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Covis Pharma, agreed to withdraw the drug from the US market.[11][12][13] The approval of this drug substance was withdrawn by the US Food and Drug Administration (FDA) in April 2023.[10] In May 2024, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency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]
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 untill the FDA banned 17α-OHPC in 2023.[27]
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[update], 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]
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 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]
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]
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]
Hydroxyprogesterone caproate is not likely to affect most cytochrome P450enzymes at therapeutic concentrations.[3]Drug interaction studies have not been performed with hydroxyprogesterone caproate.[3]
Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the PRTooltip progesterone receptor, dexamethasone for the GRTooltip glucocorticoid receptor, and estradiol for the ERTooltip estrogen receptor. Sources: See template.
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 microcrystallineaqueous 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 expressionin vitro.[1][96]
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 gonadotropinsecretion 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]
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 expressionin vitro.[1][96][111]
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]
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
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]
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 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]
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]
OHPC levels after a single intramuscular injection of 1,000 mg OHPC in five women with endometrial cancer.[7]
OHPC levels over the course of a month after a final dose following continuous therapy with 250 mg per week OHPC by intramuscular injection in pregnant women with singleton gestation.[120]
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]
Hydroxyprogesterone caproate is the generic name of OHPC and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANMTooltip British Approved Name, and JANTooltip Japanese Accepted Name, while hydroxyprogesterone hexanoate was its former BANMTooltip British Approved Name.[25][42][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]
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]
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 legal reprisals.[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]
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 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]
^ abMickelson KE, Forsthoefel J, Westphal U (October 1981). "Steroid-protein interactions. Human corticosteroid binding globulin: some physicochemical properties and binding specificity". Biochemistry. 20 (21): 6211–8. doi:10.1021/bi00524a047. PMID7306509.
^ abDunn JF, Nisula BC, Rodbard D (July 1981). "Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma". The Journal of Clinical Endocrinology and Metabolism. 53 (1): 58–68. doi:10.1210/jcem-53-1-58. PMID7195404.
^ abcdefghiOnsrud M, Paus E, Haug E, Kjørstad K (1985). "Intramuscular administration of hydroxyprogesterone caproate in patients with endometrial carcinoma. Pharmacokinetics and effects on adrenal function". Acta Obstetricia et Gynecologica Scandinavica. 64 (6): 519–23. doi:10.3109/00016348509156732. PMID2932883. S2CID12007439.
^ abcdeHines M, Lyseng-Williamson KA, Deeks ED (March 2013). "17 α-hydroxyprogesterone caproate (Makena): a guide to its use in the prevention of preterm birth". Clinical Drug Investigation. 33 (3): 223–7. doi:10.1007/s40261-013-0060-6. PMID23413110. S2CID23221264.
^ abNewton JR, D'arcangues C, Hall PE (1994). "A review of "once-a-month" combined injectable contraceptives". Journal of Obstetrics and Gynaecology. 4 (Suppl 1): S1-34. doi:10.3109/01443619409027641. PMID12290848.
^ abcDorfman RI (5 December 2016). Steroidal Activity in Experimental Animals and Man. Elsevier Science. pp. 398–. ISBN978-1-4832-7299-3. Archived from the original on 8 March 2023. Retrieved 2 February 2018. 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).
^ abcSammour MB, El-Kabarity H, Khalifa AS (1975). "Progesterone therapy in pre-eclamptic toxaemia". Acta Obstetricia et Gynecologica Scandinavica. 54 (3): 195–202. doi:10.3109/00016347509157760. PMID1163210. S2CID38002155. 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.
^ abcdGeller J, Bora R, Roberts T, Newman H, Lin A, Silva R (July 1965). "Treatment of benign prostatic hypertrophy with hydroxyprogesterone caproate: effect on clinical symptoms, morphology, and endocrine function". JAMA. 193 (2): 121–8. doi:10.1001/jama.1965.03090020035009. PMID14304354.
^ abcdefghijklmnoByrns MC (January 2014). "Regulation of progesterone signaling during pregnancy: implications for the use of progestins for the prevention of preterm birth". The Journal of Steroid Biochemistry and Molecular Biology. 139: 173–81. doi:10.1016/j.jsbmb.2013.01.015. PMID23410596. S2CID23414730.
^ abInternational Agency for Research on Cancer (1979). Sex Hormones (II). International Agency for Research on Cancer. p. 401. ISBN978-92-832-1221-8. 17α-Hydroxyprogesterone caproate was first marketed commercially in Japan in 1954-1955.
^Johnson JW, Austin KL, Jones GS, Davis GH, King TM (October 1975). "Efficacy of 17alpha-hydroxyprogesterone caproate in the prevention of premature labor". The New England Journal of Medicine. 293 (14): 675–80. doi:10.1056/nejm197510022931401. PMID1099445.
^Yemini M, Borenstein R, Dreazen E, Apelman Z, Mogilner BM, Kessler I, et al. (March 1985). "Prevention of premature labor by 17 alpha-hydroxyprogesterone caproate". American Journal of Obstetrics and Gynecology. 151 (5): 574–7. doi:10.1016/0002-9378(85)90141-3. PMID3976757.
^Northen AT, Norman GS, Anderson K, Moseley L, Divito M, Cotroneo M, et al. (October 2007). "Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo". Obstetrics and Gynecology. 110 (4): 865–72. doi:10.1097/01.AOG.0000281348.51499.bc. PMID17906021. S2CID29485152.
^Hendrickx AG, Korte R, Leuschner F, Neumann BW, Poggel A, Binkerd P, et al. (February 1987). "Embryotoxicity of sex steroidal hormones in nonhuman primates: II. Hydroxyprogesterone caproate, estradiol valerate". Teratology. 35 (1): 129–36. doi:10.1002/tera.1420350116. PMID3563931.
^Duke University Medical Center, New England Journal of Medicine, correspondence, vol 349.
^Hauth JC, Gilstrap LC, Brekken AL, Hauth JM (May 1983). "The effect of 17 alpha-hydroxyprogesterone caproate on pregnancy outcome in an active-duty military population". American Journal of Obstetrics and Gynecology. 146 (2): 187–90. doi:10.1016/0002-9378(83)91051-7. PMID6682631.
^ abcCastro JE (9 March 2013). The Treatment of Prostatic Hypertrophy and Neoplasia. Springer Science & Business Media. pp. 39, 132. ISBN978-94-015-7190-6. 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.
^ abcdefghUfer J (1968). "Die therapeutische Anwendung der Gestagene beim Menschen" [Therapeutic Use of Progestogens in Humans]. Die Gestagene [Progestogens]. Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology. Springer-Verlag. pp. 1026–1124. doi:10.1007/978-3-642-99941-3_7. ISBN978-3-642-99941-3. Archived from the original on 8 March 2023. Retrieved 15 September 2018. 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].
^Noguchi M, Tajiri K, Taniya T, Kumaki T, Ashikari A, Miyazaki I (1990). "Influence of hormones on proliferation of ER-positive cells and ER-negative cells of human breast cancer (MCF-7)". Oncology. 47 (1): 19–24. doi:10.1159/000226779. PMID2137212. 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.
^Tyler ET, Olson HJ (April 1959). "Fertility promoting and inhibiting effects of new steroid hormonal substances". J Am Med Assoc. 169 (16): 1843–54. doi:10.1001/jama.1959.03000330015003. PMID13640942.
^ abHall NR (June 2011). "What agent should be used to prevent recurrent preterm birth: 17-P or natural progesterone?". Obstetrics and Gynecology Clinics of North America. 38 (2): 235–46, ix–x. doi:10.1016/j.ogc.2011.02.014. PMID21575799.
^ abVarga A, Henriksen E. Clinical and Histopathologic Evaluation of the Effect of 17-alpha-Hydroxyprogesterone-17-n-caproate on Endometrial Carcinoma. Obstetrics & Gynecology. December 1961. Volume 18. Issue 6. pp. 658-672.
^Henzl MR, Edwards JA (10 November 1999). "Pharmacology of Progestins: 17α-Hydroxyprogesterone Derivatives and Progestins of the First and Second Generation". In Sitruk-Ware R, Mishell DR (eds.). Progestins and Antiprogestins in Clinical Practice. Taylor & Francis. pp. 101–132. ISBN978-0-8247-8291-7.
^Becker H, Düsterberg B, Klosterhalfen H (1980). "[Bioavailability of cyproterone acetate after oral and intramuscular application in men (author's transl)]" [Bioavailability of Cyproterone Acetate after Oral and Intramuscular Application in Men]. Urologia Internationalis. 35 (6): 381–385. doi:10.1159/000280353. PMID6452729.
^Moltz L, Haase F, Schwartz U, Hammerstein J (May 1983). "[Treatment of virilized women with intramuscular administration of cyproterone acetate]" [Efficacy of Intra muscularly Applied Cyproterone Acetate in Hyperandrogenism]. Geburtshilfe und Frauenheilkunde. 43 (5): 281–287. doi:10.1055/s-2008-1036893. PMID6223851.
^Chu YH, Li Q, Zhao ZF (April 1986). "Pharmacokinetics of megestrol acetate in women receiving IM injection of estradiol-megestrol long-acting injectable contraceptive". The Chinese Journal of Clinical Pharmacology. 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.
^Kistner RW (December 1960). "The use of progestational agents in obstetrics and gynecology". Clinical Obstetrics and Gynecology. 3 (4): 1047–67. doi:10.1097/00003081-196003040-00019. PMID13756432. 50 mg of [medroxyprogesterone acetate], intramuscularly, is equivalent to 250 mg [hydroxyprogesterone caproate]
^"Depo_Provera"(PDF). FDA. 2016. Archived(PDF) from the original on 29 July 2020. Retrieved 31 March 2018.
^Yang D, Zhu RL (April 1994). "[Changes in reproductive hormones levels in the treatment of endometrial precancerous lesion with hydroxyprogesterone caproate]". Zhonghua Fu Chan Ke Za Zhi (in Chinese). 29 (4): 205–6, 251. PMID8082440. 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).
^Benign Prostatic Hypertrophy. Springer Science & Business Media. 6 December 2012. pp. 266–. ISBN978-1-4612-5476-8. Archived from the original on 11 January 2023. Retrieved 3 October 2016. 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.
^Meiraz D, Margolin Y, Lev-Ran A, Lazebnik J (February 1977). "Treatment of benign prostatic hyperplasia with hydroxyprogesterone-caproate: placebo-controlled study". Urology. 9 (2): 144–8. doi:10.1016/0090-4295(77)90184-4. PMID65818.
^Geller J, Fruchtman B, Newman H, Roberts T, Silva R (February 1967). "Effect of progestational agents on carcinoma of the prostate". Cancer Chemother Rep. 51 (1): 41–6. PMID6039663.
^ abMoe N (1972). "Short-term progestogen treatment of endometrial carcinoma. Histological, histochemical and hormonal studies". Acta Obstetricia et Gynecologica Scandinavica. 51 (1): 55–62. doi:10.3109/00016347209154968. PMID4261828. S2CID7181971.
^ abcSander S, Nissen-Meyer R, Aakvaag A (1978). "On gestagen treatment of advanced prostatic carcinoma". Scandinavian Journal of Urology and Nephrology. 12 (2): 119–21. doi:10.3109/00365597809179977. PMID694436.
^ abKjeld JM, Puah CM, Kaufman B, Loizou S, Vlotides J, Gwee HM, et al. (November 1979). "Effects of norgestrel and ethinyloestradiol ingestion on serum levels of sex hormones and gonadotrophins in men". Clinical Endocrinology. 11 (5): 497–504. doi:10.1111/j.1365-2265.1979.tb03102.x. PMID519881. S2CID5836155. 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).
^Knuth UA, Hano R, Nieschlag E (November 1984). "Effect of flutamide or cyproterone acetate on pituitary and testicular hormones in normal men". The Journal of Clinical Endocrinology and Metabolism. 59 (5): 963–9. doi:10.1210/jcem-59-5-963. PMID6237116.
^Jacobi GH, Altwein JE, Kurth KH, Basting R, Hohenfellner R (June 1980). "Treatment of advanced prostatic cancer with parenteral cyproterone acetate: a phase III randomised trial". British Journal of Urology. 52 (3): 208–15. doi:10.1111/j.1464-410x.1980.tb02961.x. PMID7000222.
^Sherman AI, Woolf RB (February 1959). "An endocrine basis for endometrial carcinoma". American Journal of Obstetrics and Gynecology. 77 (2): 233–42. doi:10.1016/0002-9378(59)90223-6. PMID13617315.
^ abBardin CW, Brown T, Isomaa VV, Jänne OA (1983). "Progestins can mimic, inhibit and potentiate the actions of androgens". Pharmacology & Therapeutics. 23 (3): 443–59. doi:10.1016/0163-7258(83)90023-2. PMID6371845.
^ abAnderson L, Martin W, Higgins C, Nelson SM, Norman JE (November 2009). "The effect of progesterone on myometrial contractility, potassium channels, and tocolytic efficacy". Reproductive Sciences. 16 (11): 1052–61. doi:10.1177/1933719109340926. PMID19602723. S2CID6856556.
^ abSchumacher M, Mattern C, Ghoumari A, Oudinet JP, Liere P, Labombarda F, et al. (February 2014). "Revisiting the roles of progesterone and allopregnanolone in the nervous system: resurgence of the progesterone receptors". Progress in Neurobiology. 113: 6–39. doi:10.1016/j.pneurobio.2013.09.004. hdl:11336/6678. PMID24172649. S2CID207407117.
^DelConte A, Chidambaram N, Nachaegari S, Patel M, Venkateshwaran S (January 2015). "770: Pharmacokinetics and tolerability of oral 17-hydroxyprogesterone caproate (HPC) relative to intramuscular (IM) HPC". American Journal of Obstetrics & Gynecology. 212 (1): S374. doi:10.1016/j.ajog.2014.10.976.
^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. ISBN978-3-642-99941-3. 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.
^Junkmann K (1954). "Über protrahiert wirksame Gestagene". Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie. 223 (3). doi:10.1007/BF00246995. S2CID33591186.
^Wied GL, Davis ME (July 1958). "Comparative activity of progestational agents on the human endometrium and vaginal epithelium of surgical castrates". Annals of the New York Academy of Sciences. 71 (5): 599–616. Bibcode:1958NYASA..71..599W. doi:10.1111/j.1749-6632.1958.tb46791.x (inactive 1 July 2024). PMID13583817. 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 July 2024 (link)
^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
^Dorfman RI (1966). Methods in Hormone Research. Academic Press. p. 86. Junkmann (1954) reported that the acetate, butyrate, and caproate forms had both increased and prolonged activity, [...]
^Applezweig N (1962). Steroid Drugs. Blakiston Division, McGraw-Hill. pp. 101–102. 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.
^New and Nonofficial Drugs. Lippincott. 1958. p. 662. Supplied by.—E. R. Squibb & Sons (Delalutin). Year of introduction: 1956.
^Tausk M (1975). Pharmacology of hormones. Thieme. p. 105. ISBN978-3-13-518901-7. 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.
^ abcSweetman SC, ed. (2009). "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. pp. 2110–2111. ISBN978-0-85369-840-1.
^Toppozada MK (1983). "Monthly Injectable Contraceptives". In Goldsmith A, Toppozada M (eds.). Long-Acting Contraception. pp. 93–103. OCLC35018604. Archived from the original on 10 June 2022. Retrieved 27 December 2019.
^Toppozada M (June 1977). "The clinical use of monthly injectable contraceptive preparations". Obstetrical & Gynecological Survey. 32 (6): 335–47. doi:10.1097/00006254-197706000-00001. PMID865726.
^Geller J, Volk H, Lewin M (October 1961). "Objective remission of metastatic breast carcinoma in a male who received 17-alpha hydroxy progesterone caproate (delalutin)". Cancer Chemotherapy Reports. 14: 77–81. PMID13897631.
^Firusian N, Schietzel M (September 1976). "[Additive treatment of metastasizing breast cancer with special reference to postmenopausal age (results of a randomized study)]" [Additive treatment of metastasizing breast cancer with special reference to postmenopausal age (results of a randomized study)]. Strahlentherapie (in German). 152 (3): 235–247. PMID968923.
Facchinetti F, Vaccaro V (October 2009). "Pharmacological use of progesterone and 17-alpha-hydroxyprogesterone caproate in the prevention of preterm delivery". Minerva Ginecologica. 61 (5): 401–9. PMID19749671.
O'Brien JM (October 2012). "The safety of progesterone and 17-hydroxyprogesterone caproate administration for the prevention of preterm birth: an evidence-based assessment". American Journal of Perinatology. 29 (9): 665–72. doi:10.1055/s-0032-1316444. PMID22773279. S2CID20625020.
Saccone G, Suhag A, Berghella V (July 2015). "17-alpha-hydroxyprogesterone caproate for maintenance tocolysis: a systematic review and metaanalysis of randomized trials". American Journal of Obstetrics and Gynecology. 213 (1): 16–22. doi:10.1016/j.ajog.2015.01.054. PMID25659469.
O'Brien JM, Lewis DF (January 2016). "Prevention of preterm birth with vaginal progesterone or 17-alpha-hydroxyprogesterone caproate: a critical examination of efficacy and safety". American Journal of Obstetrics and Gynecology. 214 (1): 45–56. doi:10.1016/j.ajog.2015.10.934. PMID26558340. S2CID39636928.
Oler E, Eke AC, Hesson A (July 2017). "Meta-analysis of randomized controlled trials comparing 17α-hydroxyprogesterone caproate and vaginal progesterone for the prevention of recurrent spontaneous preterm delivery". International Journal of Gynaecology and Obstetrics. 138 (1): 12–16. doi:10.1002/ijgo.12166. hdl:2027.42/137297. PMID28369874. S2CID24480427.