substance was withdrawn by the US [[Food and Drug Administration]] (FDA) in April 2023.<ref name="FDA PR 20230406">{{cite press release | title=FDA Commissioner and Chief Scientist Announce Decision to Withdraw Approval of Makena | website=U.S. Food and Drug Administration | date=6 April 2023 | url=https://www.fda.gov/news-events/press-announcements/fda-commissioner-and-chief-scientist-announce-decision-withdraw-approval-makena | access-date=7 April 2023 | archive-date=6 April 2023 | archive-url=https://web.archive.org/web/20230406150454/https://www.fda.gov/news-events/press-announcements/fda-commissioner-and-chief-scientist-announce-decision-withdraw-approval-makena | url-status=live }} {{PD-notice}}</ref> In May 2024, the [[Pharmacovigilance Risk Assessment Committee]] of the [[European Medicines Agency]] recommended suspending the marketing authorizations of medications containing 17-hydroxyprogesterone caproate in the European Union.<ref>{{cite web | title=Hydroxyprogesterone caproate medicines to be suspended from the EU market | website=[[European Medicines Agency]] (EMA) | date=17 May 2024 | url=https://www.ema.europa.eu/en/news/hydroxyprogesterone-caproate-medicines-be-suspended-eu-market | access-date=18 May 2024}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>

Hydroxyprogesterone caproate is a [[progestin]] medication which was used to prevent [[preterm birth]] in [[pregnancy|pregnant]] women with a history of the condition and to treat [[gynecological disorder]]s.<ref name="pmid21888448">{{cite journal | vauthors = Deeks ED | title = 17 α-Hydroxyprogesterone caproate (Makena): in the prevention of preterm birth | journal = Paediatric Drugs | volume = 13 | issue = 5 | pages = 337–45 | date = October 2011 | pmid = 21888448 | doi = 10.2165/11208140-000000000-00000 | s2cid = 207297651 }}</ref><ref name="pmid23413110">{{cite journal | vauthors = Hines M, Lyseng-Williamson KA, Deeks ED | title = 17 α-hydroxyprogesterone caproate (Makena): a guide to its use in the prevention of preterm birth | journal = Clinical Drug Investigation | volume = 33 | issue = 3 | pages = 223–7 | date = March 2013 | pmid = 23413110 | doi = 10.1007/s40261-013-0060-6 | s2cid = 23221264 }}</ref><ref name="pmid25256193" /><ref name="pmid28947068">{{cite journal | vauthors = Manuck TA | title = 17-alpha hydroxyprogesterone caproate for preterm birth prevention: Where have we been, how did we get here, and where are we going? | journal = Seminars in Perinatology | volume = 41 | issue = 8 | pages = 461–467 | date = December 2017 | pmid = 28947068 | doi = 10.1053/j.semperi.2017.08.004 | s2cid = 36945947 | url = https://cdr.lib.unc.edu/downloads/028712685 | access-date = 2 November 2021 | archive-date = 12 December 2020 | archive-url = https://web.archive.org/web/20201212021914/https://cdr.lib.unc.edu/downloads/028712685 | url-status = live }}</ref><ref name="Makena FDA label">{{cite web | title=Makena- hydroxyprogesterone caproate injection | website=DailyMed | date=19 December 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a1998c1d-8337-4f00-8dcb-af3b54d39b77 | access-date=13 March 2023 | archive-date=13 March 2023 | archive-url=https://web.archive.org/web/20230313233619/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a1998c1d-8337-4f00-8dcb-af3b54d39b77 | url-status=live }}</ref> It has also been formulated in combination with [[estrogen (medication)|estrogen]]s for various indications (brand names [[Gravibinon]] and [[Primosiston]]) and as a form of long-lasting [[combined injectable birth control|injectable birth control]] (brand name [[Chinese Injectable No. 1]]).<ref name="pmid12290848">{{cite journal | vauthors = Newton JR, D'arcangues C, Hall PE | title = A review of "once-a-month" combined injectable contraceptives | journal = Journal of Obstetrics and Gynaecology | volume = 4 | issue = Suppl 1 | pages = S1-34 | year = 1994 | pmid = 12290848 | doi = 10.3109/01443619409027641 }}</ref> It is not used [[oral administration|by mouth]] and is instead given by [[intramuscular injection|injection into muscle]] or [[subcutaneous injection|fat]].<ref name="pmid21888448" /><ref name="pmid26153441" /><ref name="Makena FDA label" />

<!-- Side effects and mechanism -->

Hydroxyprogesterone caproate is generally [[tolerability|well tolerated]] and produces few [[side effect]]s.<ref name="pmid21888448" /> [[Injection site reaction]]s such as [[pain]] and [[swelling (medical)|swelling]] are the most common side effect of hydroxyprogesterone caproate.<ref name="pmid21888448" /> The medication may increase the risk of [[gestational diabetes]] when used in pregnant women.<ref name="pmid21888448" /><ref name="pmid23643669" /> Hydroxyprogesterone caproate is a progestin, or a [[synthetic compound|synthetic]] [[progestogen (medication)|progestogen]], and hence is an [[agonist]] of the [[progesterone receptor]], the [[biological target]] of progestogens like [[progesterone]].<ref name="pmid23643669" /> It has some [[antimineralocorticoid]] activity and no other important [[hormonal agent|hormonal]] activity.<ref name="Horsky-2012">{{cite book|vauthors=Horsky J, Presl J|title=Ovarian Function and its Disorders: Diagnosis and Therapy|url=https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA95|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-009-8195-9|pages=95–|access-date=16 September 2018|archive-date=8 March 2023|archive-url=https://web.archive.org/web/20230308182355/https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA95|url-status=live}}</ref><ref name="Dorfman-2016" /><ref name="pmid1163210" /><ref name="pmid14304354" /><ref name="pmid15863556" /> The medication shows a number of differences from [[natural product|natural]] [[progesterone (medication)|progesterone]].<ref name="pmid23643669" /><ref name="pmid23410596" />

<!-- History, society, and culture -->

Hydroxyprogesterone caproate was discovered in 1953 and was introduced for medical use in 1954 or 1955.<ref name="Cancer1979" /> It was marketed in the United States under the brand name Delalutin and throughout Europe under the brand name Proluton.<ref name="IndexNominum2000" /> The medication was discontinued in the United States in 1999.<ref name="Heinonline">{{cite journal|vauthors=Kim S|url=http://heinonline.org/HOL/LandingPage?handle=hein.journals%2Fnwteintp11&div=30&id=&page=|title=The Orphan Drug Act: How the FDA Unlawfully Usurped Market Exclusivity|journal=Northwestern Journal of Technology and Intellectual Property|volume=11|pages=&#91;v&#93|publisher=Heinonline|access-date=18 July 2016|archive-date=8 March 2023|archive-url=https://web.archive.org/web/20230308182327/https://heinonline.org/HOL/LandingPage?handle=hein.journals%252Fnwteintp11&div=30&id=&page=|url-status=live}}</ref> However, hydroxyprogesterone caproate was subsequently reintroduced in the United States under the brand name Makena for the treatment of preterm birth in 2011 untill the FDA banned 17α-OHPC in 2023.<ref name="pmid21410391" />

{{TOC limit|3}}

==Medical uses==

===Preterm birth===

The use of hydroxyprogesterone caproate in pregnancy to prevent [[preterm birth]] in women with a history of preterm delivery between 20 weeks and 36 weeks and 6 days is supported by the Society of Maternal Fetal Medicine Clinic Guidelines put out in May 2012 as Level I and III evidence, Level A recommendation.<ref name="SMFM Clinical Guideline-2012">SMFM Clinical Guideline: Progesterone and preterm birth prevention: translating clinical trials data into clinical practice, AJOG May 2012</ref> Level I evidence refers to a properly powered [[randomized controlled trial]], and level III evidence is support from expert opinion, while a Level A recommendation confers that the recommendation is made based on good and consistent scientific evidence. Hydroxyprogesterone caproate 250&nbsp;mg IM weekly preferably starting at 16–20 weeks until 36 weeks is recommended. In these women, if the transvaginal ultrasound cervical length shortens to <25&nbsp;mm at < 24 weeks, [[Cerclage|cervical cerclage]] may be offered. In the 2013 study the guideline recommendation is based on,<ref name="pmid12802023">{{cite journal | vauthors = Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, Spong CY, Hauth JC, Miodovnik M, Varner MW, Leveno KJ, Caritis SN, Iams JD, Wapner RJ, Conway D, O'Sullivan MJ, Carpenter M, Mercer B, Ramin SM, Thorp JM, Peaceman AM, Gabbe S | title = Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate | journal = The New England Journal of Medicine | volume = 348 | issue = 24 | pages = 2379–85 | date = June 2003 | pmid = 12802023 | doi = 10.1056/NEJMoa035140 | doi-access = free }}</ref> there was also a significant decrease of neonatal morbidity including lower rates of [[necrotizing enterocolitis]] (0 in the treatment group vs 4 in the control), [[intraventricular hemorrhage]] (4 in the treatment group compared with 8 in the control for a relative risk of 0.25), and need for supplemental oxygen (14% in the treatment group vs 24% in the placebo for a relative risk of 0.42). Furthermore, this study contained 463&nbsp;women, 310 of whom received injection. Of these women, 9 had infants with congenital malformations (2%), but there was no consistent pattern and none involved internal organs.

There is no evidence of fetal risk with use of hydroxyprogesterone caproate during pregnancy.{{medcn|date=March 2023}} A review concluded that information about the potential harms was lacking.<ref name="pmid15330887">{{cite journal | vauthors = Keirse MJ | title = Progesterone and preterm: seventy years of "déjà vu" or "still to be seen"? | journal = Birth | volume = 31 | issue = 3 | pages = 230–5 | date = September 2004 | pmid = 15330887 | doi = 10.1111/j.0730-7659.2004.00315.x }}</ref> Three clinical studies in singleton pregnancies of 250&nbsp;mg/week of [[intramuscular injection|intramuscular]] hydroxyprogesterone caproate have all shown a trend for an increase in pregnancy loss due to miscarriage compared to placebo.<ref name="pmid1099445">{{cite journal | vauthors = Johnson JW, Austin KL, Jones GS, Davis GH, King TM | title = Efficacy of 17alpha-hydroxyprogesterone caproate in the prevention of premature labor | journal = The New England Journal of Medicine | volume = 293 | issue = 14 | pages = 675–80 | date = October 1975 | pmid = 1099445 | doi = 10.1056/nejm197510022931401 }}</ref><ref name="pmid3976757">{{cite journal | vauthors = Yemini M, Borenstein R, Dreazen E, Apelman Z, Mogilner BM, Kessler I, Lancet M | title = Prevention of premature labor by 17 alpha-hydroxyprogesterone caproate | journal = American Journal of Obstetrics and Gynecology | volume = 151 | issue = 5 | pages = 574–7 | date = March 1985 | pmid = 3976757 | doi = 10.1016/0002-9378(85)90141-3 }}</ref><ref name="pmid12802023" /> One of them, a large [[National Institutes of Health]] (NIH) study in 2003, looked at the effect of hydroxyprogesterone caproate injections in women at risk for repeat [[premature birth]] and found that the treated group experienced premature birth in 37% versus 55% in the controls.<ref name="pmid12802023" /> A follow-up study of the offspring showed no evidence that hydroxyprogesterone caproate affected the children in the first years of life.<ref name="pmid17906021">{{cite journal | vauthors = Northen AT, Norman GS, Anderson K, Moseley L, Divito M, Cotroneo M, Swain M, Bousleiman S, Johnson F, Dorman K, Milluzzi C, Tillinghast JA, Kerr M, Mallett G, Thom E, Pagliaro S, Anderson GD | title = Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo | journal = Obstetrics and Gynecology | volume = 110 | issue = 4 | pages = 865–72 | date = October 2007 | pmid = 17906021 | doi = 10.1097/01.AOG.0000281348.51499.bc | s2cid = 29485152 }}</ref> Based on these NIH data, hydroxyprogesterone caproate was approved by the US [[Food and Drug Administration]] (FDA) in 2011, as a medication to reduce the risk of premature birth in selected women at risk.{{cn|date=March 2023}}

The FDA expressed concern about miscarriage at the 2006 advisory committee meeting; the committee voted unanimously that further study was needed to evaluate the potential association of hydroxyprogesterone caproate with increased risk of second trimester miscarriage and stillbirth.<ref name="FDA-Advisory Committees: CDER 2006 Meeting Documents">{{Cite web |url=https://www.fda.gov/ohrms/dockets/ac/cder06.html#rhdac |title=Advisory Committees: CDER 2006 Meeting Documents<!-- Bot generated title --> |website=[[Food and Drug Administration]] |access-date=16 December 2019 |archive-date=8 May 2017 |archive-url=https://web.archive.org/web/20170508161922/https://www.fda.gov/ohrms/dockets/ac/cder06.html#rhdac |url-status=live }}</ref> A toxicology study in rhesus monkeys resulted in the death of all rhesus fetuses exposed to 1 and 10 times the human dose equivalent of hydroxyprogesterone caproate.<ref name="pmid3563931">{{cite journal | vauthors = Hendrickx AG, Korte R, Leuschner F, Neumann BW, Poggel A, Binkerd P, Prahalada S, Günzel P | title = Embryotoxicity of sex steroidal hormones in nonhuman primates: II. Hydroxyprogesterone caproate, estradiol valerate | journal = Teratology | volume = 35 | issue = 1 | pages = 129–36 | date = February 1987 | pmid = 3563931 | doi = 10.1002/tera.1420350116 }}</ref> {{As of|2008}}, hydroxyprogesterone caproate was a [[Pregnancy category|category]] D progestin according to the FDA (that is, there is evidence of fetal harm). There is speculation that the [[castor oil]] in the hydroxyprogesterone caproate formulation may not be beneficial for pregnancy.<ref name="Duke University Medical Center">Duke University Medical Center, New England Journal of Medicine, correspondence, vol 349.</ref><ref name="pmid6682631">{{cite journal | vauthors = Hauth JC, Gilstrap LC, Brekken AL, Hauth JM | title = The effect of 17 alpha-hydroxyprogesterone caproate on pregnancy outcome in an active-duty military population | journal = American Journal of Obstetrics and Gynecology | volume = 146 | issue = 2 | pages = 187–90 | date = May 1983 | pmid = 6682631 | doi = 10.1016/0002-9378(83)91051-7 }}</ref> Of note, the above-mentioned NEJM study by Meirs et al. compares the effect of hydroxyprogesterone caproate (with the castor oil component) to castor oil injection as the placebo.

A study published in February 2016, found amongst other findings:<ref name="pmid26921136">{{cite journal | vauthors = Norman JE, Marlow N, Messow CM, Shennan A, Bennett PR, Thornton S, Robson SC, McConnachie A, Petrou S, Sebire NJ, Lavender T, Whyte S, Norrie J | title = Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial | language = en | journal = Lancet | volume = 387 | issue = 10033 | pages = 2106–2116 | date = May 2016 | pmid = 26921136 | pmc = 5406617 | doi = 10.1016/S0140-6736(16)00350-0 }}</ref>

{{Quotation|OPPTIMUM strongly suggests that the efficacy of progesterone in improving outcomes is either non-existent or weak. Given the heterogeneity of the preterm labour syndrome we cannot exclude benefit in specific phenotypic or genotypic subgroups of women at risk. However, the subgroups of women who might benefit do not appear to be easily identifiable by current selection strategies, including cervical length measurement and fibronectin testing.

Reassuringly, our study suggests that progesterone is safe for those who wish to take it for preterm birth prophylaxis. The overall rate of maternal or child adverse events was similar in the progesterone and placebo groups. There were few differences in the incidence of adverse secondary outcomes in the two groups, with the exception of a higher rate of renal, gastrointestinal, and respiratory complications in childhood in the progesterone groups. Importantly, the absolute rates of these complications was low. Follow-up of other babies exposed ''in utero'' to vaginal progesterone would be helpful in determining whether the increased rate of some renal, gastrointestinal, and respiratory complications is a real effect or a type I error.}}

The journal reviewer made the following notable commentary on the OPPTIMUM study: "That's it. This story is ended, and nobody need ever use vaginal progesterone again to prevent preterm birth."<ref name="blogs.bmj.com-2016">{{Cite web|url=http://blogs.bmj.com/bmj/2016/05/23/richard-lehmans-journal-review-23-may-2016/|title=BMJ Blogs: The BMJ » Blog Archive » Richard Lehman's journal review—23 May 2016|website=blogs.bmj.com|access-date=25 May 2016|date=23 May 2016|archive-date=26 May 2016|archive-url=https://web.archive.org/web/20160526090631/http://blogs.bmj.com/bmj/2016/05/23/richard-lehmans-journal-review-23-may-2016/|url-status=live}}</ref>

A [[Cochrane review]] on progestogen for preventing preterm birth concluded that there was little evidence that either vaginal or intramuscular progesterone helped to reduce the risk of preterm birth in women with a multiple pregnancy.<ref name="pmid31745984">{{cite journal | vauthors = Dodd JM, Grivell RM, OBrien CM, Dowswell T, Deussen AR | title = Prenatal administration of progestogens for preventing spontaneous preterm birth in women with a multiple pregnancy | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 11 | date = November 2019 | pmid = 31745984 | pmc = 6864412 | doi = 10.1002/14651858.CD012024.pub3 }}</ref>

===Gynecological disorders===

Hydroxyprogesterone caproate is used in the treatment of [[threatened miscarriage]], [[gynecological disorder]]s such as [[dysmenorrhea]], [[premenstrual syndrome]], [[fibrocystic breast disease]], [[adenosis]], and [[breast pain]].<ref name="pmid25256193" /> In addition, hydroxyprogesterone caproate is used in the treatment of [[endometrial cancer]] and has been found to be significantly effective in extending life in both premenopausal and postmenopausal women with the disease.<ref name="pmid5549492">{{cite journal | vauthors = Reifenstein EC | title = Hydroxyprogesterone caproate therapy in advanced endometrial cancer | journal = Cancer | volume = 27 | issue = 3 | pages = 485–502 | date = March 1971 | pmid = 5549492 | doi = 10.1002/1097-0142(197103)27:3<485::AID-CNCR2820270302>3.0.CO;2-1 | s2cid = 37473914 | doi-access = free }}</ref> The medication was used widely in the 1950s through the 1970s for such indications, but hydroxyprogesterone caproate more recently has received the most attention in the prevention of [[preterm birth]].<ref name="pmid25256193" />

===Birth control===

Hydroxyprogesterone caproate is available in combination with [[estradiol valerate]] as a once-monthly [[combined injectable contraceptive]] in a some countries.<ref name="pmid12290848" /><ref name="Drugs.com-Hydroxyprogesterone" />

===Other uses===

Hydroxyprogesterone caproate has been used as a component of [[menopausal hormone therapy]] in women.<ref name="Shoupe-1987">{{cite book | vauthors = Shoupe D, Mishell DR | chapter = Therapeutic Regimens | pages = 335–351 | veditors = Mishell DR | title = Menopause: Physiology and Pharmacology | year = 1987 | publisher = Year Book Medical | isbn = 9780815159148 | url = https://books.google.com/books?id=0q1sAAAAMAAJ | access-date = 3 December 2019 | archive-date = 8 March 2023 | archive-url = https://web.archive.org/web/20230308182325/https://books.google.com/books?id=0q1sAAAAMAAJ | url-status = live }}</ref><ref name="pmid16373245">{{cite journal | vauthors = Agostini R, Casini ML, Costabile L, Paragona M, Marzano F, Unfer V | title = Efficacy and safety of 17alpha-hydroxyprogesterone caproate in hormone replacement therapy | journal = Gynecological Endocrinology | volume = 21 | issue = 5 | pages = 265–267 | date = November 2005 | pmid = 16373245 | doi = 10.1080/09513590500368650 | s2cid = 71508663 }}</ref>

Hydroxyprogesterone caproate has been used to treat [[benign prostatic hyperplasia]] in men, although evidence of effectiveness is marginal and uncertain.<ref name="Springer2012">{{cite book|title=Benign Prostatic Hypertrophy|url=https://books.google.com/books?id=Z5K-BwAAQBAJ&pg=PA266|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4612-5476-8|pages=266–|access-date=3 October 2016|archive-date=11 January 2023|archive-url=https://web.archive.org/web/20230111123403/https://books.google.com/books?id=Z5K-BwAAQBAJ&pg=PA266|url-status=live}}</ref> It has also been used to treat [[prostate cancer]], at a dosage of 1,500&nbsp;mg twice per week.<ref name="Ablin-2007">{{cite book| vauthors = Ablin RJ, Mason MD |title=Metastasis of Prostate Cancer|url=https://books.google.com/books?id=AAo2qVvcVJcC&pg=PA286|date=5 September 2007|publisher=Springer Science & Business Media|isbn=978-1-4020-5847-9|pages=286–|access-date=23 December 2018|archive-date=8 March 2023|archive-url=https://web.archive.org/web/20230308182331/https://books.google.com/books?id=AAo2qVvcVJcC&pg=PA286|url-status=live}}</ref><ref name="Smith-2013">{{cite book|vauthors=Smith PH|title=Cancer of the Prostate and Kidney|url=https://books.google.com/books?id=gtAFCAAAQBAJ&pg=PA309|date=29 June 2013|publisher=Springer Science & Business Media|isbn=978-1-4684-4349-3|pages=309, 339|access-date=23 December 2018|archive-date=8 March 2023|archive-url=https://web.archive.org/web/20230308182408/https://books.google.com/books?id=gtAFCAAAQBAJ&pg=PA309|url-status=live}}</ref><ref name="Hafez-2012">{{cite book|vauthors=Hafez ES, Spring-Mills E|title=Prostatic Carcinoma: Biology and Diagnosis|url=https://books.google.com/books?id=XNt9BwAAQBAJ&pg=PT128|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-009-8887-3|pages=128–|access-date=23 December 2018|archive-date=8 March 2023|archive-url=https://web.archive.org/web/20230308182339/https://books.google.com/books?id=XNt9BwAAQBAJ&pg=PT128|url-status=live}}</ref><ref name="Castro-2013" /> The mechanism of action of hydroxyprogesterone caproate in these uses is suppression of testicular androgen production via suppression of [[luteinizing hormone]] secretion, which are the result of the progestogenic and [[antigonadotropic]] activity of hydroxyprogesterone caproate.<ref name="Springer2012" /> However, symptoms of [[hypogonadism]] may develop when hydroxyprogesterone caproate is used for this indication, with two-thirds of men reportedly experiencing [[impotence]].<ref name="Aronson-2009">{{cite book| vauthors = Aronson JK |title=Meyler's Side Effects of Endocrine and Metabolic Drugs|url=https://books.google.com/books?id=BWMeSwVwfTkC&pg=PA289|date=21 February 2009|publisher=Elsevier|isbn=978-0-08-093292-7|pages=289–|access-date=3 October 2016|archive-date=8 March 2023|archive-url=https://web.archive.org/web/20230308182348/https://books.google.com/books?id=BWMeSwVwfTkC&pg=PA289|url-status=live}}</ref>

Hydroxyprogesterone caproate has been used as a component of [[feminizing hormone therapy]] for [[transgender women]].<ref name="Israel-2001">{{cite book | vauthors = Israel GE, Tarver DE, Shaffer JD | title = Transgender Care: Recommended Guidelines, Practical Information, and Personal Accounts | url = https://books.google.com/books?id=IlPX6E5glDEC&pg=PA58 | date = 1 March 2001 | publisher = Temple University Press | isbn = 978-1-56639-852-7 | pages = 58– | access-date = 3 October 2016 | archive-date = 8 March 2023 | archive-url = https://web.archive.org/web/20230308182350/https://books.google.com/books?id=IlPX6E5glDEC&pg=PA58 | url-status = live }}</ref><ref name="Ekins-2006">{{cite book| vauthors = Ekins R, King D |title=The Transgender Phenomenon|url=https://books.google.com/books?id=2TlvmbN9X7wC&pg=PA48|date=23 October 2006|publisher=SAGE Publications|isbn=978-1-84787-726-0|pages=48–|access-date=3 October 2016|archive-date=8 March 2023|archive-url=https://web.archive.org/web/20230308182412/https://books.google.com/books?id=2TlvmbN9X7wC&pg=PA48|url-status=live}}</ref><ref name="Adler-2012">{{cite book| vauthors = Adler RK, Hirsch S, Mordaunt M |title=Voice and Communication Therapy for The Transgender/Transsexual Client: A Comprehensive Clinical Guide|url=https://books.google.com/books?id=zVc0BwAAQBAJ&pg=PA486|date=1 May 2012|publisher=Plural Publishing|isbn=978-1-59756-631-5|pages=486–}}</ref><ref name="pmid22372595">{{cite journal | vauthors = Masumori N | title = Status of sex reassignment surgery for gender identity disorder in Japan | journal = International Journal of Urology | volume = 19 | issue = 5 | pages = 402–414 | date = May 2012 | pmid = 22372595 | doi = 10.1111/j.1442-2042.2012.02975.x | s2cid = 38888396 }}</ref><ref name="pmid22487218">{{cite journal | vauthors = Chekir C, Emi Y, Arai F, Kikuchi Y, Sasaki A, Matsuda M, Shimizu K, Tabuchi K, Kamada Y, Hiramatsu Y, Nakatsuka M | title = Altered arterial stiffness in male-to-female transsexuals undergoing hormonal treatment | journal = The Journal of Obstetrics and Gynaecology Research | volume = 38 | issue = 6 | pages = 932–940 | date = June 2012 | pmid = 22487218 | doi = 10.1111/j.1447-0756.2011.01815.x | url = http://ousar.lib.okayama-u.ac.jp/48439 | access-date = 18 August 2019 | url-status = live | s2cid = 39877004 | archive-url = https://web.archive.org/web/20230308182402/https://ousar.lib.okayama-u.ac.jp/en/48439 | archive-date = 8 March 2023 }}</ref> Due to [[micronization]], bioidentical progestogens are more commonly used.

===Available forms===

{{See also|Estradiol valerate/hydroxyprogesterone caproate|Estradiol benzoate/hydroxyprogesterone caproate|Estradiol dipropionate/hydroxyprogesterone caproate}}

[[File:Proluton Depot (hydroxyprogesterone caproate) packs.jpg|thumb|right|300px|Single-use packs of Proluton Depot (OHPC). Contain 1-mL ampoules of 250 mg/mL hydroxyprogesterone caproate (250 mg total) in castor oil and benzyl benzoate solution as well as a 21 G needles and disposable syringes and indicated for use by intramuscular injection.]]

Hydroxyprogesterone caproate is available alone in the form of [[ampoule]]s and [[vial]]s of 125 and 250&nbsp;mg/mL [[oil solution]]s for [[intramuscular injection]] (brand names Proluton, Makena).<ref name="Becker-2001" /><ref name="Nema-2016">{{cite book| vauthors = Nema S, Ludwig JD |title=Pharmaceutical Dosage Forms - Parenteral Medications, Third Edition: Volume 1: Formulation and Packaging|url=https://books.google.com/books?id=Hkm3BgAAQBAJ&pg=PA161|date=19 April 2016|publisher=CRC Press|isbn=978-1-4200-8644-7|pages=161–|access-date=15 September 2018|archive-date=8 March 2023|archive-url=https://web.archive.org/web/20230308182421/https://books.google.com/books?id=Hkm3BgAAQBAJ&pg=PA161|url-status=live}}</ref> It is also available alone in the form of a 250&nbsp;mg/mL [[autoinjector]] for use by [[subcutaneous injection]] (brand name Makena).<ref name="Makena FDA label" />

Hydroxyprogesterone caproate is or was available in combination with [[estradiol valerate]] in the form of ampoules and vials of 250&nbsp;mg/mL OHPC and 5&nbsp;mg/mL estradiol valerate oil solutions for intramuscular injection (brand names Gravibinon, Chinese Injectable No. 1).<ref name="Muller-1998">{{cite book | vauthors = Muller NF, Dessing RP | title = European Drug Index: European Drug Registrations | edition = Fourth | url = https://books.google.com/books?id=2HBPHmclMWIC&pg=PA561 | date = 19 June 1998 | publisher = CRC Press | isbn = 978-3-7692-2114-5 | pages = 561– | access-date = 15 September 2018 | archive-date = 8 March 2023 | archive-url = https://web.archive.org/web/20230308182356/https://books.google.com/books?id=2HBPHmclMWIC&pg=PA561 | url-status = live }}</ref><ref name="pmid8013219">{{cite journal | vauthors = Garza-Flores J | title = Pharmacokinetics of once-a-month injectable contraceptives | journal = Contraception | volume = 49 | issue = 4 | pages = 347–59 | date = April 1994 | pmid = 8013219 | doi = 10.1016/0010-7824(94)90032-9 }}</ref><ref name="pmid8013220">{{cite journal | vauthors = Sang GW | title = Pharmacodynamic effects of once-a-month combined injectable contraceptives | journal = Contraception | volume = 49 | issue = 4 | pages = 361–385 | date = April 1994 | pmid = 8013220 | doi = 10.1016/0010-7824(94)90033-7 }}</ref><ref name="Bagade-2014">{{cite journal |vauthors= Bagade O, Pawar V, Patel R, Patel B, Awasarkar V, Diwate S | title = Increasing use of long-acting reversible contraception: safe, reliable, and cost-effective birth control | journal = World J Pharm Pharm Sci | volume = 3 | issue = 10 | pages = 364–392 |year=2014 |issn=2278-4357 |url=http://www.wjpps.com/download/article/1412071798.pdf | access-date = 15 September 2018 | archive-url = https://web.archive.org/web/20170810000242/http://www.wjpps.com/download/article/1412071798.pdf | archive-date = 10 August 2017 | url-status = dead }}</ref> The medication is or was available in combination with [[estradiol benzoate]] in the form of ampoules of 125–250&nbsp;mg OHPC and 10&nbsp;mg estradiol benzoate in oil solution for intramuscular injection (brand name Primosiston) as well.<ref name="Leidenberger-2013">{{cite book| vauthors = Leidenberger FA |title=Klinische Endokrinologie für Frauenärzte|url=https://books.google.com/books?id=YTiuBgAAQBAJ&pg=PA533|date=17 April 2013|publisher=Springer-Verlag|isbn=978-3-662-08110-5|pages=533–|access-date=15 September 2018|archive-date=8 March 2023|archive-url=https://web.archive.org/web/20230308182402/https://books.google.com/books?id=YTiuBgAAQBAJ&pg=PA533|url-status=live}}</ref><ref name="Knörr-2013-Lehrbuch der Gynäkologie" /><ref name="Kahr-2013">{{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=PA22|date=8 March 2013|publisher=Springer-Verlag|isbn=978-3-7091-5694-0|pages=22–|access-date=15 September 2018|archive-date=8 March 2023|archive-url=https://web.archive.org/web/20230308182421/https://books.google.com/books?id=Hte1BgAAQBAJ&pg=PA22|url-status=live}}</ref><ref name="Kern-2013">{{cite book|vauthors=Kern W, Auterhoff H, Neuwald F, Schmid W|title=Hagers Handbuch der Pharmazeutischen Praxis: Für Apotheker, Arzneimittelhersteller, Drogisten, Ärzte und Medizinalbeamte|url=https://books.google.com/books?id=C_SgBgAAQBAJ&pg=PA1163|date=9 March 2013|publisher=Springer-Verlag|isbn=978-3-642-49759-9|pages=1163–|access-date=15 September 2018|archive-date=8 March 2023|archive-url=https://web.archive.org/web/20230308182347/https://books.google.com/books?id=C_SgBgAAQBAJ&pg=PA1163|url-status=live}}</ref><ref name="Ufer-1968">{{cite book | vauthors = Ufer J | chapter = Die therapeutische Anwendung der Gestagene beim Menschen | trans-chapter = Therapeutic Use of Progestogens in Humans | pages = 1026–1124 | doi = 10.1007/978-3-642-99941-3_7 | title = Die Gestagene | series = Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology | trans-title = Progestogens | year = 1968 | publisher = Springer-Verlag | isbn = 978-3-642-99941-3 | url = https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA1045 | quote = Depotinjektionen [...] 2. Einmalige Injektion von 125mg oder 250mg 17α-Hydroxyprogesteroncapronat als Depotgestagen und 10 mg Oestradiolbenzoat in öliger Lösung (Primosiston) [47, 81, 110, 563, 523, 571, 718, 721, 732, 733, 864, 872, 933, 973, 400]. | access-date = 15 September 2018 | archive-date = 8 March 2023 | archive-url = https://web.archive.org/web/20230308182357/https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA1045 | url-status = live }}</ref>{{Rp|1045}} In addition, hydroxyprogesterone caproate has been marketed in combination with [[estradiol dipropionate]] in the form of 50&nbsp;mg/mL hydroxyprogesterone caproate and 1&nbsp;mg/mL estradiol dipropionate (brand name EP Hormone Depot) in Japan.<ref name="Drugs.com-EP-Hormone">{{Cite web |url=https://www.drugs.com/international/ep-hormone.html |title=EP Hormone - Drugs.com |access-date=1 June 2019 |archive-date=7 April 2019 |archive-url=https://web.archive.org/web/20190407210353/https://www.drugs.com/international/ep-hormone.html |url-status=dead }}</ref><ref name="pmid2137212">{{cite journal | vauthors = Noguchi M, Tajiri K, Taniya T, Kumaki T, Ashikari A, Miyazaki I | title = Influence of hormones on proliferation of ER-positive cells and ER-negative cells of human breast cancer (MCF-7) | journal = Oncology | volume = 47 | issue = 1 | pages = 19–24 | date = 1990 | pmid = 2137212 | doi = 10.1159/000226779 | quote = After the transplantation, each mouse received an intramuscular injection of 0.1 ml EP Hormone Depot consisting of 1 mg/ml 17-β-estradiol dipropionate and 50 mg/ml hydroxyprogesterone caproate every week.}}</ref>

==Contraindications==

[[Contraindication]]s of hydroxyprogesterone caproate include previous or current [[thrombosis]] or [[thromboembolic disease]], known or suspected [[breast cancer]], past or present history of other [[hormone-sensitive cancer]], undiagnosed [[abnormal vaginal bleeding]] unrelated to [[pregnancy]], [[cholestatic jaundice of pregnancy]], [[liver tumor]]s or active [[liver disease]], and uncontrolled [[hypertension]].<ref name="Makena FDA label" /> A few relative contraindications also exist for hydroxyprogesterone caproate.<ref name="Makena FDA label" />

==Side effects==

{{See also|Progestin#Side effects}}

Hydroxyprogesterone caproate is generally [[tolerability|well tolerated]] and produces relatively few [[side effect]]s.<ref name="pmid21888448" /> [[Injection site reaction]]s such as [[pain]], [[soreness]], [[swelling (medical)|swelling]], [[itching]], [[bruising]], and [[swelling (medical)|lump]]s are the most common side effect of hydroxyprogesterone caproate.<ref name="pmid21888448" /> In contrast to large doses of progesterone however, which produce moderate-to-severe such reactions, hydroxyprogesterone caproate is relatively free from injection site reactions.<ref name="pmid13640942">{{cite journal | vauthors = Tyler ET, Olson HJ | title = Fertility promoting and inhibiting effects of new steroid hormonal substances | journal = J Am Med Assoc | volume = 169 | issue = 16 | pages = 1843–54 | date = April 1959 | pmid = 13640942 | doi = 10.1001/jama.1959.03000330015003 }}</ref> Side effects of hydroxyprogesterone caproate that occur in greater than or equal to 2% of users include injection site pain (34.8%), injection site swelling (17.1%), [[urticaria]] (12.3%), [[pruritus]] (7.7%), injection site pruritus (5.8%), [[nausea]] (5.8%), injection site [[nodule (medicine)|nodule]]s (4.5%), and [[diarrhea]] (2.3%).<ref name="Makena FDA label" /> Numerically increased rates relative to controls of [[miscarriage]] (2.4% vs. 0%), [[stillbirth]] (2.0% vs. 1.3%), admission for [[preterm labor]] (16.0% vs. 13.8%), [[preeclampsia]] or [[gestational hypertension]] (8.8% vs. 4.6%), [[gestational diabetes]] (5.6% vs. 4.6%),<ref name="pmid21888448" /><ref name="pmid23643669" /> and [[oligohydramnios]] (3.6% vs. 1.3%) have been observed with hydroxyprogesterone caproate in clinical trials in which it was given to pregnant women to prevent preterm birth.<ref name="Makena FDA label" />

==Overdose==

There have been no reports of [[overdose]] of hydroxyprogesterone caproate.<ref name="Makena FDA label" /> In the event of overdose, treatment should be based on [[symptom]]s.<ref name="Makena FDA label" /> Hydroxyprogesterone caproate has been studied in humans at high doses of 2,000 to 5,000&nbsp;mg per week by intramuscular injection, without [[drug safety|safety]] concerns.<ref name="pmid2932883" /><ref name="pmid15863556" /><ref name="pmid21575799">{{cite journal | vauthors = Hall NR | title = What agent should be used to prevent recurrent preterm birth: 17-P or natural progesterone? | journal = Obstetrics and Gynecology Clinics of North America | volume = 38 | issue = 2 | pages = 235–46, ix–x | date = June 2011 | pmid = 21575799 | doi = 10.1016/j.ogc.2011.02.014 }}</ref><ref name="Varga1961" />

== Interactions ==

Hydroxyprogesterone caproate is not likely to affect most [[cytochrome P450]] [[enzyme]]s at therapeutic concentrations.<ref name="Makena FDA label" /> [[Drug interaction]] studies have not been performed with hydroxyprogesterone caproate.<ref name="Makena FDA label" />

==Pharmacology==

===Pharmacodynamics===

Hydroxyprogesterone caproate has [[progestogen (medication)|progestogen]]ic activity, some [[antimineralocorticoid]] activity, and no other important [[hormone|hormonal]] activity.<ref name="Horsky-2012" /><ref name="pmid23413110" /><ref name="Dorfman-2016" /><ref name="pmid1163210" /><ref name="pmid21575799" />

{{Relative affinities of hydroxyprogesterone and related steroids}}

{{Parenteral potencies and durations of progestogens}}

====Progestogenic activity====

Hydroxyprogesterone caproate, also known as 17α-hydroxyprogesterone caproate, is closer to [[progesterone (medication)|progesterone]] in terms of [[chemical structure|structure]] and [[pharmacology]] than most other [[progestin]]s, and is essentially a pure [[progestogen (medication)|progestogen]] – that is, a [[binding selectivity|selective]] [[agonist]] of the [[progesterone receptor]] (PR) with minimal or no other [[hormone|hormonal]] activity.<ref name="pmid14304354" /><ref name="pmid15863556" /> However, hydroxyprogesterone caproate has improved [[pharmacokinetics]] compared to progesterone, namely a much longer [[duration of action|duration]] with [[intramuscular injection]] in [[oil solution]].<ref name="pmid25256193" /><ref name="pmid16112947" /><ref name="Knörr-2013-Lehrbuch der Gynäkologie" /><ref name="Knörr-2013- Geburtshilfe und Gynäkologie">{{cite book | vauthors = Knörr K, Knörr-Gärtner H, Beller FK, Lauritzen C | title = Geburtshilfe und Gynäkologie: Physiologie und Pathologie der Reproduktion | url = https://books.google.com/books?id=tpmgBgAAQBAJ&pg=PA583 | date = 8 March 2013 | publisher = Springer-Verlag | isbn = 978-3-642-95583-9 | pages = 583– | access-date = 29 March 2019 | archive-date = 11 January 2023 | archive-url = https://web.archive.org/web/20230111061914/https://books.google.com/books?id=tpmgBgAAQBAJ&pg=PA583 | url-status = live }}</ref>

Administered by intramuscular injection, the [[endometrial transformation]] dosage of hydroxyprogesterone caproate per cycle is 250 to 500&nbsp;mg, and the weekly substitution dosage of hydroxyprogesterone caproate is 250&nbsp;mg, while the effective dosage of hydroxyprogesterone caproate in the menstrual delay test (Greenblatt) is 25&nbsp;mg per week.<ref name="Knörr-2013-Lehrbuch der Gynäkologie">{{cite book | vauthors = Knörr K, Beller FK, Lauritzen C | title = Lehrbuch der Gynäkologie | url = https://books.google.com/books?id=ACybBwAAQBAJ&pg=PA214 | date = 17 April 2013 | publisher = Springer-Verlag | isbn = 978-3-662-00942-0 | pages = 214, 255 | access-date = 15 September 2018 | archive-date = 11 January 2023 | archive-url = https://web.archive.org/web/20230111061914/https://books.google.com/books?id=ACybBwAAQBAJ&pg=PA214 | url-status = live }}</ref><ref name="Knörr-2013- Geburtshilfe und Gynäkologie"/><ref name="pmid2215269">{{cite journal | vauthors = Lauritzen C | title = Clinical use of oestrogens and progestogens | journal = Maturitas | volume = 12 | issue = 3 | pages = 199–214 | date = September 1990 | pmid = 2215269 | doi = 10.1016/0378-5122(90)90004-P }}</ref> An effective [[ovulation]]-inhibiting dosage of hydroxyprogesterone caproate is 500&nbsp;mg once per month by intramuscular injection.<ref name="pmid8013220" /><ref name="pmid8013216">{{cite journal | vauthors = Toppozada MK | title = Existing once-a-month combined injectable contraceptives | journal = Contraception | volume = 49 | issue = 4 | pages = 293–301 | date = April 1994 | pmid = 8013216 | doi = 10.1016/0010-7824(94)90029-9 }}</ref><ref name="pmid13992789">{{cite journal | vauthors = Siegel I | title = Conception control by long-acting progestogens: preliminary report | journal = Obstetrics and Gynecology | volume = 21 | pages = 666–8 | date = June 1963 | pmid = 13992789 | url = https://journals.lww.com/greenjournal/Citation/1963/06000/Conception_Control_by_Long_acting_Progestogens_.3.aspx | access-date = 12 February 2020 | archive-date = 12 February 2020 | archive-url = https://web.archive.org/web/20200212204045/https://journals.lww.com/greenjournal/Citation/1963/06000/Conception_Control_by_Long_acting_Progestogens_.3.aspx | url-status = live }}</ref> However, the dose of hydroxyprogesterone caproate used in once-a-month [[combined injectable contraceptive]]s is 250&nbsp;mg, and this combination is effective for inhibition of ovulation similarly.<ref name="pmid8013220" /><ref name="pmid13992789" /> For comparison, the dose of [[medroxyprogesterone acetate]] (MPA; 6α-methyl-17α-hydroxyprogesterone acetate), a close [[structural analog|analogue]] of hydroxyprogesterone caproate, used by intramuscular injection in [[microcrystalline]] [[aqueous suspension]] in once-a-month combined injectable contraceptives, is 25&nbsp;mg.<ref name="pmid8013220" /><ref name="pmid8013216" /> It has also been said that given by intramuscular injection, 250&nbsp;mg hydroxyprogesterone caproate in oil solution is equivalent in progestogenic potency to 50&nbsp;mg medroxyprogesterone acetate in microcrystalline aqueous suspension.<ref name="pmid13756432">{{cite journal | vauthors = Kistner RW | title = The use of progestational agents in obstetrics and gynecology | journal = Clinical Obstetrics and Gynecology | volume = 3 | issue = 4 | pages = 1047–67 | date = December 1960 | pmid = 13756432 | doi = 10.1097/00003081-196003040-00019 | quote = 50 mg of [medroxyprogesterone acetate], intramuscularly, is equivalent to 250 mg [hydroxyprogesterone caproate] }}</ref> Although the [[elimination half-life]] of intramuscular hydroxyprogesterone caproate in oil solution in non-pregnant women is about 8&nbsp;days,<ref name="pmid2932883" /><ref name="pmid23413110" /> the elimination half-life of intramuscular medroxyprogesterone acetate in microcrystalline aqueous suspension in women is around 50&nbsp;days.<ref name="DepoProveraLabel">{{cite web|title=Depo_Provera|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020246s058lbl.pdf|website=FDA|access-date=31 March 2018|date=2016|archive-date=29 July 2020|archive-url=https://web.archive.org/web/20200729234219/https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020246s058lbl.pdf|url-status=live}}</ref> Hydroxyprogesterone caproate is also to some degree less potent than the more closely related ester [[hydroxyprogesterone acetate]] (OHPA; 17α-hydroxyprogesterone acetate).<ref name="pmid18060946" />

[[17α-Hydroxyprogesterone]] (OHP) has weak [[progestogen (medication)|progestogen]]ic activity, but C17α [[esterification]] results in higher progestogenic activity.<ref name="Ufer-1968" /> Of a variety of different [[ester]]s, the [[caproate]] (hexanoate) ester was found to have the strongest progestogenic activity, and this served as the basis for the development of hydroxyprogesterone caproate, as well as other caproate [[progestogen ester]]s such as [[gestonorone caproate]].<ref name="Ufer-1968" /> Hydroxyprogesterone caproate is a much more potent progestogen than 17α-hydroxyprogesterone, but does not have as high of [[affinity (pharmacology)|affinity]] for the PR as progesterone.<ref name="pmid18060946" /> Hydroxyprogesterone caproate has about 26% and 30% of the affinity of progesterone for the human [[progesterone receptor A|PR-A]] and [[progesterone receptor B|PR-B]], respectively.<ref name="pmid21888448" /><ref name="pmid18060946" /> The medication was no more [[intrinsic activity|efficacious]] than progesterone in activating these receptors and eliciting associated [[gene expression]] ''[[in vitro]]''.<ref name="pmid21888448" /><ref name="pmid18060946" />

====Antigonadotropic effects====

Due to activation of the PR, hydroxyprogesterone caproate has [[antigonadotropic]] effects, or produces suppression of the [[hypothalamic–pituitary–gonadal axis]],<ref name="pmid8082440">{{cite journal | vauthors = Yang D, Zhu RL | title = [Changes in reproductive hormones levels in the treatment of endometrial precancerous lesion with hydroxyprogesterone caproate] | language = zh | journal = Zhonghua Fu Chan Ke Za Zhi | volume = 29 | issue = 4 | pages = 205–6, 251 | date = April 1994 | pmid = 8082440 | quote = In this paper, 14 cases of precancerous lesion of endometrium were treated with hydroxyprogesterone caproate and a series of hormone determination was analysed before and after treatment. Results showed that LH and LH/FSH were dramatically decreased. (LH P < 0.05, LH/FSH P < 0.01). }}</ref><ref name="Springer2012B">{{cite book|title=Benign Prostatic Hypertrophy|url=https://books.google.com/books?id=Z5K-BwAAQBAJ&pg=PA266|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4612-5476-8|pages=266–|quote=Since the initial report by Geller and associates28 on the use of hydroxyprogesterone caproate in the treatment of BPH, a variety of progestins have been studied in the medical management of this disease: hydroxyprogesterone caproate, chlormadinone acetate,27 and medrogestone (6-methyl-6-dehydro-17-methylprogesterone).50 These drugs should have a beneficial effect in BPH as they inhibit testicular function by suppressing serum LH and have no intrinsic estrogenic or androgenic activity.|access-date=3 October 2016|archive-date=11 January 2023|archive-url=https://web.archive.org/web/20230111123403/https://books.google.com/books?id=Z5K-BwAAQBAJ&pg=PA266|url-status=live}}</ref> and can significantly suppress [[gonadotropin]] [[secretion]] and gonadal [[sex hormone]] production at sufficiently high doses.<ref name="Castro-2013">{{cite book| vauthors = Castro JE |title=The Treatment of Prostatic Hypertrophy and Neoplasia|url=https://books.google.com/books?id=Nc8hBQAAQBAJ&pg=PA39|date=9 March 2013|publisher=Springer Science & Business Media|isbn=978-94-015-7190-6|pages=39,132|quote=Geller has also demonstrated significant decreases in plasma or urine testosterone glucuronide levels following the administration of three other anti-androgens. These include Delalutin [hydroxyprogesterone caproate], chlormadinone acetate, and PH-218. It would appear that decreased androgen production is a property shared by all anti-androgens to date.}}</ref> One study found that hydroxyprogesterone caproate by intramuscular injection at a dosage of 200&nbsp;mg twice weekly for the first two weeks and then 200&nbsp;mg once weekly for 12&nbsp;weeks did not significantly influence urinary excretion of [[estrogen]]s, [[luteinizing hormone]], or [[follicle-stimulating hormone]] in men with benign prostatic hyperplasia.<ref name="pmid65818">{{cite journal | vauthors = Meiraz D, Margolin Y, Lev-Ran A, Lazebnik J | title = Treatment of benign prostatic hyperplasia with hydroxyprogesterone-caproate: placebo-controlled study | journal = Urology | volume = 9 | issue = 2 | pages = 144–8 | date = February 1977 | pmid = 65818 | doi = 10.1016/0090-4295(77)90184-4 }}</ref> In another study that used an unspecified dosage of intramuscular hydroxyprogesterone caproate, testosterone secretion was assessed in a single man and was found to decrease from 4.2&nbsp;mg/day to 2.0&nbsp;mg/day (or by approximately 52%) by 6&nbsp;weeks of treatment, whereas secretion of luteinizing hormone remained unchanged in the man.<ref name="pmid14304354">{{cite journal | vauthors = Geller J, Bora R, Roberts T, Newman H, Lin A, Silva R | title = Treatment of benign prostatic hypertrophy with hydroxyprogesterone caproate: effect on clinical symptoms, morphology, and endocrine function | journal = JAMA | volume = 193 | issue = 2 | pages = 121–8 | date = July 1965 | pmid = 14304354 | doi = 10.1001/jama.1965.03090020035009 }}</ref> Yet another study found that 3,000&nbsp;mg/week hydroxyprogesterone caproate by intramuscular injection suppressed testosterone levels from 640&nbsp;ng/dL to 320–370&nbsp;ng/dL (by 42–50%) in a single man with prostate cancer, which was similar to the testosterone suppression with [[cyproterone acetate]] or [[chlormadinone acetate]].<ref name="pmid6039663">{{cite journal | vauthors = Geller J, Fruchtman B, Newman H, Roberts T, Silva R | title = Effect of progestational agents on carcinoma of the prostate | journal = Cancer Chemother Rep | volume = 51 | issue = 1 | pages = 41–6 | date = February 1967 | pmid = 6039663 }}</ref> [[Gestonorone caproate]], a closely related progestin to hydroxyprogesterone caproate with about 5- to 10-fold greater potency in humans,<ref name="pmid5556820">{{cite journal | vauthors = Karlstedt K | title = Progesterone treatment for local recurrence and metastases in carcinoma corporis uteri | journal = Acta Radiologica | volume = 10 | issue = 2 | pages = 187–92 | date = April 1971 | pmid = 5556820 | doi = 10.3109/02841867109129755 | quote = The preparations used were Proluton Depot (17a-hydroxy-progesterone caproate) and in 3 patients SH 5132 (17a-hydroxy-19-norprogesterone caproate); 100 mg of the latter corresponds to 1000 mg of Proluton Depot. | doi-access = free }}</ref><ref name="pmid4261828" /> was found to suppress testosterone levels by 75% at a dosage of 400&nbsp;mg/week in men with prostate cancer.<ref name="pmid694436">{{cite journal | vauthors = Sander S, Nissen-Meyer R, Aakvaag A | title = On gestagen treatment of advanced prostatic carcinoma | journal = Scandinavian Journal of Urology and Nephrology | volume = 12 | issue = 2 | pages = 119–21 | year = 1978 | pmid = 694436 | doi = 10.3109/00365597809179977 }}</ref><ref name="pmid519881">{{cite journal | vauthors = Kjeld JM, Puah CM, Kaufman B, Loizou S, Vlotides J, Gwee HM, Kahn F, Sood R, Joplin GF | title = Effects of norgestrel and ethinyloestradiol ingestion on serum levels of sex hormones and gonadotrophins in men | journal = Clinical Endocrinology | volume = 11 | issue = 5 | pages = 497–504 | date = November 1979 | pmid = 519881 | doi = 10.1111/j.1365-2265.1979.tb03102.x | s2cid = 5836155 | quote = Another synthetic gestogen, 17-hydroxy-19-norprogesterone caproate (Depostat-Schering), 400 mg by i.m. weekly injections suppressed T levels to 25% of pretreatment values (Sander er al., 1978). }}</ref> For comparison, [[orchiectomy]] decreased testosterone levels by 91%.<ref name="pmid694436" /> In general, progestins are able to maximally suppress testosterone levels by about 70 to 80%.<ref name="Wein-2011">{{cite book | vauthors = Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA | title = Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set | url = https://books.google.com/books?id=fu3BBwAAQBAJ&pg=PA2938 | date = 25 August 2011 | publisher = Elsevier Health Sciences | isbn = 978-1-4160-6911-9 | pages = 2938– | access-date = 23 December 2018 | archive-date = 11 January 2023 | archive-url = https://web.archive.org/web/20230111061407/https://books.google.com/books?id=fu3BBwAAQBAJ&pg=PA2938 | url-status = live }}</ref><ref name="pmid6237116">{{cite journal | vauthors = Knuth UA, Hano R, Nieschlag E | title = Effect of flutamide or cyproterone acetate on pituitary and testicular hormones in normal men | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 59 | issue = 5 | pages = 963–9 | date = November 1984 | pmid = 6237116 | doi = 10.1210/jcem-59-5-963 }}</ref><ref name="pmid7000222">{{cite journal | vauthors = Jacobi GH, Altwein JE, Kurth KH, Basting R, Hohenfellner R | title = Treatment of advanced prostatic cancer with parenteral cyproterone acetate: a phase III randomised trial | journal = British Journal of Urology | volume = 52 | issue = 3 | pages = 208–15 | date = June 1980 | pmid = 7000222 | doi = 10.1111/j.1464-410x.1980.tb02961.x }}</ref><ref name="pmid694436" /><ref name="pmid519881" /> The antigonadotropic effects of hydroxyprogesterone caproate and hence its testosterone suppression are the basis of the use of hydroxyprogesterone caproate in the treatment of [[benign prostatic hyperplasia]] and [[prostate cancer]] in men.<ref name="Springer2012" /><ref name="Ablin-2007" /><ref name="Hafez-2012" /><ref name="Castro-2013" /> Suppression of luteinizing hormone levels by hydroxyprogesterone caproate has also been observed in women.<ref name="pmid13617315">{{cite journal | vauthors = Sherman AI, Woolf RB | title = An endocrine basis for endometrial carcinoma | journal = American Journal of Obstetrics and Gynecology | volume = 77 | issue = 2 | pages = 233–42 | date = February 1959 | pmid = 13617315 | doi = 10.1016/0002-9378(59)90223-6 }}</ref><ref name="pmid4261828">{{cite journal | vauthors = Moe N | title = Short-term progestogen treatment of endometrial carcinoma. Histological, histochemical and hormonal studies | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 51 | issue = 1 | pages = 55–62 | date = 1972 | pmid = 4261828 | doi = 10.3109/00016347209154968 | s2cid = 7181971 }}</ref>

====Glucocorticoid activity====

Hydroxyprogesterone caproate is said not to have any [[glucocorticoid]] activity.<ref name="pmid15863556" /> In accordance, hydroxyprogesterone caproate has been found not to alter [[cortisol]] levels in humans even with very high doses by intramuscular injection.<ref name="pmid2932883" /> This is of relevance because medications with significant glucocorticoid activity suppress cortisol levels due to increased [[negative feedback]] on the [[hypothalamic–pituitary–adrenal axis]].<ref name="Becker-2001">{{cite book| vauthors = Becker KL |title=Principles and Practice of Endocrinology and Metabolism|url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA757|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=757–759, 2168|access-date=2 February 2018|archive-date=8 March 2023|archive-url=https://web.archive.org/web/20230308182345/https://books.google.com/books?id=FVfzRvaucq8C&pg=PA757|url-status=live}}</ref><ref name="Geer-2016">{{cite book| vauthors = Geer EB |title=The Hypothalamic-Pituitary-Adrenal Axis in Health and Disease: Cushing's Syndrome and Beyond|url=https://books.google.com/books?id=Yw2kDQAAQBAJ&pg=PA28|date=1 December 2016|publisher=Springer|isbn=978-3-319-45950-9|pages=28–|access-date=2 February 2018|archive-date=8 March 2023|archive-url=https://web.archive.org/web/20230308182358/https://books.google.com/books?id=Yw2kDQAAQBAJ&pg=PA28|url-status=live}}</ref><ref name="Aschenbrenner-2009">{{cite book| vauthors = Aschenbrenner DS, Venable SJ |title=Drug Therapy in Nursing|url=https://books.google.com/books?id=5zd_W_PUwvYC&pg=PA674|year=2009|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6587-9|pages=674–|access-date=2 February 2018|archive-date=8 March 2023|archive-url=https://web.archive.org/web/20230308182357/https://books.google.com/books?id=5zd_W_PUwvYC&pg=PA674|url-status=live}}</ref> Hydroxyprogesterone caproate has been studied in humans at doses as high as 5,000&nbsp;mg per week by intramuscular injection, with [[drug safety|safety]] and without glucocorticoid effects observed.<ref name="pmid2932883" /><ref name="Varga1961">Varga A, Henriksen E. Clinical and Histopathologic Evaluation of the Effect of 17-alpha-Hydroxyprogesterone-17-n-caproate on Endometrial Carcinoma. Obstetrics & Gynecology. December 1961. Volume 18. Issue 6. pp. 658-672.</ref> The medication does interact with the [[glucocorticoid receptor]] however; it has about 4% of the affinity of [[dexamethasone]] for the rabbit glucocorticoid receptor.<ref name="pmid21888448" /><ref name="pmid18060946" /> But it acts as a [[partial agonist]] of the receptor and has no greater [[efficacy]] than progesterone in activating the receptor and eliciting associated [[gene expression]] ''[[in vitro]]''.<ref name="pmid21888448" /><ref name="pmid18060946" /><ref name="pmid19255438">{{cite journal | vauthors = Gerber AN, Masuno K, Diamond MI | title = Discovery of selective glucocorticoid receptor modulators by multiplexed reporter screening | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 12 | pages = 4929–34 | date = March 2009 | pmid = 19255438 | pmc = 2660744 | doi = 10.1073/pnas.0812308106 | bibcode = 2009PNAS..106.4929G | doi-access = free }}</ref>

====Other activities====

As a pure progestogen, hydroxyprogesterone caproate has no [[androgen]]ic, [[antiandrogen]]ic, [[estrogen (medication)|estrogen]]ic, or [[glucocorticoid]] activity.<ref name="pmid14304354" /><ref name="pmid15863556">{{cite journal | vauthors = Meis PJ | title = 17 hydroxyprogesterone for the prevention of preterm delivery | journal = Obstetrics and Gynecology | volume = 105 | issue = 5 Pt 1 | pages = 1128–35 | date = May 2005 | pmid = 15863556 | doi = 10.1097/01.AOG.0000160432.95395.8f }}</ref><ref name="pmid6371845">{{cite journal | vauthors = Bardin CW, Brown T, Isomaa VV, Jänne OA | title = Progestins can mimic, inhibit and potentiate the actions of androgens | journal = Pharmacology & Therapeutics | volume = 23 | issue = 3 | pages = 443–59 | date = 1983 | pmid = 6371845 | doi = 10.1016/0163-7258(83)90023-2 }}</ref> The absence of androgenic and antiandrogenic activity with hydroxyprogesterone caproate is in contrast to most other [[17α-hydroxyprogesterone]]-derivative progestins.<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 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf | access-date = 25 March 2018 | archive-date = 22 August 2016 | archive-url = https://web.archive.org/web/20160822055012/http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf | url-status = live }}</ref><ref name="pmid6371845" /> Due to its lack of androgenic properties, similarly to progesterone, hydroxyprogesterone caproate does not have any [[teratogen]]ic effects on the [[fetus]], making it safe for use during [[pregnancy]].<ref name="pmid15863556" /> Although hydroxyprogesterone caproate has been described as a pure progestogen, there is evidence that it possesses some [[antimineralocorticoid]] activity, similarly to progesterone and 17α-hydroxyprogesterone.<ref name="Dorfman-2016">{{cite book| vauthors = Dorfman RI |title=Steroidal Activity in Experimental Animals and Man|url=https://books.google.com/books?id=BbLfBAAAQBAJ&pg=PA398|date=5 December 2016|publisher=Elsevier Science|isbn=978-1-4832-7299-3|pages=398–|quote=Intramuscular administration of 17α-hydroxyprogesterone caproate produced signs and symptoms of adrenal insufficiency in Addisonians maintained on cortisol and 9α-fluorocortisol (Melby, 1961) and thereby showed properties similar to progesterone and 17α-hydroxyprogesterone. However, further tests will be required to eludicate its pharmacodynamics properties. Contrastingly, there was no evidence for salt dissipation with the test of a smaller dose of the steroid to normal subjects (Landau et al., 1958).|access-date=2 February 2018|archive-date=8 March 2023|archive-url=https://web.archive.org/web/20230308182407/https://books.google.com/books?id=BbLfBAAAQBAJ&pg=PA398|url-status=live}}</ref><ref name="pmid14278040"/><ref name="pmid1163210">{{cite journal | vauthors = Sammour MB, El-Kabarity H, Khalifa AS | title = Progesterone therapy in pre-eclamptic toxaemia | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 54 | issue = 3 | pages = 195–202 | year = 1975 | pmid = 1163210 | doi = 10.3109/00016347509157760 | s2cid = 38002155 | quote = Melby (14) found that when progesterone was administered to patients suffering from the syndrome of idiopathic oedema, they experienced a diuresis, with a high excretion of sodium and water within 24 hours after a single injection of 500 mg of 17-α-hydroxyprogesterone caproate. }}</ref> This includes clinically important [[diuretic]] effects and reversal of estrogen-induced [[water retention (medicine)|fluid retention]] and [[edema]].<ref name="pmid14278040" /> Unlike progesterone, hydroxyprogesterone caproate and its metabolites are not anticipated to interact with [[cell surface receptor|non-genomic receptor]]s such as [[membrane progesterone receptor]]s or the [[GABAA receptor|GABA_A receptor]].<ref name="pmid23410596" /> In accordance, hydroxyprogesterone caproate is not thought to possess the [[neurosteroid]] activities of progesterone or its associated [[sedative]] effects.<ref name="pmid23410596" />

In relation to [[cytochrome P450]] [[enzyme]]s, hydroxyprogesterone caproate has no effect on [[CYP1A]], [[CYP2D6]], [[CYP2C9]], or [[CYP3A4]], but is a modest [[enzyme inducer|inducer]] of [[CYP2C19]].<ref name="pmid25256193" />

====Differences from progesterone====

There are [[pharmacodynamics|pharmacodynamic]] differences between progesterone and hydroxyprogesterone caproate, which may have implications for [[obstetrics|obstetrical]] use.<ref name="pmid23643669">{{cite journal | vauthors = Romero R, Stanczyk FZ | title = Progesterone is not the same as 17α-hydroxyprogesterone caproate: implications for obstetrical practice | journal = American Journal of Obstetrics and Gynecology | volume = 208 | issue = 6 | pages = 421–6 | date = June 2013 | pmid = 23643669 | pmc = 4120746 | doi = 10.1016/j.ajog.2013.04.027 }}</ref><ref name="pmid23410596">{{cite journal | vauthors = Byrns MC | title = Regulation of progesterone signaling during pregnancy: implications for the use of progestins for the prevention of preterm birth | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 139 | pages = 173–81 | date = January 2014 | pmid = 23410596 | doi = 10.1016/j.jsbmb.2013.01.015 | s2cid = 23414730 }}</ref> These include:<ref name="pmid23643669" /><ref name="pmid23410596" />

* Decreased [[myometrium|myometrial]] activity with progesterone ''[[in vitro]]'' but no effect or increased myometrial activity with hydroxyprogesterone caproate<ref name="pmid19602723">{{cite journal | vauthors = Anderson L, Martin W, Higgins C, Nelson SM, Norman JE | title = The effect of progesterone on myometrial contractility, potassium channels, and tocolytic efficacy | journal = Reproductive Sciences | volume = 16 | issue = 11 | pages = 1052–61 | date = November 2009 | pmid = 19602723 | doi = 10.1177/1933719109340926 | s2cid = 6856556 }}</ref>

* Prevention of [[cervical ripening]] with progesterone but unknown effect with hydroxyprogesterone caproate

* A non-significantly increased rate of [[stillbirth]] and [[miscarriage]]s with hydroxyprogesterone caproate (in one study)

* A possibly increased incidence of [[gestational diabetes]] with hydroxyprogesterone caproate (increased in two studies, no difference in one study) but no such effect with progesterone

* A significantly increased risk of [[wikt:perinatal|perinatal]] adverse effects such as [[stillbirth|fetal loss]] and [[preterm birth|preterm delivery]] in [[multiple birth|multiple gestations]] with hydroxyprogesterone caproate (in two studies)

Differences in the [[metabolism]] of progesterone and hydroxyprogesterone caproate and differences in the formation and activities of [[metabolite]]s may be responsible for or involved in these observed biological and pharmacological differences.<ref name="pmid23410596" /> Progesterone is metabolized by [[5α-reductase|5α-]] and [[5β-reductase]]s, [[3α-hydroxysteroid dehydrogenase|3α-]] and [[3β-hydroxysteroid dehydrogenase]]s, and [[20α-hydroxysteroid dehydrogenase|20α-]] and [[20β-hydroxysteroid dehydrogenase]] in various [[tissue (biology)|tissue]]s.<ref name="pmid23410596" /><ref name="Cupps-1991">{{cite book| vauthors = Cupps PT |title=Reproduction in Domestic Animals|url=https://books.google.com/books?id=bbb-ow0N7K4C&pg=PA101|date=20 February 1991|publisher=Elsevier|isbn=978-0-08-057109-6|pages=101–}}</ref> In target tissues, particularly the [[cervix]] and myometrium, these enzymes regulate local progesterone concentrations and can activate or inactivate progesterone signaling.<ref name="pmid23410596" /> In addition, these enzymes catalyze the formation of metabolites of progesterone such as [[5β-dihydroprogesterone]] and [[allopregnanolone]], which signal through their own [[cell surface receptor|non-genomic receptor]]s such as [[membrane progesterone receptor]]s and the [[GABAA receptor|GABA_A receptor]] and have their own important effects in pregnancy.<ref name="pmid19602723" /><ref name="pmid18936037">{{cite journal | vauthors = Gellersen B, Fernandes MS, Brosens JJ | title = Non-genomic progesterone actions in female reproduction | journal = Human Reproduction Update | volume = 15 | issue = 1 | pages = 119–38 | year = 2009 | pmid = 18936037 | doi = 10.1093/humupd/dmn044 | doi-access = free }}</ref><ref name="pmid24172649">{{cite journal | vauthors = Schumacher M, Mattern C, Ghoumari A, Oudinet JP, Liere P, Labombarda F, Sitruk-Ware R, De Nicola AF, Guennoun R | title = Revisiting the roles of progesterone and allopregnanolone in the nervous system: resurgence of the progesterone receptors | journal = Progress in Neurobiology | volume = 113 | pages = 6–39 | date = February 2014 | pmid = 24172649 | doi = 10.1016/j.pneurobio.2013.09.004 | hdl = 11336/6678 | s2cid = 207407117 | hdl-access = free }}</ref> As examples, 5β-dihydroprogesterone has been found to play an important role in suppressing myometrial activity while allopregnanolone has potent [[sedation|sedative]] and [[anesthetic]] effects in the mother and especially the [[fetus]] and is involved in [[development of the nervous system in humans|fetal nervous system development]].<ref name="pmid23410596" /><ref name="pmid18936037" /><ref name="pmid24172649" /><ref name="pmid16269314">{{cite journal | vauthors = Mellor DJ, Diesch TJ, Gunn AJ, Bennet L | title = The importance of 'awareness' for understanding fetal pain | journal = Brain Research. Brain Research Reviews | volume = 49 | issue = 3 | pages = 455–71 | date = November 2005 | pmid = 16269314 | doi = 10.1016/j.brainresrev.2005.01.006 | s2cid = 9833426 }}</ref><ref name="pmid19092726">{{cite journal | vauthors = Lagercrantz H, Changeux JP | title = The emergence of human consciousness: from fetal to neonatal life | journal = Pediatric Research | volume = 65 | issue = 3 | pages = 255–60 | date = March 2009 | pmid = 19092726 | doi = 10.1203/PDR.0b013e3181973b0d | s2cid = 39391626 | quote = [...] the fetus is sedated by the low oxygen tension of the fetal blood and the neurosteroid anesthetics pregnanolone and the sleep-inducing prostaglandin D2 provided by the placenta (36). | url = https://philpapers.org/rec/LAGTEO-5 | doi-access = free | access-date = 18 August 2019 | archive-date = 15 October 2021 | archive-url = https://web.archive.org/web/20211015090548/https://philpapers.org/rec/LAGTEO-5 | url-status = live }}</ref> In contrast to progesterone, hydroxyprogesterone caproate is not metabolized by traditional [[steroidogenic enzyme|steroid-transforming enzyme]]s and instead is metabolized exclusively via [[oxidation]] at the [[caproate]] [[side chain]] by [[cytochrome P450]] enzymes.<ref name="pmid23410596" /> As such, it is not thought to have the same tissue-specific activation and inactivation patterns that progesterone does nor the same non-genomic actions that progesterone and its metabolites possess.<ref name="pmid23410596" />

Further clinical research is anticipated to provide additional data to help clarify the issue of safety with hydroxyprogesterone caproate.<ref name="pmid23643669" /> In any case, it has been recommended by the [[American College of Obstetricians and Gynecologists]] that pregnant women treated with hydroxyprogesterone caproate receive counseling about its risks and benefits.<ref name="pmid23643669" />

===Pharmacokinetics===

{| class="wikitable floatright"

|+ Pharmacokinetics of OHPC^a in pregnant women

|-

! Parameter !! Singleton !! Twin

|-

| [[Cmax (pharmacology)|{{abbr|C_max|Peak levels}}]] (ng/mL) || 22.6 (15.8–27.4) || 17.3 (12–27)

|-

| [[Cmean (pharmacology)|{{abbr|C_mean(0–t)|Mean levels}}]] (ng/mL) || 16.8 (12.8–22.7) || 12.3 (8.4–18.7)

|-

| [[Ctrough (pharmacology)|{{abbr|C_trough|Trough levels}}]] (ng/mL) || 14.1 (10–18.1) || 11.2 (4.8–16.3)

|-

| [[Area under the curve (pharmacokinetics)|{{abbr|AUC_0–t|Area-under-the-curve levels (total exposure)}}]] (ng/mL/day) || 117.3 (89.9–159.1) || 86.1 (59–131)

|-

| [[Elimination half-life|{{abbr|t_1/2|Elimination half-life}}]] (days) || 16.2 (10.6–21.0) || 10 (6–16)

|-

| [[Tmax (pharmacology)|{{abbr|T_max|Time to peak levels}}]] (days) || 1.0 (1–3) || 1.2 (1–2)

|-

| [[Volume of distribution|{{abbr|V_d/F|Volume of distribution}}]] (×10³) (L) || 56 (25.2–69.6) || 16.9 (9.1–24.5)

|-

| [[Clearance (pharmacology)|{{abbr|Cl/F|Clearance}}]] (×10³) (L) || 2.1 (1.5–2.7) || 1.2 (0.9–1.7)

|- class="sortbottom"

| colspan="3" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Footnotes:''' ^a = OHPC 250&nbsp;mg once per week by intramuscular injection. '''Sources:''' <ref name="pmid25256193" /><ref name="pmid22967833">{{cite journal | vauthors = Caritis SN, Sharma S, Venkataramanan R, Hankins GD, Miodovnik M, Hebert MF, Umans JG, Benedetti T, Mattison D, Zajicek A, Fischer D, Jackson A | title = Pharmacology and placental transport of 17-hydroxyprogesterone caproate in singleton gestation | journal = American Journal of Obstetrics and Gynecology | volume = 207 | issue = 5 | pages = 398.e1–8 | date = November 2012 | pmid = 22967833 | pmc = 3586341 | doi = 10.1016/j.ajog.2012.08.015 }}</ref><ref name="pmid21620357">{{cite journal | vauthors = Caritis SN, Sharma S, Venkataramanan R, Rouse DJ, Peaceman AM, Sciscione A, Spong CY, Varner MW, Malone FD, Iams JD, Mercer BM, Thorp JM, Sorokin Y, Carpenter M, Lo J, Ramin S, Harper M | title = Pharmacokinetics of 17-hydroxyprogesterone caproate in multifetal gestation | journal = American Journal of Obstetrics and Gynecology | volume = 205 | issue = 1 | pages = 40.e1–8 | date = July 2011 | pmid = 21620357 | pmc = 3165062 | doi = 10.1016/j.ajog.2011.03.028 }}</ref>

|}

====Absorption====

In animals, the [[bioavailability]] of hydroxyprogesterone caproate with intramuscular injection is nearly 100%, but its [[oral administration|oral]] bioavailability is very low at less than 3%.<ref name="pmid26153441">{{cite journal | vauthors = Shaik IH, Bastian JR, Zhao Y, Caritis SN, Venkataramanan R | title = Route of administration and formulation dependent pharmacokinetics of 17-hydroxyprogesterone caproate in rats | journal = Xenobiotica; the Fate of Foreign Compounds in Biological Systems | volume = 46 | issue = 2 | pages = 169–74 | year = 2015 | pmid = 26153441 | pmc = 4809632 | doi = 10.3109/00498254.2015.1057547 }}</ref> In women, 70&nbsp;mg/day oral hydroxyprogesterone caproate has similar endometrial potency as 70&nbsp;mg/day oral OHPA and 2.5&nbsp;mg/day oral [[medroxyprogesterone acetate]], indicating that oral hydroxyprogesterone caproate and OHPA have almost 30-fold lower potency than medroxyprogesterone acetate via oral administration.<ref name="Ferin-1972-Orally-Active">{{cite book | vauthors = Ferin J | chapter = Orally Active Progestational Compounds. Human Studies: Effects on the Utero-Vaginal Tract | pages = 245–273 <!-- Table on page 259 --> | veditors = Tausk M | title = Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents | volume = II | chapter-url = https://books.google.com/books?id=Nv5sAAAAMAAJ | date = September 1972 | publisher = Pergamon Press | isbn = 978-0080168128 | oclc = 278011135}}</ref> Studies on progestogenic [[endometrium|endometrial]] changes with oral hydroxyprogesterone caproate in women are mixed however, with one finding weak effects with 100&nbsp;mg/day whereas another found that doses of 250 to 1,000&nbsp;mg produced no effects.<ref name="pmid13583829">{{cite journal | vauthors = Boschann HW | title = Observations of the role of progestational agents in human gynecologic disorders and pregnancy complications | journal = Ann. N. Y. Acad. Sci. | volume = 71 | issue = 5 | pages = 727–52 | date = July 1958 | pmid = 13583829 | doi = 10.1111/j.1749-6632.1958.tb46803.x | doi-broken-date = 1 July 2024 | bibcode = 1958NYASA..71..727B }}</ref><ref name="pmid13443471">{{cite journal | vauthors = Pots P | title = Die perorale wirksamkeit synthetischer gestagene | trans-title = The effectiveness of peroral synthetic gestagens | language = de | journal = Zentralbl Gynakol | volume = 79 | issue = 14 | pages = 529–39 | date = April 1957 | pmid = 13443471 }}</ref> As a result of its low oral potency, hydroxyprogesterone caproate has not been used by the oral route and has instead been administered by intramuscular injection.<ref name="pmid26153441" /> However, a novel oral formulation of hydroxyprogesterone caproate (developmental code name LPCN-1107) is under development and has been found to be effective, though it required administration twice a day in a clinical study.<ref name="AdisInsight">{{Cite web | url=https://adisinsight.springer.com/drugs/800038483 | title=Hydroxyprogesterone caproate oral - Lipocine - AdisInsight | access-date=24 February 2019 | archive-date=1 November 2017 | archive-url=https://web.archive.org/web/20171101140919/http://adisinsight.springer.com/drugs/800038483 | url-status=live }}</ref><ref name="DelConte-2015">{{cite journal| vauthors = DelConte A, Chidambaram N, Nachaegari S, Patel M, Venkateshwaran S | title = 770: Pharmacokinetics and tolerability of oral 17-hydroxyprogesterone caproate (HPC) relative to intramuscular (IM) HPC. | journal = American Journal of Obstetrics & Gynecology | date = January 2015 | volume = 212 | issue = 1 | pages = S374 | doi = 10.1016/j.ajog.2014.10.976 }}</ref><ref name="pmid29765789">{{cite journal | vauthors = Boggess KA, Baker JB, Murtha AP, Peaceman AM, Shah DM, Siegfried SL, Birch R | title = Pharmacokinetics of Hydroxyprogesterone Caproate and its Primary Metabolites during Pregnancy | journal = AJP Reports | volume = 8 | issue = 2 | pages = e106–e112 | date = April 2018 | pmid = 29765789 | pmc = 5951785 | doi = 10.1055/s-0038-1639331 }}</ref>

A [[depot effect]] occurs when hydroxyprogesterone caproate is injected intramuscularly or [[subcutaneous injection|subcutaneously]], such that the medication has a prolonged [[duration of action]].<ref name="pmid29191450" /><ref name="pmid25256193" /> Following a single intramuscular injection of 1,000&nbsp;mg hydroxyprogesterone caproate in five women with [[endometrial cancer]], peak levels of hydroxyprogesterone caproate were 27.8 ± 5.3&nbsp;ng/mL and the [[Tmax (pharmacology)|time to peak concentrations]] was 4.6 ± 1.7 (3–7)&nbsp;days.<ref name="pmid2932883" /><ref name="MakenaLabel2011">{{cite web | title = Highlight of Prescribing Information: MAKENATM (hydroxyprogesterone caproate injection) for intramuscular use. | date = February 2011 | publisher = U.S. Food and Drug Administration | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021945s000lbl.pdf | archive-url = https://web.archive.org/web/20170227232340/http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021945s000lbl.pdf | archive-date=27 February 2017 }}</ref> Following 13&nbsp;weeks of continuous administration of 1,000&nbsp;mg hydroxyprogesterone caproate per week, [[Ctrough (pharmacokinetics)|trough levels]] of hydroxyprogesterone caproate were 60.0 ± 14&nbsp;ng/mL.<ref name="pmid2932883" /><ref name="MakenaLabel2011" /> The [[pharmacokinetic]] parameters of 250&nbsp;mg hydroxyprogesterone caproate once per week by intramuscular injection have also been studied in pregnant women with singleton and multiple (twin and triplet) gestation.<ref name="pmid25256193" /><ref name="pmid22967833" /><ref name="pmid21620357" /> [[Steady state (pharmacokinetics)|Steady state level]]s of the medication are achieved within 4 to 12&nbsp;weeks of administration in pregnant women.<ref name="pmid21888448" /> The duration of clinical [[biological effect]] of hydroxyprogesterone caproate by intramuscular injection has also been studied in women.<ref name="Ferin-1972-Effects-Duration">{{cite book | vauthors = Ferin J | chapter = Effects, Duration of Action and Metabolism in Man | pages = 13–24 <!-- Tables on pages 17–19 --> | veditors = Tausk M | title = Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents | volume = II | chapter-url = https://books.google.com/books?id=Nv5sAAAAMAAJ | date = September 1972 | publisher = Pergamon Press | isbn = 978-0080168128 | oclc = 278011135}}</ref> A single intramuscular injection of 65 to 500&nbsp;mg hydroxyprogesterone caproate in oil solution has been found to have a [[duration of action]] of 5 to 21&nbsp;days in terms of effect in the [[uterus]] and on [[body temperature]] in women.<ref name="Ferin-1972-Effects-Duration" />

Hydroxyprogesterone caproate has been found to possess similar pharmacokinetics, including [[Cmax (pharmacology)|peak levels]], [[Tmax (pharmacology)|time to peak levels]], [[area under the curve (pharmacokinetics)|area-under-the-curve levels]] (i.e., total exposure), and [[elimination half-life]], with administration via intramuscular injection or [[subcutaneous injection|subcutaneous]] [[autoinjector|autoinjection]].<ref name="pmid29191450">{{cite journal | vauthors = Krop J, Kramer WG | title = Comparative Bioavailability of Hydroxyprogesterone Caproate Administered via Intramuscular Injection or Subcutaneous Autoinjector in Healthy Postmenopausal Women: A Randomized, Parallel Group, Open-label Study | journal = Clinical Therapeutics | volume = 39 | issue = 12 | pages = 2345–2354 | date = December 2017 | pmid = 29191450 | doi = 10.1016/j.clinthera.2017.10.020 | doi-access = free }}</ref> However, there was a higher incidence of [[injection site pain]] with subcutaneous autoinjection than with intramuscular injection (37.3% vs. 8.2%).<ref name="pmid29191450" />

====Distribution====

Hydroxyprogesterone caproate is extensively [[plasma protein binding|bound to plasma proteins]], of which include [[human serum albumin|albumin]].<ref name="pmid21888448" /> Unlike progesterone and [[17α-hydroxyprogesterone]], hydroxyprogesterone caproate has very low [[affinity (pharmacology)|affinity]] for [[corticosteroid-binding globulin]] (less than 0.01% of that of [[cortisol]]).<ref name="pmid7306509">{{cite journal | vauthors = Mickelson KE, Forsthoefel J, Westphal U | title = Steroid-protein interactions. Human corticosteroid binding globulin: some physicochemical properties and binding specificity | journal = Biochemistry | volume = 20 | issue = 21 | pages = 6211–8 | date = October 1981 | pmid = 7306509 | doi = 10.1021/bi00524a047 }}</ref> Progesterone and 17α-hydroxyprogesterone have low affinity for [[sex hormone-binding globulin]], and for this reason, only a very small fraction of them (less than 0.5%) is bound to this protein in the circulation.<ref name="pmid7195404">{{cite journal | vauthors = Dunn JF, Nisula BC, Rodbard D | title = Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 53 | issue = 1 | pages = 58–68 | date = July 1981 | pmid = 7195404 | doi = 10.1210/jcem-53-1-58 }}</ref>

====Metabolism====

Hydroxyprogesterone caproate appears to be [[metabolism|metabolized]] primarily by the [[cytochrome P450]] [[enzyme]]s [[CYP3A4]] and [[CYP3A5]].<ref name="pmid21888448" /> It may also be metabolized by [[CYP3A7]] in [[fetus|fetal]] [[liver]] and the [[placenta]].<ref name="pmid21888448" /> Unlike progesterone, hydroxyprogesterone caproate is not metabolized by traditional [[steroidogenic enzyme|steroid-transforming enzyme]]s and does not form similar [[metabolite]]s.<ref name="pmid23410596" /> The metabolism of hydroxyprogesterone caproate is by [[redox|reduction]], [[hydroxylation]], and [[conjugation (biochemistry)|conjugation]], including [[glucuronidation]], [[sulfation]], and [[acetylation]].<ref name="pmid23410596" /> The [[caproate]] [[ester]] of hydroxyprogesterone caproate is not cleaved during [[metabolism]], so [[17α-hydroxyprogesterone]] is not formed from hydroxyprogesterone caproate.<ref name="pmid23410596" /><ref name="pmid18060946">{{cite journal | vauthors = Attardi BJ, Zeleznik A, Simhan H, Chiao JP, Mattison DR, Caritis SN | title = Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17-alpha hydroxyprogesterone caproate, and related progestins | journal = American Journal of Obstetrics and Gynecology | volume = 197 | issue = 6 | pages = 599.e1–7 | date = December 2007 | pmid = 18060946 | pmc = 2278032 | doi = 10.1016/j.ajog.2007.05.024 }}</ref> As such, hydroxyprogesterone caproate is not a [[prodrug]] of 17α-hydroxyprogesterone, nor of [[progesterone (medication)|progesterone]].<ref name="pmid23410596" /><ref name="pmid18060946" />

Hydroxyprogesterone caproate has been found to have an [[elimination half-life]] of 7.8&nbsp;days when given by [[intramuscular injection]] in an oil-based formulation to non-pregnant women.<ref name="pmid2932883" /><ref name="pmid23413110" /> Its total duration is said to be 10 to 14&nbsp;days, which is much longer than the duration of intramuscularly administered progesterone in an oil formulation (2 to 3&nbsp;days).<ref name="pmid13598928" /> In pregnant women, the elimination half-life of hydroxyprogesterone caproate appears to be longer, about 16 or 17&nbsp;days.<ref name="pmid21888448" /><ref name="pmid25256193">{{cite journal | vauthors = Feghali M, Venkataramanan R, Caritis S | title = Prevention of preterm delivery with 17-hydroxyprogesterone caproate: pharmacologic considerations | journal = Seminars in Perinatology | volume = 38 | issue = 8 | pages = 516–22 | date = December 2014 | pmid = 25256193 | pmc = 4253874 | doi = 10.1053/j.semperi.2014.08.013 }}</ref> However, in women pregnant with twins rather than a singlet, the elimination half-life of hydroxyprogesterone caproate was found to be shorter than this, at 10&nbsp;days.<ref name="pmid25256193" /> Hydroxyprogesterone caproate has been detected in pregnant women up to 44&nbsp;days after the last dose.<ref name="pmid25256193" />

====Elimination====

Hydroxyprogesterone caproate is [[elimination (pharmacology)|eliminated]] 50% in [[feces]] and 30% in [[urine]] when given by intramuscular injection to pregnant women.<ref name="pmid21888448" /> Both the free steroid and conjugates are [[excretion|excreted]] by these routes, with the conjugates more prominent in feces.<ref name="pmid21888448" />

====Time–concentration curves====

{{Gallery

| title=Hormone levels with hydroxyprogesterone caproate

| width=470 | height=280

| align=center

| style="font-size:small;"

| File:Hydroxyprogesterone caproate levels after a single intramuscular injection of 1,000 mg hydroxyprogesterone caproate in women.png | OHPC levels after a single intramuscular injection of 1,000&nbsp;mg OHPC in five women with endometrial cancer.<ref name="pmid2932883"/>

| File:Hydroxyprogesterone caproate levels after a final dose following continuous therapy with 250 mg per week by intramuscular injection in pregnant women.png | OHPC levels over the course of a month after a final dose following continuous therapy with 250&nbsp;mg per week OHPC by intramuscular injection in pregnant women with singleton gestation.<ref name="pmid22967833"/>

}}

==Chemistry==

{{See also|List of progestogens|Progestogen ester|List of progestogen esters}}

Hydroxyprogesterone caproate, also known as 17α-hydroxyprogesterone caproate or as 17α-hydroxypregn-4-ene-3,20-dione 17α-hexanoate, is a [[synthetic compound|synthetic]] [[pregnane]] [[steroid]] and a [[chemical derivative|derivative]] of [[progesterone]].<ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA532|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=532–}}</ref><ref name="Elks-2014">{{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=PA664|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=664–}}</ref> It is specifically a derivative of [[17α-hydroxyprogesterone]] with a [[hexanoate]] (caproate) [[ester]] at the C17α position.<ref name="IndexNominum2000" /><ref name="Elks-2014" /> [[Structural analogue|Analogue]]s of hydroxyprogesterone caproate include other 17α-hydroxyprogesterone derivatives such as [[algestone acetophenide]] (dihydroxyprogesterone acetophenide), [[chlormadinone acetate]], [[cyproterone acetate]], [[hydroxyprogesterone acetate]], [[hydroxyprogesterone heptanoate]], [[medroxyprogesterone acetate]], and [[megestrol acetate]], as well as the [[caproate]] esters [[chlormadinone caproate]], [[gestonorone caproate]] (norhydroxyprogesterone caproate), [[medroxyprogesterone caproate]], [[megestrol caproate]], and [[methenmadinone caproate]].<ref name="IndexNominum2000" /><ref name="Elks-2014" />

===Synthesis===

[[Chemical synthesis|Chemical syntheses]] of hydroxyprogesterone caproate have been described.<ref name="Engel-2014">{{cite book | vauthors = Engel J, Kleemann A, Kutscher B, Reichert D | title = Pharmaceutical Substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs | url = https://books.google.com/books?id=4lCGAwAAQBAJ&pg=PA677 | date = 14 May 2014 | publisher = Thieme | isbn = 978-3-13-179275-4 | pages = 677–679 | access-date = 6 September 2018 | archive-date = 8 March 2023 | archive-url = https://web.archive.org/web/20230308182347/https://books.google.com/books?id=4lCGAwAAQBAJ&pg=PA677 | url-status = live }}</ref><ref name="Elsevier-2013-Pharmaceutical Manufacturing Encyclopedia">{{cite book |author=William Andrew Publishing |title=Pharmaceutical Manufacturing Encyclopedia |url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1865 |date=22 October 2013 |publisher=Elsevier |isbn=978-0-8155-1856-3 |pages=1865–1866 |access-date=6 September 2018 |archive-date=8 March 2023 |archive-url=https://web.archive.org/web/20230308182939/https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1865 |url-status=live }}</ref><ref name="Junkmann-1968">{{cite book | vauthors = Junkmann K, Langecker H, Damrosch L | chapter = Chemie der Gestagene | trans-chapter = Chemistry of Progestogens | pages = 1–44 | doi = 10.1007/978-3-642-99941-3_1 | title = Die Gestagene | series = Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology | trans-title = Progestogens | year = 1968 | publisher = Springer-Verlag | isbn = 978-3-642-99941-3 | url = https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA1045 | quote = 3. Hydroxyprogesteron-caproat. C27H4004, Mol.-Gew.: 428,62; chemische Bezeichnung Δ4-Pregnen-17α-ol-3,20-dion-17α-capronat, Trivialnamen: Hydroxyprogesteroncapronat, 17α-Hydroxyprogesteron-17α-capronat. Synthese: [88]. Darstellung: [88]. Eigenschaften: weißes kristallines Pulver (aus Isopropyläther) oder Methanol, F.: 119-122⁰, [α]D: +60⁰ (Chlf.) UV-Absorption: λmax.: 240 mμ, ε = 17000. Dipolmoment: [μ = 2,21 (Benzol). Leicht löslich in Äthanol, Äther, Essigester, Benzol, Chloroform, löslich in: Petroläther, unlöslich in Wasser. Bei 20⁰ lösen 100 ml Sesamöl ca. 4,0 g, Ricinusöl ca. 2,5 g, Ricinusöl: Benzylbenzoat (4: 6) ca. 26,5 g, Benzylbenzoat ca. 36,0 g. [...] Abb. 3. IR-Spektrum [126] und Formel des Hydroxyprogesteron-caproat. | access-date = 15 September 2018 | archive-date = 8 March 2023 | archive-url = https://web.archive.org/web/20230308182357/https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA1045 | url-status = live }}</ref>{{Rp|6}}

==History==

Along with [[hydroxyprogesterone acetate]], hydroxyprogesterone caproate was developed by Karl Junkmann of [[Schering AG]] in 1953 and was first reported by him in the [[medical literature]] in 1954.<ref name="Junkmann-1954">{{cite journal| vauthors = Junkmann K |title=Über protrahiert wirksame Gestagene|journal=Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie|volume=223|issue=3|year=1954 |doi=10.1007/BF00246995|s2cid=33591186 }}</ref><ref name="pmid13583817">{{cite journal | vauthors = Wied GL, Davis ME | title = Comparative activity of progestational agents on the human endometrium and vaginal epithelium of surgical castrates | journal = Annals of the New York Academy of Sciences | volume = 71 | issue = 5 | pages = 599–616 | date = July 1958 | pmid = 13583817 | doi = 10.1111/j.1749-6632.1958.tb46791.x | doi-broken-date = 1 July 2024 | quote = In the group of new parenteral progestational agents, three substances developed by Karl Junkmann1,2 are the most outstanding and interesting: 17a-hydroxyprogesterone caproate and 17a-hydroxyprogesterone acetate, introduced in 1953, and the most potent of all new parenteral progestational agents, 17-ethynyl-19-nortestosterone enanthate, introduced in 1956. | bibcode = 1958NYASA..71..599W }}</ref><ref name="ACRH1960">{{cite book|title=ACRH|url=https://books.google.com/books?id=HQVYAAAAYAAJ|year=1960|publisher=U.S. Dept. of Energy|page=71|quote=[The] minimal activity [of 17(a)-hydroxyprogesterone] is magnified to an unexpected degree by the esterification of this steroid with caproic acid to produce 17(a)-hydroxyprogesterone-17-n-caproate, first reported by Karl Junkmann in 1954.6,7}}</ref><ref name="Dorfman-1966">{{cite book| vauthors = Dorfman RI |title=Methods in Hormone Research|url=https://books.google.com/books?id=mQVHAAAAYAAJ|year=1966|publisher=Academic Press|page=86|quote=Junkmann (1954) reported that the acetate, butyrate, and caproate forms had both increased and prolonged activity, [...]}}</ref><ref name="Applezweig-1962">{{cite book| vauthors = Applezweig N |title=Steroid Drugs|url=https://books.google.com/books?id=SIhLAAAAYAAJ|year=1962|publisher=Blakiston Division, McGraw-Hill|pages=101–102|quote=Junkmann of Schering, AG., however, was able to show that long chain esters of 17a-hydroxyprogesterones such as the 17a-caproate produced powerful long-acting progestational effect. This compound is marketed in the United States as Delalutin by Squibb, and has been heavily used for the treatment of habitual abortion.}}</ref> It was reportedly first marketed in [[Japan]] in 1954 or 1955,<ref name="Cancer1979">{{cite book|author=International Agency for Research on Cancer|title=Sex Hormones (II).|url=https://books.google.com/books?id=nrhrAAAAMAAJ|year=1979|publisher=International Agency for Research on Cancer|isbn=978-92-832-1221-8|page=401|quote=17α-Hydroxyprogesterone caproate was first marketed commercially in Japan in 1954-1955.}}</ref> and was subsequently introduced as Delalutin in the United States in 1956.<ref name="pmid25256193" /><ref name="Lippincott-1958">{{cite book|title=New and Nonofficial Drugs|url=https://books.google.com/books?id=eY4wAAAAIAAJ|year=1958|publisher=Lippincott|page=662|quote=Supplied by.—E. R. Squibb & Sons (Delalutin). Year of introduction: 1956.}}</ref> Due to its much longer duration than parenteral progesterone, hydroxyprogesterone caproate had largely replaced progesterone in clinical practice by 1975.<ref name="Tausk-1975">{{cite book| vauthors = Tausk M |title=Pharmacology of hormones|url=https://books.google.com/books?id=9WhNAQAAIAAJ|year=1975|publisher=Thieme|isbn=978-3-13-518901-7|page=105|quote=Progesterone itself is now almost never used for the management of any imminent threat to pregnancy. For oral therapy, it is in any event unsuitable and for injections, it has now been replaced by the long-acting esters of 17α-hydroxyprogesterone. The caproate (Proluton, Delalutin), a long-acting ester, is available in [...] Progesterone is rarely used therapeutically. It has largely been superseded by a long-acting ester of 17α-hydroxyprogesterone, for parenteral therapy.}}</ref> After decades of use, [[Bristol-Myers Squibb|Squibb]], the manufacturer, voluntarily withdrew the Delalutin product in the United States in 1999.<ref name="Heinonline" /> Renewed interest in hydroxyprogesterone caproate in the United States was sparked with a large NIH-sponsored study in 2003 that found that hydroxyprogesterone caproate reduced the risk of premature birth in selected at-risk pregnant women.<ref name="pmid12802023" /> With follow-up data showing no evidence of harmful effects on the offspring, the FDA approved the medication Makena, sponsored by [[KV Pharmaceutical]], as an [[orphan drug]] in February 2011 to reduce the risk of premature birth in women prior to 37 weeks gestation with a single fetus who had at least one previous premature birth.<ref name="pmid21410391" /><ref name="FDA-press release regarding Makena approva">{{Cite web |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm242234.htm |title=FDA press release regarding Makena approval |website=[[Food and Drug Administration]] |access-date=16 December 2019 |archive-date=18 January 2017 |archive-url=https://web.archive.org/web/20170118093045/http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm242234.htm |url-status=live }}</ref>

Under the FDA Accelerated Approval Programs, drugs that fill an unmet need for serious conditions can be approved based on a surrogate endpoint. The pharmaceutical company is required to conduct confirmatory studies to show the drug provides a clinical benefit.<ref name="FDA-Accelerated Approval Program">{{Cite web |url= https://www.fda.gov/drugs/nda-and-bla-approvals/accelerated-approval-program |title= Accelerated Approval Program |website= [[Food and Drug Administration]] |date= 30 January 2023 |access-date= 14 March 2023 |url-status= live |archive-date= 13 March 2023 |archive-url= https://web.archive.org/web/20230313171707/https://www.fda.gov/drugs/nda-and-bla-approvals/accelerated-approval-program }}</ref> The confirmatory trial, the PROLONG study, was completed in 2019 and showed no benefit in preventing preterm birth.<ref name="pmid31652479">{{cite journal | vauthors = Blackwell, SC, et al | title = 17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial | journal = American Journal of Perinatology | volume = 37 | issue = 2 | pages = 127–136 | date = January 2020| pmid = 31652479 | doi = 10.1055/s-0039-3400227 | s2cid = 204908640 | doi-access = free }}</ref> The FDA proposed withdrawal of approval for Makena in 2020. <ref name="FDA-CDER proposes withdrawal of approval for Makena">{{Cite web |url= https://www.fda.gov/drugs/drug-safety-and-availability/cder-proposes-withdrawal-approval-makena |title= CDER proposes withdrawal of approval for Makena |website= [[Food and Drug Administration]] |date= 5 October 2020 |access-date= 14 March 2023 |url-status= live |archive-date= 7 April 2023 |archive-url= https://web.archive.org/web/20230407220250/https://www.fda.gov/drugs/drug-safety-and-availability/cder-proposes-withdrawal-approval-makena }}</ref>

==Society and culture==

=== Names ===

Hydroxyprogesterone caproate is the [[generic term|generic name]] of OHPC and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|BANM|British Approved Name}}, and {{abbrlink|JAN|Japanese Accepted Name}}, while hydroxyprogesterone hexanoate was its former {{abbrlink|BANM|British Approved Name}}.<ref name="IndexNominum2000" /><ref name="Drugs.com-Hydroxyprogesterone">{{Cite web | url=https://www.drugs.com/international/hydroxyprogesterone.html | title=Hydroxyprogesterone | access-date=29 July 2017 | archive-date=29 July 2017 | archive-url=https://web.archive.org/web/20170729131704/https://www.drugs.com/international/hydroxyprogesterone.html | url-status=live }}</ref><ref name="Elks-2014" />

Hydroxyprogesterone caproate is often mislabeled as and confused with [[progesterone (medication)|progesterone]] and [[17α-hydroxyprogesterone]].<ref name="pmid23495199">{{cite journal | vauthors = O'Brien JM | title = Medication safety is still an issue in obstetrics 50 years after the Kefauver-Harris amendments: the case of progestogens | journal = Ultrasound in Obstetrics & Gynecology | volume = 42 | issue = 3 | pages = 247–53 | date = September 2013 | pmid = 23495199 | doi = 10.1002/uog.12456 | s2cid = 45600479 | doi-access = free }}</ref> It should also not be confused with [[hydroxyprogesterone acetate]], [[hydroxyprogesterone heptanoate]], or [[medroxyprogesterone acetate]].<ref name="Elks-2014" />

Hydroxyprogesterone caproate is marketed throughout the world under a variety of brand names including Proluton, Proluton Depot, and Makena, among many others.<ref name="IndexNominum2000" /><ref name="Drugs.com-Hydroxyprogesterone" /><ref name="Elks-2014" /> It was also formerly marketed under brand names including Delalutin, Prodrox, and Hylutin among others, but these formulations have been discontinued.<ref name="IndexNominum2000" /><ref name="Elks-2014" /> It has been marketed under the brand names Gravibinon and Injectable No. 1 (or Chinese Injectable No. 1) in combination with [[estradiol valerate]]<ref name="Muller-1998" /><ref name="pmid8013219" /><ref name="pmid8013220" /><ref name="Bagade-2014" /> and under the brand name Primosiston in combination with [[estradiol benzoate]].<ref name="Leidenberger-2013" /><ref name="Knörr-2013-Lehrbuch der Gynäkologie" /><ref name="Kahr-2013" /><ref name="Kern-2013" /><ref name="Ufer-1968" />

===Availability===

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

[[File:Hydroxyprogesterone caproate availability.png|thumb|right|400px|Known availability of hydroxyprogesterone caproate in countries throughout the world (as of August 2018). Alone is hydroxyprogesterone caproate as a standalone medication. With E2 is in combination with an [[estradiol ester]]. Discontinued is no longer available.]]

Hydroxyprogesterone caproate is marketed in the United States and throughout Europe, Asia, and Central and South America.<ref name="IndexNominum2000" /><ref name="Drugs.com-Hydroxyprogesterone" /><ref name="Martindale">{{cite book | veditors = Sweetman SC |chapter=Sex hormones and their modulators |title=Martindale: The Complete Drug Reference |edition=36th |year=2009 |pages=2110–2111 |publisher=Pharmaceutical Press |location=London|isbn=978-0-85369-840-1}}</ref> It is not available in Canada, the United Kingdom, New Zealand, or South Africa, and only veterinary formulations are available in Australia.<ref name="IndexNominum2000" /><ref name="Drugs.com-Hydroxyprogesterone" /><ref name="Martindale" /> Hydroxyprogesterone caproate is also marketed in combination with [[estradiol valerate]] as a [[combined injectable contraceptive]] in a number of countries including in South America, Mexico, Japan, and China.<ref name="IndexNominum2000" /><ref name="Drugs.com-Hydroxyprogesterone" /><ref name="Martindale" /> It has been marketed as an injectable preparation in combination with [[estradiol benzoate]] in some countries as well.<ref name="Leidenberger-2013" /><ref name="Knörr-2013-Lehrbuch der Gynäkologie" /><ref name="Kahr-2013" /><ref name="Kern-2013" /><ref name="Ufer-1968" />

=== Economics ===

{{See also|KV Pharmaceutical#Makena pricing controversy}}

With the designation of hydroxyprogesterone caproate as an [[orphan drug]] by the FDA and approval of Makena in 2011, the price of hydroxyprogesterone caproate in the United States was going to increase from {{US$|15}} to {{US$|1,500}} for a single dose, or from about {{US$|300}} to between {{US$|25,000}} and {{US$|30,000}} for a typical single month of treatment.<ref name="pmid21410391" /> This was about a 100-fold increase in cost, with "minimal added clinical benefit", and was a [[KV Pharmaceutical#Makena pricing controversy|strongly criticized pricing strategy]].<ref name="pmid21410391">{{cite journal | vauthors = Armstrong J | title = Unintended consequences--the cost of preventing preterm births after FDA approval of a branded version of 17OHP | journal = The New England Journal of Medicine | volume = 364 | issue = 18 | pages = 1689–91 | date = May 2011 | pmid = 21410391 | doi = 10.1056/NEJMp1102796 | doi-access = free }}</ref> The FDA subsequently announced that [[compounding pharmacy|compounding pharmacies]] could continue to sell hydroxyprogesterone caproate at their usual cost of approximately {{US$|10}} to {{US$|20}} per dose without fear of legal reprisals.<ref name="pmid21410391"/><ref name="Macleans">{{cite web |url=http://www.macleans.ca/article.jsp?content=w6411446 |title=Macleans.ca - Canada's national current affairs and news magazine since 1905 |access-date=30 March 2011 |url-status=dead |archive-url=https://web.archive.org/web/20111214041544/http://www.macleans.ca/article.jsp?content=w6411446 |archive-date=14 December 2011 }}</ref> KV Pharmaceutical also opted to reduced its price of Makena to {{US$|690}} per dose.<ref name="pmid21410391"/><ref name="www.boston.com-2011">{{cite news|url=http://www.boston.com/news/nation/washington/articles/2011/04/02/price_of_preterm_birth_medicine_cut/|publisher=Boston.com|agency=Associated Press|title=Price of preterm birth medicine cut|date=2 April 2011|access-date=2 April 2011|archive-date=3 November 2012|archive-url=https://web.archive.org/web/20121103054918/http://www.boston.com/news/nation/washington/articles/2011/04/02/price_of_preterm_birth_medicine_cut/|url-status=live}}</ref> Hydroxyprogesterone caproate continued to be available at low cost from compounding pharmacies until late 2016, after which time the FDA published new guidance documents prohibiting compounding pharmacies from selling products that are "essentially copies" of commercially available drug products.<ref name="U.S. Food and Drug Administration-2019">{{Cite web|url=https://www.fda.gov/regulatory-information/search-fda-guidance-documents/compounded-drug-products-are-essentially-copies-commercially-available-drug-product-under-section|title=Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance for Industry|date=1 April 2019|website=U.S. Food and Drug Administration|access-date=14 June 2019|archive-date=19 June 2019|archive-url=https://web.archive.org/web/20190619220220/https://www.fda.gov/regulatory-information/search-fda-guidance-documents/compounded-drug-products-are-essentially-copies-commercially-available-drug-product-under-section|url-status=live}}</ref><ref name="RAPS.com-2016">{{cite web|url=https://www.raps.org/regulatory-focus%E2%84%A2/news-articles/2016/7/fda-to-restrict-compounders-from-making-copies-of-commercially-available-drugs|title=FDA to Restrict Compounders from Making Copies of Commercially Available Drugs|date=7 July 2016|website=RAPS.com|access-date=14 June 2019|archive-date=6 October 2019|archive-url=https://web.archive.org/web/20191006145556/https://www.raps.org/regulatory-focus%E2%84%A2/news-articles/2016/7/fda-to-restrict-compounders-from-making-copies-of-commercially-available-drugs|url-status=live}}</ref>

==Research==

Cyclical therapy with 150&nbsp;mg hydroxyprogesterone caproate by intramuscular injection was found to be effective in the treatment of 76&nbsp;women with persistent, treatment-refractory [[acne]] in a preliminary study, with 84% responding to the therapy and experiencing a "good-to-excellent" improvement in symptoms.<ref name="pmid13598928">{{cite journal | vauthors = Baker KC | title = Treatment of persistent acne in women with 17 alpha hydroxyprogesterone caproate (delalutin); a preliminary report | journal = The Journal of Investigative Dermatology | volume = 31 | issue = 5 | pages = 247–50 | date = November 1958 | pmid = 13598928 | doi = 10.1038/jid.1958.114 | doi-access = free }}</ref><ref name="Antibiotics1959">{{cite book |title=Antibiotic Medicine and Clinical Therapy |url=https://books.google.com/books?id=Q6pKAQAAIAAJ |year=1959 |page=249}}</ref>

Hydroxyprogesterone caproate was studied by [[Schering AG|Schering]] for use as a [[progestogen-only injectable contraceptive]] at a dose of 250 to 500&nbsp;mg once a month by [[intramuscular injection]] but produced poor cycle control at these doses and was never marketed.<ref name="Toppozada-1983">{{cite book | vauthors = Toppozada MK | chapter = Monthly Injectable Contraceptives | pages = 93–103 | veditors = Goldsmith A, Toppozada M | title = Long-Acting Contraception | year = 1983 | oclc = 35018604 | url = https://scholar.google.com/scholar?cluster=14664537528797672080 | access-date = 27 December 2019 | archive-date = 10 June 2022 | archive-url = https://web.archive.org/web/20220610034743/https://scholar.google.com/scholar?cluster=14664537528797672080 | url-status = live }}</ref><ref name="pmid865726">{{cite journal | vauthors = Toppozada M | title = The clinical use of monthly injectable contraceptive preparations | journal = Obstetrical & Gynecological Survey | volume = 32 | issue = 6 | pages = 335–47 | date = June 1977 | pmid = 865726 | doi = 10.1097/00006254-197706000-00001 }}</ref>

Hydroxyprogesterone caproate by itself has been found to have little or no effectiveness in the treatment of [[breast cancer]] in women.<ref name="Ufer-1968" /><ref name="Dao-1975">{{cite book | vauthors = Dao TL | chapter = Pharmacology and Clinical Utility of Hormones in Hormone Related Neoplasms | year = 1975 | pages = 170–192 | doi = 10.1007/978-3-642-65806-8_11 | veditors = Sartorelli AC, Johns DG | title = Antineoplastic and Immunosuppressive Agents | series = Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology | publisher = Springer | chapter-url = https://books.google.com/books?id=aU_oCAAAQBAJ&pg=PA170 | isbn = 978-3-642-65806-8 | access-date = 31 May 2019 | archive-date = 10 January 2023 | archive-url = https://web.archive.org/web/20230110033051/https://books.google.com/books?id=aU_oCAAAQBAJ&pg=PA170 | url-status = live }}</ref><ref name="pmid14024037">{{cite journal | vauthors = Crowley LG, Macdonald I | title = Clinical trial of delautin in the treatment of advanced mammary carcinoma in postmenopausal women | journal = Cancer | volume = 15 | issue = 6 | pages = 1218–1220 | year = 1962 | pmid = 14024037 | doi = 10.1002/1097-0142(196211/12)15:6<1218::AID-CNCR2820150619>3.0.CO;2-Y | s2cid = 8005246 }}</ref><ref name="pmid13897631">{{cite journal | vauthors = Geller J, Volk H, Lewin M | title = Objective remission of metastatic breast carcinoma in a male who received 17-alpha hydroxy progesterone caproate (delalutin) | journal = Cancer Chemotherapy Reports | volume = 14 | pages = 77–81 | date = October 1961 | pmid = 13897631 }}</ref> Conversely, the combination of [[estradiol valerate]] and hydroxyprogesterone caproate has been found to be effective in the treatment of breast cancer in women.<ref name="Ufer-1968" /><ref name="pmid14278040">{{cite journal | vauthors = Crowley LG, Macdonald I | title = Delalutin and estrogens for the treatment of advanced mammary carcinoma in the postmenopausal woman | journal = Cancer | volume = 18 | issue = 4 | pages = 436–446 | date = April 1965 | pmid = 14278040 | doi = 10.1002/1097-0142(196504)18:4<436::AID-CNCR2820180407>3.0.CO;2-D | s2cid = 31370289 }}</ref><ref name="Crowley-1966">{{cite journal| vauthors = Crowley LG, MacDonald J |title=Delalutin und Östrogene als Behandlung des vorgeschrittenen Mammakarzinoms bei Frauen nach der Menopause|trans-title=Delalutin and estrogens as a treatment for advanced breast cancer in postmenopausal women|journal=Gynäkologisch-geburtshilfliche Rundschau|volume=3|issue=4|year=1966|pages=271–272|issn=1018-8843|doi=10.1159/000266855|doi-access=free}}</ref> Initial research based on limited clinical data reported that the breast-cancer response rate with a combination of estradiol valerate and hydroxyprogesterone caproate seemed to be greater than with an estrogen alone (35% vs. 50%).<ref name="Ufer-1968" /> However, subsequent research using the related but more potent progestin [[gestonorone caproate]] found that the combination of estradiol valerate and gestonorone caproate had effectiveness that was not significantly different from that of an estrogen alone in the treatment of breast cancer in women.<ref name="pmid968923">{{cite journal | vauthors = Firusian N, Schietzel M | title = [Additive treatment of metastasizing breast cancer with special reference to postmenopausal age (results of a randomized study)] | language = de | journal = Strahlentherapie | volume = 152 | issue = 3 | pages = 235–247 | date = September 1976 | pmid = 968923 | trans-title = Additive treatment of metastasizing breast cancer with special reference to postmenopausal age (results of a randomized study) }}</ref>

== Veterinary uses ==

The pharmacokinetics of hydroxyprogesterone caproate in various [[ungulate]]s including cattle, buffalo, sheep, and goat have been studied.<ref name="Santhosh-2006">{{cite thesis | vauthors = Santhosh CR | date = 2006 | title = Pharmacokinetics of 17α-Hydroxy Progesterone Caproate in Cattle, Buffalo, Sheep and Goat | degree = Ph.D. | publisher = Karnataka Veterinary, Animal and Fisheries Sciences University, Bidar | url = http://krishikosh.egranth.ac.in/handle/1/68575 | archive-url = https://web.archive.org/web/20181215224604/http://krishikosh.egranth.ac.in/handle/1/68575 | archive-date=15 December 2018 }}</ref>

==References==

{{Reflist}}

==Further reading==

{{refbegin|30em}}

* {{cite journal | vauthors = Meis PJ | title = 17 hydroxyprogesterone for the prevention of preterm delivery | journal = Obstetrics and Gynecology | volume = 105 | issue = 5 Pt 1 | pages = 1128–35 | date = May 2005 | pmid = 15863556 | doi = 10.1097/01.AOG.0000160432.95395.8f }}

* {{cite journal | vauthors = Facchinetti F, Vaccaro V | title = Pharmacological use of progesterone and 17-alpha-hydroxyprogesterone caproate in the prevention of preterm delivery | journal = Minerva Ginecologica | volume = 61 | issue = 5 | pages = 401–9 | date = October 2009 | pmid = 19749671 }}

* {{cite journal | vauthors = Deeks ED | title = 17 α-Hydroxyprogesterone caproate (Makena™): in the prevention of preterm birth | journal = Paediatric Drugs | volume = 13 | issue = 5 | pages = 337–45 | date = October 2011 | pmid = 21888448 | doi = 10.2165/11208140-000000000-00000 | s2cid = 207297651 }}

* {{cite journal | vauthors = Merlob P, Stahl B, Klinger G | title = 17α Hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth | journal = Reproductive Toxicology | volume = 33 | issue = 1 | pages = 15–9 | date = January 2012 | pmid = 22120850 | doi = 10.1016/j.reprotox.2011.10.017 | bibcode = 2012RepTx..33...15M }}

* {{cite journal | vauthors = O'Brien JM | title = The safety of progesterone and 17-hydroxyprogesterone caproate administration for the prevention of preterm birth: an evidence-based assessment | journal = American Journal of Perinatology | volume = 29 | issue = 9 | pages = 665–72 | date = October 2012 | pmid = 22773279 | doi = 10.1055/s-0032-1316444 | s2cid = 20625020 }}

* {{cite journal | vauthors = Romero R, Stanczyk FZ | title = Progesterone is not the same as 17α-hydroxyprogesterone caproate: implications for obstetrical practice | journal = American Journal of Obstetrics and Gynecology | volume = 208 | issue = 6 | pages = 421–6 | date = June 2013 | pmid = 23643669 | pmc = 4120746 | doi = 10.1016/j.ajog.2013.04.027 }}

* {{cite journal | vauthors = Feghali M, Venkataramanan R, Caritis S | title = Prevention of preterm delivery with 17-hydroxyprogesterone caproate: pharmacologic considerations | journal = Seminars in Perinatology | volume = 38 | issue = 8 | pages = 516–22 | date = December 2014 | pmid = 25256193 | pmc = 4253874 | doi = 10.1053/j.semperi.2014.08.013 }}

* {{cite journal | vauthors = Saccone G, Suhag A, Berghella V | title = 17-alpha-hydroxyprogesterone caproate for maintenance tocolysis: a systematic review and metaanalysis of randomized trials | journal = American Journal of Obstetrics and Gynecology | volume = 213 | issue = 1 | pages = 16–22 | date = July 2015 | pmid = 25659469 | doi = 10.1016/j.ajog.2015.01.054 }}

* {{cite journal | vauthors = O'Brien JM, Lewis DF | title = Prevention of preterm birth with vaginal progesterone or 17-alpha-hydroxyprogesterone caproate: a critical examination of efficacy and safety | journal = American Journal of Obstetrics and Gynecology | volume = 214 | issue = 1 | pages = 45–56 | date = January 2016 | pmid = 26558340 | doi = 10.1016/j.ajog.2015.10.934 | s2cid = 39636928 }}

* {{cite journal | vauthors = Caritis SN, Feghali MN, Grobman WA, Rouse DJ | title = What we have learned about the role of 17-alpha-hydroxyprogesterone caproate in the prevention of preterm birth | journal = Seminars in Perinatology | volume = 40 | issue = 5 | pages = 273–80 | date = August 2016 | pmid = 27105940 | pmc = 4983195 | doi = 10.1053/j.semperi.2016.03.002 }}

* {{cite journal | vauthors = Saccone G, Khalifeh A, Elimian A, Bahrami E, Chaman-Ara K, Bahrami MA, Berghella V | title = Vaginal progesterone vs intramuscular 17α-hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth in singleton gestations: systematic review and meta-analysis of randomized controlled trials | journal = Ultrasound in Obstetrics & Gynecology | volume = 49 | issue = 3 | pages = 315–321 | date = March 2017 | pmid = 27546354 | doi = 10.1002/uog.17245 | s2cid = 11445977 | url = https://touroscholar.touro.edu/nymc_fac_pubs/863 | doi-access = free | access-date = 19 May 2019 | archive-date = 30 May 2020 | archive-url = https://web.archive.org/web/20200530124735/https://touroscholar.touro.edu/nymc_fac_pubs/863/ | url-status = live }}

* {{cite journal | vauthors = Oler E, Eke AC, Hesson A | title = Meta-analysis of randomized controlled trials comparing 17α-hydroxyprogesterone caproate and vaginal progesterone for the prevention of recurrent spontaneous preterm delivery | journal = International Journal of Gynaecology and Obstetrics | volume = 138 | issue = 1 | pages = 12–16 | date = July 2017 | pmid = 28369874 | doi = 10.1002/ijgo.12166 | hdl = 2027.42/137297 | s2cid = 24480427 | hdl-access = free }}

* {{cite journal | vauthors = Manuck TA | title = 17-alpha hydroxyprogesterone caproate for preterm birth prevention: Where have we been, how did we get here, and where are we going? | journal = Seminars in Perinatology | volume = 41 | issue = 8 | pages = 461–467 | date = December 2017 | pmid = 28947068 | doi = 10.1053/j.semperi.2017.08.004 | s2cid = 36945947 | url = https://cdr.lib.unc.edu/downloads/028712685 | access-date = 2 November 2021 | archive-date = 12 December 2020 | archive-url = https://web.archive.org/web/20201212021914/https://cdr.lib.unc.edu/downloads/028712685 | url-status = live }}

{{refend}}

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