Hydroxyprogesterone caproate

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. 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, 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. A review concluded that information about the potential harms was lacking. 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. 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. 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. 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. , 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. 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: 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." 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. 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. 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. Hydroxyprogesterone caproate has been used to treat benign prostatic hyperplasia in men, although evidence of effectiveness is marginal and uncertain. It has also been used to treat prostate cancer, at a dosage of 1,500 mg twice per week. Hydroxyprogesterone caproate has been used as a component of feminizing hormone therapy for transgender women. Due to micronization, bioidentical progestogens are more commonly used. Available forms 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). It is also available alone in the form of a 250 mg/mL autoinjector for use by subcutaneous injection (brand name Makena). 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. 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. ==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. A few relative contraindications also exist for hydroxyprogesterone caproate. ==Side effects==

Hydroxyprogesterone caproate is generally well tolerated and produces relatively few side effects. 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%). 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%), 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. ==Overdose==

There have been no reports of overdose of hydroxyprogesterone caproate. == Interactions ==

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

Pharmacodynamics Hydroxyprogesterone caproate has progestogenic activity, some antimineralocorticoid activity, and no other important hormonal activity. 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. An effective ovulation-inhibiting dosage of hydroxyprogesterone caproate is 500 mg once per month by intramuscular injection. 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. Although the elimination half-life of intramuscular hydroxyprogesterone caproate in oil solution in non-pregnant women is about 8 days, Hydroxyprogesterone caproate is also to some degree less potent than the more closely related ester hydroxyprogesterone acetate (OHPA; 17α-hydroxyprogesterone acetate). and can significantly suppress gonadotropin secretion and gonadal sex hormone production at sufficiently high doses. 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. 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. 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. Gestonorone caproate, a closely related progestin to hydroxyprogesterone caproate with about 5- to 10-fold greater potency in humans, For comparison, orchiectomy decreased testosterone levels by 91%. Glucocorticoid activity Hydroxyprogesterone caproate is said not to have any glucocorticoid activity. 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. The medication does interact with the glucocorticoid receptor however; it has about 4% of the affinity of dexamethasone for the rabbit glucocorticoid receptor. Other activities As a pure progestogen, hydroxyprogesterone caproate has no androgenic, antiandrogenic, estrogenic, or glucocorticoid activity. The absence of androgenic and antiandrogenic activity with hydroxyprogesterone caproate is in contrast to most other 17α-hydroxyprogesterone-derivative progestins. This includes clinically important diuretic effects and reversal of estrogen-induced fluid retention and edema. These include: • 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. In target tissues, particularly the cervix and myometrium, these enzymes regulate local progesterone concentrations and can activate or inactivate progesterone signaling. 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. 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. 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. 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. 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. A depot effect occurs when hydroxyprogesterone caproate is injected intramuscularly or subcutaneously, such that the medication has a prolonged duration of action. 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. 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. However, there was a higher incidence of injection site pain with subcutaneous autoinjection than with intramuscular injection (37.3% vs. 8.2%). 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. Metabolism Hydroxyprogesterone caproate appears to be metabolized primarily by the cytochrome P450 enzymes CYP3A4 and CYP3A5. As such, hydroxyprogesterone caproate is not a prodrug of 17α-hydroxyprogesterone, nor of progesterone. 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. Hydroxyprogesterone caproate has been detected in pregnant women up to 44 days after the last dose. Elimination Hydroxyprogesterone caproate is eliminated 50% in feces and 30% in urine when given by intramuscular injection to pregnant women. Both the free steroid and conjugates are excreted by these routes, with the conjugates more prominent in feces. 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. It is specifically a derivative of 17α-hydroxyprogesterone with a hexanoate (caproate) ester at the C17α position. ==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. It was reportedly first marketed in Japan in 1954 or 1955, and was subsequently introduced as Delalutin in the United States in 1956. Due to its much longer duration than parenteral progesterone, hydroxyprogesterone caproate had largely replaced progesterone in clinical practice by 1975. After decades of use, Squibb, the manufacturer, voluntarily withdrew the Delalutin product in the United States in 1999. 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. The confirmatory trial, the PROLONG study, was completed in 2019 and showed no benefit in preventing preterm birth. The FDA proposed withdrawal of approval for Makena in 2020. ==Society and culture==

Names Hydroxyprogesterone caproate is the generic name of OHPC and its , , , and , while hydroxyprogesterone hexanoate was its former . It should also not be confused with hydroxyprogesterone acetate, hydroxyprogesterone heptanoate, or medroxyprogesterone acetate. It is not available in Canada, the United Kingdom, New Zealand, or South Africa, and only veterinary formulations are available in Australia. The FDA subsequently announced that compounding pharmacies could continue to sell hydroxyprogesterone caproate at their usual cost of approximately to per dose without fear of enforcement action by the agency. KV Pharmaceutical also opted to reduced its price of Makena to per dose. 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. ==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. 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. Hydroxyprogesterone caproate by itself has been found to have little or no effectiveness in the treatment of breast cancer in women. Conversely, the combination of estradiol valerate and hydroxyprogesterone caproate has been found to be effective in the treatment of breast cancer in women. 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%). == Veterinary uses ==

The pharmacokinetics of hydroxyprogesterone caproate in various ungulates including cattle, buffalo, sheep, and goat have been studied. ==References==