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| Trade names | Delalutin, Proluton, Makena, others |
| Other names | 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 |
| Routes of administration | Intramuscular injection,[1]subcutaneousautoinjection[2][3] |
| Drug class | Progestogen;Progestin;Progestogen ester;Antigonadotropin |
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| Pharmacokinetic data | |
| Bioavailability | Oral: Very low (~3% in rats)[4] Intramuscular: 100% (in rats)[4] |
| Protein binding | Extensive (toalbumin, not toCBGTooltip corticosteroid-binding globulin or (likely)SHBGTooltip sex hormone-binding globulin)[1][5][6] |
| Metabolism | Reduction andhydroxylation (viaCYP3A4,CYP3A5,CYP3A7) andconjugation (glucuronidation,sulfation,acetylation)[1] |
| Eliminationhalf-life | Non-pregnant: 7.8 days[7][8] Singlet: 16–17 days[1][9] Twins: 10 days[9] |
| Excretion | Feces: 50%[1] Urine: 30%[1] |
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| ECHA InfoCard | 100.010.127 |
| Chemical and physical data | |
| Formula | C27H40O4 |
| Molar mass | 428.613 g·mol−1 |
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Hydroxyprogesterone caproate, sold under the brand nameDelalutin among others, is amedication used to reduce the risk of preterm birth in women pregnant with one baby who have a history of spontaneous preterm birth.[10] In March 2023, the manufacturer, Covis Pharma, agreed to withdraw the drug from the US market.[11][12][13] The approval of this drug substance was withdrawn by the USFood and Drug Administration (FDA) in April 2023.[10] In May 2024, thePharmacovigilance Risk Assessment Committee of theEuropean Medicines Agency recommended suspending the marketing authorizations of medications containing 17-hydroxyprogesterone caproate in the European Union.[14]
Hydroxyprogesterone caproate is aprogestin medication which was used to preventpreterm birth inpregnant women with a history of the condition and to treatgynecological disorders.[1][8][9][15][3] It has also been formulated in combination withestrogens for various indications (brand namesGravibinon andPrimosiston) and as a form of long-lastinginjectable birth control (brand nameChinese Injectable No. 1).[16] It is not usedby mouth and is instead given byinjection into muscle orfat.[1][4][3]
Hydroxyprogesterone caproate is generallywell tolerated and produces fewside effects.[1]Injection site reactions such aspain andswelling are the most common side effect of hydroxyprogesterone caproate.[1] The medication may increase the risk ofgestational diabetes when used in pregnant women.[1][17] Hydroxyprogesterone caproate is a progestin, or asyntheticprogestogen, and hence is anagonist of theprogesterone receptor, thebiological target of progestogens likeprogesterone.[17] It has someantimineralocorticoid activity and no other importanthormonal activity.[18][19][20][21][22] The medication shows a number of differences fromnaturalprogesterone.[17][23]
Hydroxyprogesterone caproate was discovered in 1953 and was introduced for medical use in 1954 or 1955.[24] It was marketed in the United States under the brand name Delalutin and throughout Europe under the brand name Proluton.[25] The medication was discontinued in the United States in 1999.[26] However, hydroxyprogesterone caproate was subsequently reintroduced in the United States under the brand name Makena for the treatment of preterm birth in 2011 until the FDA banned 17α-OHPC in 2023.[27]
The use of hydroxyprogesterone caproate in pregnancy to preventpreterm 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.[28] Level I evidence refers to a properly poweredrandomized 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 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 mm at < 24 weeks,cervical cerclage may be offered. In the 2013 study the guideline recommendation is based on,[29] there was also a significant decrease of neonatal morbidity including lower rates ofnecrotizing 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 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.[medical citation needed] A review concluded that information about the potential harms was lacking.[30] Three clinical studies in singleton pregnancies of 250 mg/week ofintramuscular hydroxyprogesterone caproate have all shown a trend for an increase in pregnancy loss due to miscarriage compared to placebo.[31][32][29] One of them, a largeNational Institutes of Health (NIH) study in 2003, looked at the effect of hydroxyprogesterone caproate injections in women at risk for repeatpremature birth and found that the treated group experienced premature birth in 37% versus 55% in the controls.[29] A follow-up study of the offspring showed no evidence that hydroxyprogesterone caproate affected the children in the first years of life.[33] Based on these NIH data, hydroxyprogesterone caproate was approved by the USFood and Drug Administration (FDA) in 2011, as a medication to reduce the risk of premature birth in selected women at risk.[citation needed]
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.[34] 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.[35] As of 2008[update], hydroxyprogesterone caproate was acategory D progestin according to the FDA (that is, there is evidence of fetal harm). There is speculation that thecastor oil in the hydroxyprogesterone caproate formulation may not be beneficial for pregnancy.[36][37] 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:[38]
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 exposedin 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."[39]
ACochrane 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.[40]
Hydroxyprogesterone caproate is used in the treatment ofthreatened miscarriage,gynecological disorders such asdysmenorrhea,premenstrual syndrome,fibrocystic breast disease,adenosis, andbreast pain.[9] In addition, hydroxyprogesterone caproate is used in the treatment ofendometrial cancer and has been found to be significantly effective in extending life in both premenopausal and postmenopausal women with the disease.[41] 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 ofpreterm birth.[9]
Hydroxyprogesterone caproate is available in combination withestradiol valerate as a once-monthlycombined injectable contraceptive in a some countries.[16][42]
Hydroxyprogesterone caproate has been used as a component ofmenopausal hormone therapy in women.[43][44]
Hydroxyprogesterone caproate has been used to treatbenign prostatic hyperplasia in men, although evidence of effectiveness is marginal and uncertain.[45] It has also been used to treatprostate cancer, at a dosage of 1,500 mg twice per week.[46][47][48][49] The mechanism of action of hydroxyprogesterone caproate in these uses is suppression of testicular androgen production via suppression ofluteinizing hormone secretion, which are the result of the progestogenic andantigonadotropic activity of hydroxyprogesterone caproate.[45] However, symptoms ofhypogonadism may develop when hydroxyprogesterone caproate is used for this indication, with two-thirds of men reportedly experiencingimpotence.[50]
Hydroxyprogesterone caproate has been used as a component offeminizing hormone therapy fortransgender women.[51][52][53][54][55] Due tomicronization, bioidentical progestogens are more commonly used.
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Hydroxyprogesterone caproate is available alone in the form ofampoules andvials of 125 and 250 mg/mLoil solutions forintramuscular injection (brand names Proluton, Makena).[56][57] It is also available alone in the form of a 250 mg/mLautoinjector for use bysubcutaneous injection (brand name Makena).[3]
Hydroxyprogesterone caproate is or was available in combination withestradiol valerate in the form of ampoules and vials of 250 mg/mL OHPC and 5 mg/mL estradiol valerate oil solutions for intramuscular injection (brand names Gravibinon, Chinese Injectable No. 1).[58][59][60][61] The medication is or was available in combination withestradiol benzoate in the form of ampoules of 125–250 mg OHPC and 10 mg estradiol benzoate in oil solution for intramuscular injection (brand name Primosiston) as well.[62][63][64][65][66]: 1045 In addition, hydroxyprogesterone caproate has been marketed in combination withestradiol dipropionate in the form of 50 mg/mL hydroxyprogesterone caproate and 1 mg/mL estradiol dipropionate (brand name EP Hormone Depot) in Japan.[67][68]
Contraindications of hydroxyprogesterone caproate include previous or currentthrombosis orthromboembolic disease, known or suspectedbreast cancer, past or present history of otherhormone-sensitive cancer, undiagnosedabnormal vaginal bleeding unrelated topregnancy,cholestatic jaundice of pregnancy,liver tumors or activeliver disease, and uncontrolledhypertension.[3] A few relative contraindications also exist for hydroxyprogesterone caproate.[3]
Hydroxyprogesterone caproate is generallywell tolerated and produces relatively fewside effects.[1]Injection site reactions such aspain,soreness,swelling,itching,bruising, andlumps are the most common side effect of hydroxyprogesterone caproate.[1] In contrast to large doses of progesterone however, which produce moderate-to-severe such reactions, hydroxyprogesterone caproate is relatively free from injection site reactions.[69] 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 sitenodules (4.5%), anddiarrhea (2.3%).[3] Numerically increased rates relative to controls ofmiscarriage (2.4% vs. 0%),stillbirth (2.0% vs. 1.3%), admission forpreterm labor (16.0% vs. 13.8%),preeclampsia orgestational hypertension (8.8% vs. 4.6%),gestational diabetes (5.6% vs. 4.6%),[1][17] andoligohydramnios (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.[3]
There have been no reports ofoverdose of hydroxyprogesterone caproate.[3] In the event of overdose, treatment should be based onsymptoms.[3] Hydroxyprogesterone caproate has been studied in humans at high doses of 2,000 to 5,000 mg per week by intramuscular injection, withoutsafety concerns.[7][22][70][71]
Hydroxyprogesterone caproate is not likely to affect mostcytochrome P450enzymes at therapeutic concentrations.[3]Drug interaction studies have not been performed with hydroxyprogesterone caproate.[3]
Hydroxyprogesterone caproate hasprogestogenic activity, someantimineralocorticoid activity, and no other importanthormonal activity.[18][8][19][20][70]
| Compound | hPR-A | hPR-B | rbPR | rbGR | rbER | |||
|---|---|---|---|---|---|---|---|---|
| Progesterone | 100 | 100 | 100 | <1 | <1 | |||
| 17α-Hydroxyprogesterone | 1 | 1 | 3 | 1 | <1 | |||
| Hydroxyprogesterone caproate | 26 | 30 | 28 | 4 | <1 | |||
| Hydroxyprogesterone acetate | 38 | 46 | 115 | 3 | ? | |||
| Notes: Values are percentages (%). Referenceligands (100%) wereprogesterone for thePRTooltip progesterone receptor,dexamethasone for theGRTooltip glucocorticoid receptor, andestradiol for theERTooltip estrogen receptor.Sources: See template. | ||||||||
| Compound | Form | Dose for specific uses (mg)[c] | DOA[d] | |||
|---|---|---|---|---|---|---|
| TFD[e] | POICD[f] | CICD[g] | ||||
| Algestone acetophenide | Oil soln. | – | – | 75–150 | 14–32 d | |
| Gestonorone caproate | Oil soln. | 25–50 | – | – | 8–13 d | |
| Hydroxyprogest. acetate[h] | Aq. susp. | 350 | – | – | 9–16 d | |
| Hydroxyprogest. caproate | Oil soln. | 250–500[i] | – | 250–500 | 5–21 d | |
| Medroxyprog. acetate | Aq. susp. | 50–100 | 150 | 25 | 14–50+ d | |
| Megestrol acetate | Aq. susp. | – | – | 25 | >14 d | |
| Norethisterone enanthate | Oil soln. | 100–200 | 200 | 50 | 11–52 d | |
| Progesterone | Oil soln. | 200[i] | – | – | 2–6 d | |
| Aq. soln. | ? | – | – | 1–2 d | ||
| Aq. susp. | 50–200 | – | – | 7–14 d | ||
Notes and sources:
| ||||||
Hydroxyprogesterone caproate, also known as 17α-hydroxyprogesterone caproate, is closer toprogesterone in terms ofstructure andpharmacology than most otherprogestins, and is essentially a pureprogestogen – that is, aselectiveagonist of theprogesterone receptor (PR) with minimal or no otherhormonal activity.[21][22] However, hydroxyprogesterone caproate has improvedpharmacokinetics compared to progesterone, namely a much longerduration withintramuscular injection inoil solution.[9][90][63][91]
Administered by intramuscular injection, theendometrial transformation dosage of hydroxyprogesterone caproate per cycle is 250 to 500 mg, and the weekly substitution dosage of hydroxyprogesterone caproate is 250 mg, while the effective dosage of hydroxyprogesterone caproate in the menstrual delay test (Greenblatt) is 25 mg per week.[63][91][92] An effectiveovulation-inhibiting dosage of hydroxyprogesterone caproate is 500 mg once per month by intramuscular injection.[60][81][93] However, the dose of hydroxyprogesterone caproate used in once-a-monthcombined injectable contraceptives is 250 mg, and this combination is effective for inhibition of ovulation similarly.[60][93] For comparison, the dose ofmedroxyprogesterone acetate (MPA; 6α-methyl-17α-hydroxyprogesterone acetate), a closeanalogue of hydroxyprogesterone caproate, used by intramuscular injection inmicrocrystallineaqueous suspension in once-a-month combined injectable contraceptives, is 25 mg.[60][81] It has also been said that given by intramuscular injection, 250 mg hydroxyprogesterone caproate in oil solution is equivalent in progestogenic potency to 50 mg medroxyprogesterone acetate in microcrystalline aqueous suspension.[94] Although theelimination half-life of intramuscular hydroxyprogesterone caproate in oil solution in non-pregnant women is about 8 days,[7][8] the elimination half-life of intramuscular medroxyprogesterone acetate in microcrystalline aqueous suspension in women is around 50 days.[95] Hydroxyprogesterone caproate is also to some degree less potent than the more closely related esterhydroxyprogesterone acetate (OHPA; 17α-hydroxyprogesterone acetate).[96]
17α-Hydroxyprogesterone (OHP) has weakprogestogenic activity, but C17αesterification results in higher progestogenic activity.[66] Of a variety of differentesters, thecaproate (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 caproateprogestogen esters such asgestonorone caproate.[66] Hydroxyprogesterone caproate is a much more potent progestogen than 17α-hydroxyprogesterone, but does not have as high ofaffinity for the PR as progesterone.[96] Hydroxyprogesterone caproate has about 26% and 30% of the affinity of progesterone for the humanPR-A andPR-B, respectively.[1][96] The medication was no moreefficacious than progesterone in activating these receptors and eliciting associatedgene expressionin vitro.[1][96]
Due to activation of the PR, hydroxyprogesterone caproate hasantigonadotropic effects, or produces suppression of thehypothalamic–pituitary–gonadal axis,[97][98] and can significantly suppressgonadotropinsecretion and gonadalsex hormone production at sufficiently high doses.[49] One study found that hydroxyprogesterone caproate by intramuscular injection at a dosage of 200 mg twice weekly for the first two weeks and then 200 mg once weekly for 12 weeks did not significantly influence urinary excretion ofestrogens,luteinizing hormone, orfollicle-stimulating hormone in men with benign prostatic hyperplasia.[99] 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 mg/day to 2.0 mg/day (or by approximately 52%) by 6 weeks of treatment, whereas secretion of luteinizing hormone remained unchanged in the man.[21] Yet another study found that 3,000 mg/week hydroxyprogesterone caproate by intramuscular injection suppressed testosterone levels from 640 ng/dL to 320–370 ng/dL (by 42–50%) in a single man with prostate cancer, which was similar to the testosterone suppression withcyproterone acetate orchlormadinone acetate.[100]Gestonorone caproate, a closely related progestin to hydroxyprogesterone caproate with about 5- to 10-fold greater potency in humans,[101][102] was found to suppress testosterone levels by 75% at a dosage of 400 mg/week in men with prostate cancer.[103][104] For comparison,orchiectomy decreased testosterone levels by 91%.[103] In general, progestins are able to maximally suppress testosterone levels by about 70 to 80%.[105][106][107][103][104] The antigonadotropic effects of hydroxyprogesterone caproate and hence its testosterone suppression are the basis of the use of hydroxyprogesterone caproate in the treatment ofbenign prostatic hyperplasia andprostate cancer in men.[45][46][48][49] Suppression of luteinizing hormone levels by hydroxyprogesterone caproate has also been observed in women.[108][102]
Hydroxyprogesterone caproate is said not to have anyglucocorticoid activity.[22] In accordance, hydroxyprogesterone caproate has been found not to altercortisol levels in humans even with very high doses by intramuscular injection.[7] This is of relevance because medications with significant glucocorticoid activity suppress cortisol levels due to increasednegative feedback on thehypothalamic–pituitary–adrenal axis.[56][109][110] Hydroxyprogesterone caproate has been studied in humans at doses as high as 5,000 mg per week by intramuscular injection, withsafety and without glucocorticoid effects observed.[7][71] The medication does interact with theglucocorticoid receptor however; it has about 4% of the affinity ofdexamethasone for the rabbit glucocorticoid receptor.[1][96] But it acts as apartial agonist of the receptor and has no greaterefficacy than progesterone in activating the receptor and eliciting associatedgene expressionin vitro.[1][96][111]
As a pure progestogen, hydroxyprogesterone caproate has noandrogenic,antiandrogenic,estrogenic, orglucocorticoid activity.[21][22][112] The absence of androgenic and antiandrogenic activity with hydroxyprogesterone caproate is in contrast to most other17α-hydroxyprogesterone-derivative progestins.[90][112] Due to its lack of androgenic properties, similarly to progesterone, hydroxyprogesterone caproate does not have anyteratogenic effects on thefetus, making it safe for use duringpregnancy.[22] Although hydroxyprogesterone caproate has been described as a pure progestogen, there is evidence that it possesses someantimineralocorticoid activity, similarly to progesterone and 17α-hydroxyprogesterone.[19][113][20] This includes clinically importantdiuretic effects and reversal of estrogen-inducedfluid retention andedema.[113] Unlike progesterone, hydroxyprogesterone caproate and its metabolites are not anticipated to interact withnon-genomic receptors such asmembrane progesterone receptors or theGABAA receptor.[23] In accordance, hydroxyprogesterone caproate is not thought to possess theneurosteroid activities of progesterone or its associatedsedative effects.[23]
In relation tocytochrome P450enzymes, hydroxyprogesterone caproate has no effect onCYP1A,CYP2D6,CYP2C9, orCYP3A4, but is a modestinducer ofCYP2C19.[9]
There arepharmacodynamic differences between progesterone and hydroxyprogesterone caproate, which may have implications forobstetrical use.[17][23] These include:[17][23]
Differences in themetabolism of progesterone and hydroxyprogesterone caproate and differences in the formation and activities ofmetabolites may be responsible for or involved in these observed biological and pharmacological differences.[23] Progesterone is metabolized by5α- and5β-reductases,3α- and3β-hydroxysteroid dehydrogenases, and20α- and20β-hydroxysteroid dehydrogenase in varioustissues.[23][115] In target tissues, particularly thecervix and myometrium, these enzymes regulate local progesterone concentrations and can activate or inactivate progesterone signaling.[23] In addition, these enzymes catalyze the formation of metabolites of progesterone such as5β-dihydroprogesterone andallopregnanolone, which signal through their ownnon-genomic receptors such asmembrane progesterone receptors and theGABAA receptor and have their own important effects in pregnancy.[114][116][117] As examples, 5β-dihydroprogesterone has been found to play an important role in suppressing myometrial activity while allopregnanolone has potentsedative andanesthetic effects in the mother and especially thefetus and is involved infetal nervous system development.[23][116][117][118][119] In contrast to progesterone, hydroxyprogesterone caproate is not metabolized by traditionalsteroid-transforming enzymes and instead is metabolized exclusively viaoxidation at thecaproateside chain bycytochrome P450 enzymes.[23] 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.[23]
Further clinical research is anticipated to provide additional data to help clarify the issue of safety with hydroxyprogesterone caproate.[17] In any case, it has been recommended by theAmerican College of Obstetricians and Gynecologists that pregnant women treated with hydroxyprogesterone caproate receive counseling about its risks and benefits.[17]
| Parameter | Singleton | Twin |
|---|---|---|
| Cmax (ng/mL) | 22.6 (15.8–27.4) | 17.3 (12–27) |
| Cmean(0–t) (ng/mL) | 16.8 (12.8–22.7) | 12.3 (8.4–18.7) |
| Ctrough (ng/mL) | 14.1 (10–18.1) | 11.2 (4.8–16.3) |
| AUC0–t (ng/mL/day) | 117.3 (89.9–159.1) | 86.1 (59–131) |
| t1/2 (days) | 16.2 (10.6–21.0) | 10 (6–16) |
| Tmax (days) | 1.0 (1–3) | 1.2 (1–2) |
| Vd/F (×103) (L) | 56 (25.2–69.6) | 16.9 (9.1–24.5) |
| Cl/F (×103) (L) | 2.1 (1.5–2.7) | 1.2 (0.9–1.7) |
| Footnotes:a = OHPC 250 mg once per week by intramuscular injection.Sources:[9][120][121] | ||
In animals, thebioavailability of hydroxyprogesterone caproate with intramuscular injection is nearly 100%, but itsoral bioavailability is very low at less than 3%.[4] In women, 70 mg/day oral hydroxyprogesterone caproate has similar endometrial potency as 70 mg/day oral OHPA and 2.5 mg/day oralmedroxyprogesterone acetate, indicating that oral hydroxyprogesterone caproate and OHPA have almost 30-fold lower potency than medroxyprogesterone acetate via oral administration.[122] Studies on progestogenicendometrial changes with oral hydroxyprogesterone caproate in women are mixed however, with one finding weak effects with 100 mg/day whereas another found that doses of 250 to 1,000 mg produced no effects.[123][124] 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.[4] 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.[125][126][127]
Adepot effect occurs when hydroxyprogesterone caproate is injected intramuscularly orsubcutaneously, such that the medication has a prolongedduration of action.[2][9] Following a single intramuscular injection of 1,000 mg hydroxyprogesterone caproate in five women withendometrial cancer, peak levels of hydroxyprogesterone caproate were 27.8 ± 5.3 ng/mL and thetime to peak concentrations was 4.6 ± 1.7 (3–7) days.[7][128] Following 13 weeks of continuous administration of 1,000 mg hydroxyprogesterone caproate per week,trough levels of hydroxyprogesterone caproate were 60.0 ± 14 ng/mL.[7][128] Thepharmacokinetic parameters of 250 mg hydroxyprogesterone caproate once per week by intramuscular injection have also been studied in pregnant women with singleton and multiple (twin and triplet) gestation.[9][120][121]Steady state levels of the medication are achieved within 4 to 12 weeks of administration in pregnant women.[1] The duration of clinicalbiological effect of hydroxyprogesterone caproate by intramuscular injection has also been studied in women.[129] A single intramuscular injection of 65 to 500 mg hydroxyprogesterone caproate in oil solution has been found to have aduration of action of 5 to 21 days in terms of effect in theuterus and onbody temperature in women.[129]
Hydroxyprogesterone caproate has been found to possess similar pharmacokinetics, includingpeak levels,time to peak levels,area-under-the-curve levels (i.e., total exposure), andelimination half-life, with administration via intramuscular injection orsubcutaneousautoinjection.[2] However, there was a higher incidence ofinjection site pain with subcutaneous autoinjection than with intramuscular injection (37.3% vs. 8.2%).[2]
Hydroxyprogesterone caproate is extensivelybound to plasma proteins, of which includealbumin.[1] Unlike progesterone and17α-hydroxyprogesterone, hydroxyprogesterone caproate has very lowaffinity forcorticosteroid-binding globulin (less than 0.01% of that ofcortisol).[5] Progesterone and 17α-hydroxyprogesterone have low affinity forsex 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.[6]
Hydroxyprogesterone caproate appears to bemetabolized primarily by thecytochrome P450enzymesCYP3A4 andCYP3A5.[1] It may also be metabolized byCYP3A7 infetalliver and theplacenta.[1] Unlike progesterone, hydroxyprogesterone caproate is not metabolized by traditionalsteroid-transforming enzymes and does not form similarmetabolites.[23] The metabolism of hydroxyprogesterone caproate is byreduction,hydroxylation, andconjugation, includingglucuronidation,sulfation, andacetylation.[23] Thecaproateester of hydroxyprogesterone caproate is not cleaved duringmetabolism, so17α-hydroxyprogesterone is not formed from hydroxyprogesterone caproate.[23][96] As such, hydroxyprogesterone caproate is not aprodrug of 17α-hydroxyprogesterone, nor ofprogesterone.[23][96]
Hydroxyprogesterone caproate has been found to have anelimination half-life of 7.8 days when given byintramuscular injection in an oil-based formulation to non-pregnant women.[7][8] Its total duration is said to be 10 to 14 days, which is much longer than the duration of intramuscularly administered progesterone in an oil formulation (2 to 3 days).[130] In pregnant women, the elimination half-life of hydroxyprogesterone caproate appears to be longer, about 16 or 17 days.[1][9] 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 days.[9] Hydroxyprogesterone caproate has been detected in pregnant women up to 44 days after the last dose.[9]
Hydroxyprogesterone caproate iseliminated 50% infeces and 30% inurine when given by intramuscular injection to pregnant women.[1] Both the free steroid and conjugates areexcreted by these routes, with the conjugates more prominent in feces.[1]
Hydroxyprogesterone caproate, also known as 17α-hydroxyprogesterone caproate or as 17α-hydroxypregn-4-ene-3,20-dione 17α-hexanoate, is asyntheticpregnanesteroid and aderivative ofprogesterone.[25][131] It is specifically a derivative of17α-hydroxyprogesterone with ahexanoate (caproate)ester at the C17α position.[25][131]Analogues of hydroxyprogesterone caproate include other 17α-hydroxyprogesterone derivatives such asalgestone acetophenide (dihydroxyprogesterone acetophenide),chlormadinone acetate,cyproterone acetate,hydroxyprogesterone acetate,hydroxyprogesterone heptanoate,medroxyprogesterone acetate, andmegestrol acetate, as well as thecaproate esterschlormadinone caproate,gestonorone caproate (norhydroxyprogesterone caproate),medroxyprogesterone caproate,megestrol caproate, andmethenmadinone caproate.[25][131]
Chemical syntheses of hydroxyprogesterone caproate have been described.[132][133][134]: 6
Along withhydroxyprogesterone acetate, hydroxyprogesterone caproate was developed by Karl Junkmann ofSchering AG in 1953 and was first reported by him in themedical literature in 1954.[135][136][137][138][139] It was reportedly first marketed inJapan in 1954 or 1955,[24] and was subsequently introduced as Delalutin in the United States in 1956.[9][140] Due to its much longer duration than parenteral progesterone, hydroxyprogesterone caproate had largely replaced progesterone in clinical practice by 1975.[141] After decades of use,Squibb, the manufacturer, voluntarily withdrew the Delalutin product in the United States in 1999.[26] 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.[29] With follow-up data showing no evidence of harmful effects on the offspring, the FDA approved the medication Makena, sponsored byKV Pharmaceutical, as anorphan 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.[27][142]
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.[143] The confirmatory trial, the PROLONG study, was completed in 2019 and showed no benefit in preventing preterm birth.[144] The FDA proposed withdrawal of approval for Makena in 2020.[145]
Hydroxyprogesterone caproate is thegeneric name of OHPC and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANMTooltip British Approved Name, andJANTooltip Japanese Accepted Name, while hydroxyprogesterone hexanoate was its formerBANMTooltip British Approved Name.[25][42][131]
Hydroxyprogesterone caproate is often mislabeled as and confused withprogesterone and17α-hydroxyprogesterone.[146] It should also not be confused withhydroxyprogesterone acetate,hydroxyprogesterone heptanoate, ormedroxyprogesterone acetate.[131]
Hydroxyprogesterone caproate is marketed throughout the world under a variety of brand names including Proluton, Proluton Depot, and Makena, among many others.[25][42][131] It was also formerly marketed under brand names including Delalutin, Prodrox, and Hylutin among others, but these formulations have been discontinued.[25][131] It has been marketed under the brand names Gravibinon and Injectable No. 1 (or Chinese Injectable No. 1) in combination withestradiol valerate[58][59][60][61] and under the brand name Primosiston in combination withestradiol benzoate.[62][63][64][65][66]
Hydroxyprogesterone caproate is marketed in the United States and throughout Europe, Asia, and Central and South America.[25][42][147] It is not available in Canada, the United Kingdom, New Zealand, or South Africa, and only veterinary formulations are available in Australia.[25][42][147] Hydroxyprogesterone caproate is also marketed in combination withestradiol valerate as acombined injectable contraceptive in a number of countries including in South America, Mexico, Japan, and China.[25][42][147] It has been marketed as an injectable preparation in combination withestradiol benzoate in some countries as well.[62][63][64][65][66]
With the designation of hydroxyprogesterone caproate as anorphan drug by the FDA and approval of Makena in 2011, the price of hydroxyprogesterone caproate in the United States was going to increase fromUS$15 toUS$1,500 for a single dose, or from aboutUS$300 to betweenUS$25,000 andUS$30,000 for a typical single month of treatment.[27] This was about a 100-fold increase in cost, with "minimal added clinical benefit", and was astrongly criticized pricing strategy.[27] The FDA subsequently announced thatcompounding pharmacies could continue to sell hydroxyprogesterone caproate at their usual cost of approximatelyUS$10 toUS$20 per dose without fear of enforcement action by the agency.[27][148] KV Pharmaceutical also opted to reduced its price of Makena toUS$690 per dose.[27][149] 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.[150][151]
Cyclical therapy with 150 mg hydroxyprogesterone caproate by intramuscular injection was found to be effective in the treatment of 76 women with persistent, treatment-refractoryacne in a preliminary study, with 84% responding to the therapy and experiencing a "good-to-excellent" improvement in symptoms.[130][152]
Hydroxyprogesterone caproate was studied bySchering for use as aprogestogen-only injectable contraceptive at a dose of 250 to 500 mg once a month byintramuscular injection but produced poor cycle control at these doses and was never marketed.[153][154]
Hydroxyprogesterone caproate by itself has been found to have little or no effectiveness in the treatment ofbreast cancer in women.[66][155][156][157] Conversely, the combination ofestradiol valerate and hydroxyprogesterone caproate has been found to be effective in the treatment of breast cancer in women.[66][113][158] 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%).[66] However, subsequent research using the related but more potent progestingestonorone 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.[159]
The pharmacokinetics of hydroxyprogesterone caproate in variousungulates including cattle, buffalo, sheep, and goat have been studied.[160]
This article incorporates text from this source, which is in thepublic domain.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).
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.
17α-Hydroxyprogesterone caproate was first marketed commercially in Japan in 1954-1955.
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.
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].
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.
17α-Hydroxyprogesterone caproate is a depot progestogen which is entirely free of side actions. The dose required to induce secretory changes in primed endometrium is about 250 mg. per menstrual cycle.
The results showed that after injection the concentration of plasma MA increased rapidly. The meantime of peak plasma MA level was 3rd day, there was a linear relationship between log of plasma MA concentration and time (day) after administration in all subjects, elimination phase half-life t1/2β = 14.35 ± 9.1 days.
50 mg of [medroxyprogesterone acetate], intramuscularly, is equivalent to 250 mg [hydroxyprogesterone caproate]
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).
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.
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.
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).
[...] 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).
{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)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.
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.
{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)[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
Junkmann (1954) reported that the acetate, butyrate, and caproate forms had both increased and prolonged activity, [...]
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.
Supplied by.—E. R. Squibb & Sons (Delalutin). Year of introduction: 1956.
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.
