Hydroxyprogesterone caproate, sold under the brand names Proluton and Makena 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Covis Pharma, agreed to withdraw the drug from the US market.[11][12][13] The approvals of Makena and its generics were withdrawn by the US
Food and Drug Administration (FDA) in April 2023.[10]
Hydroxyprogesterone caproate was discovered in 1953 and was introduced for medical use in 1954 or 1955.[23] It was marketed in the United States under the brand name Delalutin and throughout Europe under the brand name Proluton.[24] The medication was discontinued in the United States in 1999.[25] However, hydroxyprogesterone caproate was subsequently reintroduced in the United States under the brand name Makena for the treatment of preterm birth in 2011.[26]
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.[27] 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,[28] 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.[29] 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.[30][31][28] 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.[28] A follow-up study of the offspring showed no evidence that hydroxyprogesterone caproate affected the children in the first years of life.[32] 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.[33] 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.[34] 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.[35][36] 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:[37]
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."[38]
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.[39]
Hydroxyprogesterone caproate has been used to treat
benign prostatic hyperplasia in men, although evidence of effectiveness is marginal and uncertain.[44] It has also been used to treat
prostate cancer, at a dosage of 1,500 mg twice per week.[45][46][47][48] 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.[44] However, symptoms of
hypogonadism may develop when hydroxyprogesterone caproate is used for this indication, with two-thirds of men reportedly experiencing
impotence.[49]
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).[57][58][59][60] 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.[61][62][63][64][65]: 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.[66][67]
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.[68] 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][16] 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][21][69][70]
Interactions
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.[62][90][91] An effective
ovulation-inhibiting dosage of hydroxyprogesterone caproate is 500 mg once per month by intramuscular injection.[59][80][92] 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.[59][92] 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.[59][80] 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.[93] 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.[94] Hydroxyprogesterone caproate is also to some degree less potent than the more closely related ester
hydroxyprogesterone acetate (OHPA; 17α-hydroxyprogesterone acetate).[95]
17α-Hydroxyprogesterone (OHP) has weak
progestogenic activity, but C17α
esterification results in higher progestogenic activity.[65] 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.[65] Hydroxyprogesterone caproate is a much more potent progestogen than 17α-hydroxyprogesterone, but does not have as high of
affinity for the PR as progesterone.[95] Hydroxyprogesterone caproate has about 26% and 30% of the affinity of progesterone for the human
PR-A and
PR-B, respectively.[1][95] The medication was no more
efficacious than progesterone in activating these receptors and eliciting associated
gene expressionin vitro.[1][95]
Antigonadotropic effects
Due to activation of the PR, hydroxyprogesterone caproate has
antigonadotropic effects, or produces suppression of the
hypothalamic–pituitary–gonadal axis,[96][97] and can significantly suppress
gonadotropinsecretion and gonadal
sex hormone production at sufficiently high doses.[48] 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.[98] 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.[20] 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.[99]Gestonorone caproate, a closely related progestin to hydroxyprogesterone caproate with about 5- to 10-fold greater potency in humans,[100][101] was found to suppress testosterone levels by 75% at a dosage of 400 mg/week in men with prostate cancer.[102][103] For comparison,
orchiectomy decreased testosterone levels by 91%.[102] In general, progestins are able to maximally suppress testosterone levels by about 70 to 80%.[104][105][106][102][103] 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.[44][45][47][48] Suppression of luteinizing hormone levels by hydroxyprogesterone caproate has also been observed in women.[107][101]
Glucocorticoid activity
Hydroxyprogesterone caproate is said not to have any
glucocorticoid activity.[21] 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.[55][108][109] 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][70] The medication does interact with the
glucocorticoid receptor however; it has about 4% of the affinity of
dexamethasone for the rabbit glucocorticoid receptor.[1][95] 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][95][110]
Other activities
As a pure progestogen, hydroxyprogesterone caproate has no
androgenic,
antiandrogenic,
estrogenic, or
glucocorticoid activity.[20][21][111] The absence of androgenic and antiandrogenic activity with hydroxyprogesterone caproate is in contrast to most other
17α-hydroxyprogesterone-derivative progestins.[89][111] 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.[21] 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.[18][112][19] This includes clinically important
diuretic effects and reversal of estrogen-induced
fluid retention and
edema.[112] 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.[22] In accordance, hydroxyprogesterone caproate is not thought to possess the
neurosteroid activities of progesterone or its associated
sedative effects.[22]
There are
pharmacodynamic differences between progesterone and hydroxyprogesterone caproate, which may have implications for
obstetrical use.[16][22] These include:[16][22]
Decreased
myometrial activity with progesterone in vitro but no effect or increased myometrial activity with hydroxyprogesterone caproate[113]
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.[16] 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.[16]
Footnotes:a = OHPC 250 mg once per week by intramuscular injection. Sources:[9][119][120]
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.[121] 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.[122][123] 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.[124][125][126]
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][127] 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][127] 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][119][120]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.[128] 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.[128]
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).[129] 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
Hormone levels with hydroxyprogesterone caproate
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.[119]
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.[134][135][136][137][138] It was reportedly first marketed in
Japan in 1954 or 1955,[23] and was subsequently introduced as Delalutin in the United States in 1956.[9][139] Due to its much longer duration than parenteral progesterone, hydroxyprogesterone caproate had largely replaced progesterone in clinical practice by 1975.[140] After decades of use,
Squibb, the manufacturer, voluntarily withdrew the Delalutin product in the United States in 1999.[25] 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.[28] 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.[26][141]
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.[142] The confirmatory trial, the PROLONG study, was completed in 2019 and showed no benefit in preventing preterm birth.[143] The FDA proposed withdrawal of approval for Makena in 2020. [144]
Society and culture
Names
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.[24][41][130]
Hydroxyprogesterone caproate is marketed throughout the world under a variety of brand names including Proluton, Proluton Depot, and Makena (
USTooltip United States), among many others.[24][41][130] It was also formerly marketed under brand names including Delalutin, Prodrox, and Hylutin among others, but these formulations have since been discontinued.[24][130] It has been marketed under the brand names Gravibinon and Injectable No. 1 (or Chinese Injectable No. 1) in combination with
estradiol valerate[57][58][59][60] and under the brand name Primosiston in combination with
estradiol benzoate.[61][62][63][64][65]
Hydroxyprogesterone caproate is marketed in the United States and throughout Europe, Asia, and Central and South America.[24][41][146] It is not available in Canada, the United Kingdom, New Zealand, or South Africa, and only veterinary formulations are available in Australia.[24][41][146] 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.[24][41][146] It has been marketed as an injectable preparation in combination with
estradiol benzoate in some countries as well.[61][62][63][64][65]
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.[26] This was about a 100-fold increase in cost, with "minimal added clinical benefit", and was a
strongly criticized pricing strategy.[26] 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.[26][147] KV Pharmaceutical also opted to reduced its price of Makena to US$690 per dose.[26][148] 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.[149][150]
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.[129][151]
Hydroxyprogesterone caproate by itself has been found to have little or no effectiveness in the treatment of
breast cancer in women.[65][154][155][156] Conversely, the combination of
estradiol valerate and hydroxyprogesterone caproate has been found to be effective in the treatment of breast cancer in women.[65][112][157] 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%).[65] 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.[158]
A novel oral formulation of hydroxyprogesterone caproate (developmental code name LPCN-1107) is under development for the prevention of
preterm labor.[124][125] As of September 2017, it is in
phase II or
phase IIIclinical trials for this indication.[124]
Veterinary uses
The pharmacokinetics of hydroxyprogesterone caproate in various
ungulates including cattle, buffalo, sheep, and goat have been studied.[159]
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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.
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abcdefghUfer J (1968). "Die therapeutische Anwendung der Gestagene beim Menschen" [Therapeutic Use of Progestogens in Humans].
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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.
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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.
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^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.).
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^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.
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^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.
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^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.
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PMID13756432. 50 mg of [medroxyprogesterone acetate], intramuscularly, is equivalent to 250 mg [hydroxyprogesterone caproate]
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^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–.
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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.
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^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.
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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.
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abSchumacher M, Mattern C, Ghoumari A, Oudinet JP, Liere P, Labombarda F, Sitruk-Ware R, De Nicola AF, Guennoun R (February 2014). "Revisiting the roles of progesterone and allopregnanolone in the nervous system: resurgence of the progesterone receptors". Progress in Neurobiology. 113: 6–39.
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^Junkmann K, Langecker H, Damrosch L (1968). "Chemie der Gestagene" [Chemistry of Progestogens].
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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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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.
^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).
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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.
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^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.
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Merlob P, Stahl B, Klinger G (January 2012). "17α Hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth". Reproductive Toxicology. 33 (1): 15–9.
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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.
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