Hydroxyprogesterone caproate

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Hydroxyprogesterone caproate
Hydroxyprogesterone caproate.svg
Hydroxyprogesterone caproate molecule ball.png
Clinical data
Trade names Delalutin, Proluton, Makena, others
Other namesOHPC; 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] subcutaneous autoinjection [2] [3]
Drug class Progestogen; Progestin; Progestogen ester; Antigonadotropin
ATC code
Legal status
Legal status
  • US:withdrawn
Pharmacokinetic data
Bioavailability Oral: Very low (~3% in rats) [4]
Intramuscular: 100% (in rats) [4]
Protein binding Extensive (to albumin, not to CBG Tooltip corticosteroid-binding globulin or (likely) SHBG Tooltip sex hormone-binding globulin) [1] [5] [6]
Metabolism Reduction and hydroxylation (via CYP3A4, CYP3A5, CYP3A7) and conjugation (glucuronidation, sulfation, acetylation) [1]
Elimination half-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]
Identifiers
  • [(8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-17-yl] hexanoate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.010.127 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C27H40O4
Molar mass 428.613 g·mol−1
3D model (JSmol)
  • 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
  • InChI=1S/C27H40O4/c1-5-6-7-8-24(30)31-27(18(2)28)16-13-23-21-10-9-19-17-20(29)11-14-25(19,3)22(21)12-15-26(23,27)4/h17,21-23H,5-16H2,1-4H3/t21-,22+,23+,25+,26+,27+/m1/s1 Yes check.svgY
  • Key:DOMWKUIIPQCAJU-LJHIYBGHSA-N Yes check.svgY
   (verify)

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. [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 [11] [12] [13] The approval of this drug substance was withdrawn by the US Food and Drug Administration (FDA) in April 2023. [10] 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. [14]

Contents

Hydroxyprogesterone caproate is a progestin medication which was used to prevent preterm birth in pregnant women with a history of the condition and to treat gynecological disorders. [1] [8] [9] [15] [3] It has also been formulated in combination with estrogens for various indications (brand names Gravibinon and Primosiston) and as a form of long-lasting injectable birth control (brand name Chinese Injectable No. 1). [16] It is not used by mouth and is instead given by injection into muscle or fat. [1] [4] [3]

Hydroxyprogesterone caproate is generally well tolerated and produces few side effects. [1] Injection site reactions such as pain and swelling are the most common side effect of hydroxyprogesterone caproate. [1] The medication may increase the risk of gestational diabetes when used in pregnant women. [1] [17] Hydroxyprogesterone caproate is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. [17] It has some antimineralocorticoid activity and no other important hormonal activity. [18] [19] [20] [21] [22] The medication shows a number of differences from natural progesterone. [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]

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. [28] 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 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 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 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 of intramuscular 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 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. [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 US Food 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, hydroxyprogesterone caproate was a 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. [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 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." [39]

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. [40]

Gynecological disorders

Hydroxyprogesterone caproate is used in the treatment of threatened miscarriage, gynecological disorders such as dysmenorrhea, premenstrual syndrome, fibrocystic breast disease, adenosis, and breast pain. [9] 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. [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 of preterm birth. [9]

Birth control

Hydroxyprogesterone caproate is available in combination with estradiol valerate as a once-monthly combined injectable contraceptive in a some countries. [16] [42]

Other uses

Hydroxyprogesterone caproate has been used as a component of menopausal hormone therapy in women. [43] [44]

Hydroxyprogesterone caproate has been used to treat benign prostatic hyperplasia in men, although evidence of effectiveness is marginal and uncertain. [45] It has also been used to treat prostate 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 of luteinizing hormone secretion, which are the result of the progestogenic and antigonadotropic activity of hydroxyprogesterone caproate. [45] However, symptoms of hypogonadism may develop when hydroxyprogesterone caproate is used for this indication, with two-thirds of men reportedly experiencing impotence. [50]

Hydroxyprogesterone caproate has been used as a component of feminizing hormone therapy for transgender women. [51] [52] [53] [54] [55] Due to micronization, bioidentical progestogens are more commonly used.

Available forms

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. Proluton Depot (hydroxyprogesterone caproate) packs.jpg
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 ampoules and vials of 125 and 250 mg/mL oil solutions for intramuscular injection (brand names Proluton, Makena). [56] [57] It is also available alone in the form of a 250 mg/mL autoinjector for use by subcutaneous injection (brand name Makena). [3]

Hydroxyprogesterone caproate is or was available in combination with estradiol 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 with estradiol 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 with estradiol 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

Contraindications 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 tumors or active liver disease, and uncontrolled hypertension. [3] A few relative contraindications also exist for hydroxyprogesterone caproate. [3]

Side effects

Hydroxyprogesterone caproate is generally well tolerated and produces relatively few side effects. [1] Injection site reactions such as pain, soreness, swelling, itching, bruising, and lumps 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 site nodules (4.5%), and diarrhea (2.3%). [3] 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%), [1] [17] 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. [3]

Overdose

There have been no reports of overdose of hydroxyprogesterone caproate. [3] In the event of overdose, treatment should be based on symptoms. [3] Hydroxyprogesterone caproate has been studied in humans at high doses of 2,000 to 5,000 mg per week by intramuscular injection, without safety concerns. [7] [22] [70] [71]

Interactions

Hydroxyprogesterone caproate is not likely to affect most cytochrome P450 enzymes at therapeutic concentrations. [3] Drug interaction studies have not been performed with hydroxyprogesterone caproate. [3]

Pharmacology

Pharmacodynamics

Hydroxyprogesterone caproate has progestogenic activity, some antimineralocorticoid activity, and no other important hormonal activity. [18] [8] [19] [20] [70]

Relative affinities (%) of hydroxyprogesterone and related steroids
Compound hPR-A hPR-B rbPR rbGR rbER
Progesterone 100100100<1<1
17α-Hydroxyprogesterone 1131<1
Hydroxyprogesterone caproate2630284<1
Hydroxyprogesterone acetate 38461153 ?
Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the PR Tooltip progesterone receptor, dexamethasone for the GR Tooltip glucocorticoid receptor, and estradiol for the ER Tooltip estrogen receptor. Sources: See template.
Parenteral potencies and durations of progestogens [lower-alpha 1] [lower-alpha 2]
CompoundFormDose for specific uses (mg) [lower-alpha 3] DOA [lower-alpha 4]
TFD [lower-alpha 5] POICD [lower-alpha 6] CICD [lower-alpha 7]
Algestone acetophenide Oil soln.-–75–15014–32 d
Gestonorone caproate Oil soln.25–50––8–13 d
Hydroxyprogest. acetate [lower-alpha 8] Aq. susp.350––9–16 d
Hydroxyprogest. caproateOil soln.250–500 [lower-alpha 9] –250–5005–21 d
Medroxyprog. acetate Aq. susp.50–1001502514–50+ d
Megestrol acetate Aq. susp.-–25>14 d
Norethisterone enanthate Oil soln.100–2002005011–52 d
Progesterone Oil soln.200 [lower-alpha 9] ––2–6 d
Aq. soln. ?––1–2 d
Aq. susp.50–200––7–14 d
Notes and sources:
  1. ↑ Sources: [72] [73] [74] [75] [76] [77] [78] [79] [80] [60] [81] [82] [83] [84] [85] [86] [87] [88] [89]
  2. ↑ All given by intramuscular or subcutaneous injection.
  3. ↑ Progesterone production during the luteal phase is ~25 (15–50) mg/day. The OID Tooltip ovulation-inhibiting dose of OHPC is 250 to 500 mg/month.
  4. ↑ Duration of action in days.
  5. ↑ Usually given for 14 days.
  6. ↑ Usually dosed every two to three months.
  7. ↑ Usually dosed once monthly.
  8. ↑ Never marketed or approved by this route.
  9. 1 2 In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4).

Progestogenic activity

Hydroxyprogesterone caproate, also known as 17α-hydroxyprogesterone caproate, is closer to progesterone in terms of structure and pharmacology than most other progestins, and is essentially a pure progestogen – that is, a selective agonist of the progesterone receptor (PR) with minimal or no other hormonal activity. [21] [22] However, hydroxyprogesterone caproate has improved pharmacokinetics compared to progesterone, namely a much longer duration with intramuscular injection in oil solution. [9] [90] [63] [91]

Administered by intramuscular injection, the endometrial 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 effective ovulation-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-month combined injectable contraceptives is 250 mg, and this combination is effective for inhibition of ovulation similarly. [60] [93] For comparison, the dose of medroxyprogesterone acetate (MPA; 6α-methyl-17α-hydroxyprogesterone acetate), a close analogue of hydroxyprogesterone caproate, used by intramuscular injection in microcrystalline aqueous 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 the elimination 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 ester hydroxyprogesterone acetate (OHPA; 17α-hydroxyprogesterone acetate). [96]

17α-Hydroxyprogesterone (OHP) has weak progestogenic activity, but C17α esterification results in higher progestogenic activity. [66] Of a variety of different esters, 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 esters such as gestonorone caproate. [66] Hydroxyprogesterone caproate is a much more potent progestogen than 17α-hydroxyprogesterone, but does not have as high of affinity for the PR as progesterone. [96] Hydroxyprogesterone caproate has about 26% and 30% of the affinity of progesterone for the human PR-A and PR-B, respectively. [1] [96] The medication was no more efficacious than progesterone in activating these receptors and eliciting associated gene expression in vitro . [1] [96]

Antigonadotropic effects

Due to activation of the PR, hydroxyprogesterone caproate has antigonadotropic effects, or produces suppression of the hypothalamic–pituitary–gonadal axis, [97] [98] and can significantly suppress gonadotropin secretion and gonadal sex 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 of estrogens, luteinizing hormone, or follicle-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 with cyproterone acetate or chlormadinone 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 of benign prostatic hyperplasia and prostate cancer in men. [45] [46] [48] [49] Suppression of luteinizing hormone levels by hydroxyprogesterone caproate has also been observed in women. [108] [102]

Glucocorticoid activity

Hydroxyprogesterone caproate is said not to have any glucocorticoid activity. [22] In accordance, hydroxyprogesterone caproate has been found not to alter cortisol 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 increased negative feedback on the hypothalamic–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, with safety and without glucocorticoid effects observed. [7] [71] The medication does interact with the glucocorticoid receptor however; it has about 4% of the affinity of dexamethasone for the rabbit glucocorticoid receptor. [1] [96] 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 . [1] [96] [111]

Other activities

As a pure progestogen, hydroxyprogesterone caproate has no androgenic, antiandrogenic, estrogenic, or glucocorticoid activity. [21] [22] [112] The absence of androgenic and antiandrogenic activity with hydroxyprogesterone caproate is in contrast to most other 17α-hydroxyprogesterone-derivative progestins. [90] [112] Due to its lack of androgenic properties, similarly to progesterone, hydroxyprogesterone caproate does not have any teratogenic effects on the fetus, making it safe for use during pregnancy. [22] 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. [19] [113] [20] This includes clinically important diuretic effects and reversal of estrogen-induced fluid retention and edema. [113] Unlike progesterone, hydroxyprogesterone caproate and its metabolites are not anticipated to interact with non-genomic receptors such as membrane progesterone receptors or the GABAA receptor. [23] In accordance, hydroxyprogesterone caproate is not thought to possess the neurosteroid activities of progesterone or its associated sedative effects. [23]

In relation to cytochrome P450 enzymes, hydroxyprogesterone caproate has no effect on CYP1A, CYP2D6, CYP2C9, or CYP3A4, but is a modest inducer of CYP2C19. [9]

Differences from progesterone

There are pharmacodynamic differences between progesterone and hydroxyprogesterone caproate, which may have implications for obstetrical use. [17] [23] These include: [17] [23]

  • Decreased myometrial activity with progesterone in vitro but no effect or increased myometrial activity with hydroxyprogesterone caproate [114]
  • Prevention of cervical ripening with progesterone but unknown effect with hydroxyprogesterone caproate
  • A non-significantly increased rate of stillbirth and miscarriages 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 perinatal adverse effects such as fetal loss and preterm delivery in 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 metabolites may be responsible for or involved in these observed biological and pharmacological differences. [23] Progesterone is metabolized by 5α- and 5β-reductases, 3α- and 3β-hydroxysteroid dehydrogenases, and 20α- and 20β-hydroxysteroid dehydrogenase in various tissues. [23] [115] In target tissues, particularly the cervix 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 as 5β-dihydroprogesterone and allopregnanolone, which signal through their own non-genomic receptors such as membrane progesterone receptors and the GABAA 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 potent sedative and anesthetic effects in the mother and especially the fetus and is involved in fetal nervous system development. [23] [116] [117] [118] [119] In contrast to progesterone, hydroxyprogesterone caproate is not metabolized by traditional steroid-transforming enzymes and instead is metabolized exclusively via oxidation at the caproate side chain by cytochrome 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 the American College of Obstetricians and Gynecologists that pregnant women treated with hydroxyprogesterone caproate receive counseling about its risks and benefits. [17]

Pharmacokinetics

Pharmacokinetics of OHPCa in pregnant women
ParameterSingletonTwin
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]

Absorption

In animals, the bioavailability of hydroxyprogesterone caproate with intramuscular injection is nearly 100%, but its oral 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 oral medroxyprogesterone acetate, indicating that oral hydroxyprogesterone caproate and OHPA have almost 30-fold lower potency than medroxyprogesterone acetate via oral administration. [122] Studies on progestogenic endometrial 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]

A depot effect occurs when hydroxyprogesterone caproate is injected intramuscularly or subcutaneously, such that the medication has a prolonged duration of action. [2] [9] Following a single intramuscular injection of 1,000 mg hydroxyprogesterone caproate in five women with endometrial cancer, peak levels of hydroxyprogesterone caproate were 27.8 ± 5.3 ng/mL and the time 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] The pharmacokinetic 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 clinical biological 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 a duration of action of 5 to 21 days in terms of effect in the uterus and on body temperature in women. [129]

Hydroxyprogesterone caproate has been found to possess similar pharmacokinetics, including peak levels, time to peak levels, area-under-the-curve levels (i.e., total exposure), and elimination half-life, with administration via intramuscular injection or subcutaneous autoinjection. [2] However, there was a higher incidence of injection site pain with subcutaneous autoinjection than with intramuscular injection (37.3% vs. 8.2%). [2]

Distribution

Hydroxyprogesterone caproate is extensively bound to plasma proteins, of which include albumin. [1] Unlike progesterone and 17α-hydroxyprogesterone, hydroxyprogesterone caproate has very low affinity for corticosteroid-binding globulin (less than 0.01% of that of cortisol). [5] 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. [6]

Metabolism

Hydroxyprogesterone caproate appears to be metabolized primarily by the cytochrome P450 enzymes CYP3A4 and CYP3A5. [1] It may also be metabolized by CYP3A7 in fetal liver and the placenta. [1] Unlike progesterone, hydroxyprogesterone caproate is not metabolized by traditional steroid-transforming enzymes and does not form similar metabolites. [23] The metabolism of hydroxyprogesterone caproate is by reduction, hydroxylation, and conjugation, including glucuronidation, sulfation, and acetylation. [23] The caproate ester of hydroxyprogesterone caproate is not cleaved during metabolism, so 17α-hydroxyprogesterone is not formed from hydroxyprogesterone caproate. [23] [96] As such, hydroxyprogesterone caproate is not a prodrug of 17α-hydroxyprogesterone, nor of progesterone. [23] [96]

Hydroxyprogesterone caproate has been found to have an elimination half-life of 7.8 days when given by intramuscular 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]

Elimination

Hydroxyprogesterone caproate is eliminated 50% in feces and 30% in urine when given by intramuscular injection to pregnant women. [1] Both the free steroid and conjugates are excreted by these routes, with the conjugates more prominent in feces. [1]

Time–concentration curves

Chemistry

Hydroxyprogesterone caproate, also known as 17α-hydroxyprogesterone caproate or as 17α-hydroxypregn-4-ene-3,20-dione 17α-hexanoate, is a synthetic pregnane steroid and a derivative of progesterone. [25] [131] It is specifically a derivative of 17α-hydroxyprogesterone with a hexanoate (caproate) ester at the C17α position. [25] [131] Analogues 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. [25] [131]

Synthesis

Chemical syntheses of hydroxyprogesterone caproate have been described. [132] [133] [134] : 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. [135] [136] [137] [138] [139] It was reportedly first marketed in Japan 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 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. [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]

Society and culture

Names

Hydroxyprogesterone caproate is the generic name of OHPC and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, BANM Tooltip British Approved Name, and JAN Tooltip Japanese Accepted Name, while hydroxyprogesterone hexanoate was its former BANM Tooltip British Approved Name. [25] [42] [131]

Hydroxyprogesterone caproate is often mislabeled as and confused with progesterone and 17α-hydroxyprogesterone. [146] It should also not be confused with hydroxyprogesterone acetate, hydroxyprogesterone heptanoate, or medroxyprogesterone 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 with estradiol valerate [58] [59] [60] [61] and under the brand name Primosiston in combination with estradiol benzoate. [62] [63] [64] [65] [66]

Availability

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 availability.png
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. [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 with estradiol valerate as a combined 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 with estradiol benzoate in some countries as well. [62] [63] [64] [65] [66]

Economics

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. [27] This was about a 100-fold increase in cost, with "minimal added clinical benefit", and was a strongly criticized pricing strategy. [27] The FDA subsequently announced that compounding pharmacies could continue to sell hydroxyprogesterone caproate at their usual cost of approximately US$10 to US$20 per dose without fear of enforcement action by the agency. [27] [148] KV Pharmaceutical also opted to reduced its price of Makena to US$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]

Research

Cyclical therapy with 150 mg hydroxyprogesterone caproate by intramuscular injection was found to be effective in the treatment of 76 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. [130] [152]

Hydroxyprogesterone caproate was studied by Schering for use as a progestogen-only injectable contraceptive at a dose of 250 to 500 mg once a month by intramuscular 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 of breast cancer in women. [66] [155] [156] [157] Conversely, the combination of estradiol 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 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. [159]

Veterinary uses

The pharmacokinetics of hydroxyprogesterone caproate in various ungulates including cattle, buffalo, sheep, and goat have been studied. [160]

Related Research Articles

<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

<span class="mw-page-title-main">Gestonorone caproate</span> Chemical compound

Gestonorone caproate, also known as gestronol hexanoate or norhydroxyprogesterone caproate and sold under the brand names Depostat and Primostat, is a progestin medication which is used in the treatment of enlarged prostate and cancer of the endometrium. It is given by injection into muscle typically once a week.

Combined injectable contraceptives (CICs) are a form of hormonal birth control for women. They consist of monthly injections of combined formulations containing an estrogen and a progestin to prevent pregnancy.

<span class="mw-page-title-main">Estradiol benzoate</span> Chemical compound

Estradiol benzoate (EB), sold under the brand name Progynon-B among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for transgender women, and in the treatment of gynecological disorders. It is also used in the treatment of prostate cancer in men. Estradiol benzoate is used in veterinary medicine as well. When used clinically, the medication is given by injection into muscle usually two to three times per week.

<span class="mw-page-title-main">Dimethisterone</span> Chemical compound

Dimethisterone, formerly sold under the brand names Lutagan and Secrosteron among others, is a progestin medication which was used in birth control pills and in the treatment of gynecological disorders but is now no longer available. It was used both alone and in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Algestone acetophenide</span> Chemical compound

Algestone acetophenide, also known more commonly as dihydroxyprogesterone acetophenide (DHPA) and sold under the brand names Perlutal and Topasel among others, is a progestin medication which is used in combination with an estrogen as a form of long-lasting injectable birth control. It has also been used alone, but is no longer available as a standalone medication. DHPA is not active by mouth and is given once a month by injection into muscle.

<span class="mw-page-title-main">Medroxyprogesterone acetate</span> Injectable form of birth control

Medroxyprogesterone acetate (MPA), also known as depot medroxyprogesterone acetate (DMPA) in injectable form and sold under the brand name Depo-Provera among others, is a hormonal medication of the progestin type. It is used as a method of birth control and as a part of menopausal hormone therapy. It is also used to treat endometriosis, abnormal uterine bleeding, paraphilia, and certain types of cancer. The medication is available both alone and in combination with an estrogen. It is taken by mouth, used under the tongue, or by injection into a muscle or fat.

<span class="mw-page-title-main">Norethisterone enanthate</span> Chemical compound

Norethisterone enanthate (NETE), also known as norethindrone enanthate, is a form of hormonal birth control which is used to prevent pregnancy in women. It is used both as a form of progestogen-only injectable birth control and in combined injectable birth control formulations. It may be used following childbirth, miscarriage, or abortion. The failure rate per year in preventing pregnancy for the progestogen-only formulation is 2 per 100 women. Each dose of this form lasts two months with only up to two doses typically recommended.

<span class="mw-page-title-main">Nomegestrol acetate</span> Chemical compound

Nomegestrol acetate (NOMAC), sold under the brand names Lutenyl and Zoely among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. It is available both alone and in combination with an estrogen. NOMAC is taken by mouth. A birth control implant for placement under the skin was also developed but ultimately was not marketed.

<span class="mw-page-title-main">Hydroxyprogesterone acetate</span> Chemical compound

Hydroxyprogesterone acetate (OHPA), sold under the brand name Prodox, is an orally active progestin related to hydroxyprogesterone caproate (OHPC) which has been used in clinical and veterinary medicine. It has reportedly also been used in birth control pills.

<span class="mw-page-title-main">Hydroxyprogesterone heptanoate</span> Chemical compound

Hydroxyprogesterone heptanoate (OHPH), also known as hydroxyprogesterone enanthate (OHPE) and sold under the brand names H.O.P., Lutogil A.P., and Lutogyl A.P. among others, is a progestin medication used for progestogenic indications. It has been formulated both alone and in together with estrogens, androgens/anabolic steroids, and other progestogens in several combination preparations. OHPH is given by injection into muscle at regular intervals.

<span class="mw-page-title-main">Progestogen ester</span> Drug class

A progestogen ester is an ester of a progestogen or progestin. The prototypical progestogen is progesterone, an endogenous sex hormone. Esterification is frequently employed to improve the pharmacokinetics of steroids, including oral bioavailability, lipophilicity, and elimination half-life. In addition, with intramuscular injection, steroid esters are often absorbed more slowly into the body, allowing for less frequent administration. Many steroid esters function as prodrugs.

<span class="mw-page-title-main">Oxogestone phenpropionate</span> Chemical compound

Oxogestone phenpropionate, also known as xinogestone, as well as 20β-hydroxy-19-norprogesterone 20β-(3-phenylpropionate), is a progestin related to the 19-norprogesterone derivatives which was developed as an injectable hormonal contraceptive, specifically a progestogen-only injectable contraceptive, in the 1960s and early 1970s but was never marketed. It was studied at a dose of 50 to 75 mg once a month by intramuscular injection but was associated with a high failure rate with this regimen and was not further developed. OPP is the 20β-(3-phenylpropionate) ester of oxogestone, which, similarly, was never marketed.

Progestogen-only injectable contraceptives (POICs) are a form of hormonal contraception and progestogen-only contraception that are administered by injection and providing long-lasting birth control. As opposed to combined injectable contraceptives, they contain only a progestogen without an estrogen, and include two progestin preparations:

<span class="mw-page-title-main">Progesterone (medication)</span> Medication and naturally occurring steroid hormone

Progesterone (P4), sold under the brand name Prometrium among others, is a medication and naturally occurring steroid hormone. It is a progestogen and is used in combination with estrogens mainly in hormone therapy for menopausal symptoms and low sex hormone levels in women. It is also used in women to support pregnancy and fertility and to treat gynecological disorders. Progesterone can be taken by mouth, vaginally, and by injection into muscle or fat, among other routes. A progesterone vaginal ring and progesterone intrauterine device used for birth control also exist in some areas of the world.

<span class="mw-page-title-main">Levonorgestrel butanoate</span> Chemical compound

Levonorgestrel butanoate (LNG-B), or levonorgestrel 17β-butanoate, is a steroidal progestin of the 19-nortestosterone group which was developed by the World Health Organization (WHO) in collaboration with the Contraceptive Development Branch (CDB) of the National Institute of Child Health and Human Development as a long-acting injectable contraceptive. It is the C17β butanoate ester of levonorgestrel, and acts as a prodrug of levonorgestrel in the body. The drug is at or beyond the phase III stage of clinical development, but has not been marketed at this time. It was first described in the literature, by the WHO, in 1983, and has been under investigation for potential clinical use since then.

<span class="mw-page-title-main">Estradiol benzoate/progesterone</span> Drug combination

Estradiol benzoate/progesterone (EB/P4), sold under the brand names Duogynon and Sistocyclin among others, is a combination medication of estradiol benzoate (EB), an estrogen, and progesterone (P4), a progestogen. It has been formulated both as short-acting oil solutions and long-acting microcrystalline aqueous suspensions and is given by injection into muscle either once or continuously at regular intervals.

<span class="mw-page-title-main">Estradiol valerate/hydroxyprogesterone caproate</span> Pharmaceutical combination

Estradiol valerate/hydroxyprogesterone caproate (EV/OHPC), sold under the brand names Gravibinon and Injectable No. 1 among others, is a combined estrogen and progestogen medication which is used in the treatment of threatened miscarriage and other indications and as a form of combined injectable birth control to prevent pregnancy. It contains estradiol valerate (EV), an estrogen, and hydroxyprogesterone caproate (OHPC), a progestin. The medication is given by injection into muscle once a day to once a month depending on the indication.

<span class="mw-page-title-main">Lynestrenol phenylpropionate</span> Chemical compound

Lynestrenol phenylpropionate (LPP), also known as ethynylestrenol phenylpropionate, is a progestin and a progestogen ester which was developed for potential use as a progestogen-only injectable contraceptive by Organon but was never marketed. It was assessed at doses of 25 to 75 mg in an oil solution once a month by intramuscular injection. LPP was associated with high contraceptive failure at the low dose and with poor cycle control. The medication was found to produce estrogenic effects in the endometrium in women due to transformation into estrogenic metabolites.

<span class="mw-page-title-main">Estradiol valerate/gestonorone caproate</span> Combination drug

Estradiol valerate/gestonorone caproate (EV/GC), known by the developmental code names SH-834 and SH-8.0834, is a high-dose combination medication of estradiol valerate (EV), an estrogen, and gestonorone caproate, a progestin, which was developed and studied by Schering in the 1960s and 1970s for potential use in the treatment of breast cancer in women but was ultimately never marketed. It contained 90 mg EV and 300 mg GC in each 3 mL of oil solution and was intended for use by intramuscular injection once a week. The combination has also been studied incidentally in the treatment of ovarian cancer.

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  125. ↑ "Hydroxyprogesterone caproate oral - Lipocine - AdisInsight". Archived from the original on 1 November 2017. Retrieved 24 February 2019.
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  130. 1 2 Baker KC (November 1958). "Treatment of persistent acne in women with 17 alpha hydroxyprogesterone caproate (delalutin); a preliminary report". The Journal of Investigative Dermatology. 31 (5): 247–50. doi: 10.1038/jid.1958.114 . PMID   13598928.
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  134. ↑ Junkmann K, Langecker H, Damrosch L (1968). "Chemie der Gestagene" [Chemistry of Progestogens]. Die Gestagene [Progestogens]. Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology. Springer-Verlag. pp. 1–44. doi:10.1007/978-3-642-99941-3_1. ISBN   978-3-642-99941-3. Archived from the original on 8 March 2023. Retrieved 15 September 2018. 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.
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  137. ↑ ACRH. U.S. Dept. of Energy. 1960. p. 71. [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
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