Hydroxyprogesterone caproate

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Hydroxyprogesterone caproate
Hydroxyprogesterone caproate.svg
Clinical data
Trade names Delalutin, Proluton, Proluton Depot, Makena others
Synonyms OHPC; Hydroxyprogesterone hexanoate; 17α-Hydroxyprogesterone caproate; 17α-OHPC; 17-Hydroxyprogesterone caproate; 17-OHPC; 17-HPC; 17α-HPC; HPC; 17α-Hydroxypregn-4-ene-3,20-dione 17α-hexanoate
Pregnancy
category
  • US: B (No risk in non-human studies)
Routes of
administration
Intramuscular injection[1]
Subcutaneous injection[2]
Drug class Progestin; Progestogen; Progestogen ester; Antigonadotropin
ATC code
Pharmacokinetic data
Bioavailability Oral: Very low (~3% in rats)[3]
Intramuscular: 100% (in rats)[3]
Protein binding Extensive (to albumin, not to CBG or (likely) SHBG)[1][4][5]
Metabolism Reduction and hydroxylation (via CYP3A4, CYP3A5, CYP3A7) and conjugation (glucuronidation, sulfation, acetylation)[1]
Elimination half-life Non-pregnant: 7.8 days[6]
Singlet: 16–17 days[7][1]
Twins: 10 days[7]
Excretion Feces: 50%[1]
Urine: 30%[1]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ECHA InfoCard 100.010.127 Edit this at Wikidata
Chemical and physical data
Formula C27H40O4
Molar mass 428.604 g/mol
3D model (JSmol)
  (verify)

Hydroxyprogesterone caproate (OHPC), sold under the brand names Proluton and Makena among others, is a progestin medication which is used to prevent preterm birth in pregnant women with a history of the condition and to treat gynecological disorders.[1][8][7][9] It is also used in combination with an estrogen as a form of long-lasting injectable birth control.[10] It is not effective by mouth and must be given by injection into muscle, typically once per week.[1][3]

OHPC is generally well-tolerated and produces few side effects.[1] Injection site reactions such as pain and swelling are the most common side effect of OHPC.[1] The medication may increase the risk of gestational diabetes when used in pregnant women.[1][11] OHPC is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[11] It has some antimineralocorticoid activity and no other important hormonal activity.[12][13][14][15] The medication shows a number of differences from natural progesterone.[11][16]

OHPC was discovered in 1953 and was introduced for medical use in 1954 or 1955.[17][18] It was marketed in the United States under the brand name Delalutin and throughout Europe under the brand name Proluton.[17][19] The medication was discontinued in the United States in 1999.[20] However, OHPC was subsequently reintroduced in the United States under the brand name Makena for the treatment of preterm birth in 2011.[21] Due to a greatly increased price of the medication under this new formulation, a pricing controversy occurred in this country.[21] OHPC remains available at low cost from compounding pharmacies in the United States.[21][22]

Medical uses[edit]

Preterm birth[edit]

The use of OHPC 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.[23] 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. OHPC 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,[24] 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 patients, 310 of whom received injection. Of these patients, 9 had infants with congenital malformations (2%), but there was no consistent pattern and none involved internal organs.

OHPC is currently (as of June 2014) pregnancy category B, meaning there is no evidence of fetal risk with use of this drug during pregnancy. Although this is now the recommendation, this has not always been the case. A 2006 Cochrane Review concluded "...important maternal and infant outcomes have been poorly reported to date... information regarding the potential harms of progesterone therapy to prevent preterm birth is limited".[25] There was a similar conclusion from a review by Marc Keirse of Flinders University.[26] Three clinical studies in singleton pregnancies of 250 mg/week of intramuscular OHPC have all shown a trend for an increase in pregnancy loss due to miscarriage compared to placebo.[27][28][29] One of them, a large NIH study in 2003, looked at the effect of OHPC 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 OHPC affected the children in the first years of life.[30] Based on these NIH data, 17 OHPC was approved by the FDA in 2011 as a drug to reduce the risk of premature birth in selected patients at risk. (v.i.)

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 OHPC with increased risk of second trimester miscarriage and stillbirth.[31] 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 OHPC.[32] As of 2008, OHPC 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 OHPC formulation may not be beneficial for pregnancy.[33][34] Of note, the above-mentioned NEJM study by Meirs et al. compares the effect of OHPC (with the castor oil component) to castor oil injection as the placebo.

A study published in February 2016 in The Lancet stated the below, amongst other findings:[35]

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 Richard Lehman, senior Research Fellow at the Department of Primary Health Care at the University of Oxford, 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."[36]

Gynecological disorders[edit]

OHPC is used in the treatment of threatened miscarriage, gynecological disorders such as dysmenorrhea, premenstrual syndrome, fibrocystic breast disease, adenosis, and breast pain.[7] In addition, OHPC is used in the treatment of endometrial cancer and has been found to be significantly effective in extending life in both premenopausal and postmenopausal women with the disease.[37] The medication was used widely in the 1950s through the 1970s for such indications, but OHPC more recently has received the most attention in the prevention of preterm birth.[7]

Birth control[edit]

OHPC is available in combination with estradiol valerate as a once-monthly combined injectable contraceptive in a few countries.[10][38]

Other uses[edit]

OHPC has been used to treat benign prostatic hyperplasia in men, although evidence of effectiveness is marginal and uncertain.[39] The mechanism of action of OHPC in this use is suppression of testicular androgen production via suppression of luteinizing hormone secretion, which are the result of the progestogenic and antigonadotropic activity of OHPC.[39] However, symptoms of hypogonadism may develop when OHPC is used for this indication, with two-thirds of men reportedly experiencing impotence.[40]

OHPC has been used as a component of feminizing hormone therapy for transgender women.[41][42][43][44][45]

Cyclical intramuscular doses of 150 mg OHPC has been found in a study to be effective in the treatment of women with persistent, treatment-refractory acne, with 84% (64 of 76) responding to the treatment and experiencing a "good-to-excellent" improvement in symptoms.[46][47]

Side effects[edit]

OHPC is generally well-tolerated and produces few side effects.[1] Injection site reactions such as pain, soreness, swelling, itching, bruising, and lumps are the most common side effect of OHPC.[1] The medication may increase the risk of diabetes during pregnancy.[1][11]

Pharmacology[edit]

Pharmacodynamics[edit]

OHPC, unlike many other progestins, is very similar to natural progesterone both structurally and pharmacologically, and is a pure progestogen – that is, a selective agonist of the progesterone receptor (PR), without other hormonal activities.[14][15] However, relative to progesterone, OHPC has improved pharmacokinetics, namely, a much longer duration with depot injection. Via intramuscular injection, 250 mg OHPC has been said to be equivalent to 50 mg of medroxyprogesterone acetate.[48] OHPC is a much more potent progestogen than 17α-hydroxyprogesterone, but does not have as high of affinity for the PR as progesterone.[49] However, in spite of this, it is more potent than progesterone in vivo, likely due to differences in the pharmacokinetics of the two compounds.[49] OHPC is not as potent as the related ester hydroxyprogesterone acetate.[49]

As a pure progestogen, OHPC has no androgenic, antiandrogenic, estrogenic, or glucocorticoid activity.[14][15][50] The absence of androgenic and antiandrogenic activity with OHPC is in contrast to most other 17α-hydroxyprogesterone-derivative progestins.[50][51] Due to its lack of androgenic properties, similarly to progesterone, OHPC does not have any teratogenic effects on the fetus, making it safe for use during pregnancy.[15] In relation to glucocorticoid activity, OHPC has been found not to alter cortisol levels in humans even with extremely high dosages via intramuscular injection,[52] which is of relevance because drugs with significant glucocorticoid activity suppress cortisol levels (due to increased negative feedback on the hypothalamic–pituitary–adrenal axis).[53][54][55] The medication has been studied in humans at dosages as high as 5,000 mg per week via intramuscular injection (in the treatment of endometrial cancer specifically, with safety and effectiveness observed).[56] It does interact with the glucocorticoid receptor however, but as a partial agonist and with no greater efficacy than progesterone.[1][49][57] Although OHPC has been described as a pure progestogen, there is evidence that it possesses some antimineralocorticoid activity, similarly to progesterone and hydroxyprogesterone.[13][12]

OHPC has about 26% and 30% of the affinity of progesterone for the human PR-A and PR-B, respectively.[1][49] It has about 4% of the affinity of dexamethasone for the rabbit glucocorticoid receptor.[1][49] The medication was no more efficacious than progesterone in activating these receptors and eliciting associated gene expression in vitro.[1][49] Unlike progesterone, OHPC and its metabolites are not anticipated to interact with non-genomic receptors such as membrane progesterone receptors or the GABAA receptor.[16] In accordance, OHPC is not thought to possess the neurosteroid activities of progesterone and associated sedative effects.[16]

Relative affinities (%) of OHPC and related steroids[49][58]
Compound hPR-A hPR-B rbPR rbGR rbER
Progesterone 100 100 100 <1 <1
Hydroxyprogesterone 1 1 3 1 <1
Hydroxyprogesterone caproate 26 30 28 4 <1
Hydroxyprogesterone acetate 38 46 115 3 ?
Values are percentages (%). Reference ligands (100%) were progesterone for the PR, dexamethasone for the GR, and estradiol for the ER.

Antigonadotropic effects[edit]

Through activation of the PR, OHPC has the potential for antigonadotropic effects (suppression of the hypothalamic–pituitary–gonadal axis),[59][60] and can significantly suppress gonadotropin secretion and gonadal sex hormone production at sufficiently high dosages.[61] One study found that 400 mg/week intramuscular OHPC suppressed luteinizing hormone and follicle-stimulating hormone levels in men by 24–30% and 19–55%, respectively.[62] In another study that used an unspecified dosage of intramuscular OHPC, testosterone secretion was assessed in a single patient and was found to decrease from 4.2 mg/day to 2.0 mg/day (or by approximately 52%) by six weeks of treatment, whereas secretion of luteinizing hormone remained unchanged in the patient.[63]

Differences from progesterone[edit]

There are biological and pharmacological differences between progesterone and OHPC, which may have implications for the obstetrical use of OHPC.[11][16] These differences include the following:[11][16]

Differences in the metabolism of progesterone and OHPC and differences in the formation and activities of metabolites may be responsible for or involved in these observed biological and pharmacological differences.[16] Progesterone is metabolized by 5α- and 5β-reductases, 3α- and 3β-hydroxysteroid dehydrogenases, and 20α- and 20β-hydroxysteroid dehydrogenase in various tissues.[16][65] In target tissues, particularly the cervix and myometrium, these enzymes regulate local progesterone concentrations and can activate or inactivate progesterone signaling.[16] In addition, these enzymes catalyze the formation of metabolites of progesterone such as 5β-dihydroprogesterone and allopregnanolone, which signal through their own non-genomic receptors such as membrane progesterone receptors and the GABAA receptor and have their own important effects in pregnancy.[64][66][67] 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.[16][67][66][68][69] In contrast to progesterone, OHPC is not metabolized by traditional steroid-transforming enzymes and instead is metabolized exclusively via oxidation at the caproate side chain by cytochrome P450 enzymes.[16] As such, it is not thought to have the same tissue-specific activation and inactivation patterns that progesterone does nor the same non-genomic actions that progesterone and its metabolites possess.[16]

Further clinical research is anticipated to provide additional data to help clarify the issue of safety with OHPC.[11] In any case, it has been recommended by the American College of Obstetricians and Gynecologists that pregnant women treated with OHPC receive counseling about its risks and benefits and that such discussion be documented in the patient's chart.[11]

Other activities[edit]

OHPC has no effect on CYP1A, CYP2D6, CYP2C9, or CYP3A4, but is a modest inducer of CYP2C19.[7]

Pharmacokinetics[edit]

Absorption[edit]

In animals, the bioavailability of OHPC with intramuscular injection is nearly 100%, but its oral bioavailability is very low at less than 3%.[3] For this reason, oral administration of OHPC is unfeasible for medical use and the drug must instead be administered via intramuscular injection.[3] The time to peak concentrations of OHPC is 2 to 3 days following an injection.[1] Steady state levels of the medication are achieved within 4 to 12 weeks of administration in pregnant women.[1]

Distribution[edit]

OHPC is extensively bound to plasma proteins, of which include albumin.[1] Unlike progesterone and 17α-hydroxyprogesterone, OHPC has very low affinity for corticosteroid-binding globulin (less than 0.01% of that of cortisol).[4] 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.[5]

Metabolism[edit]

OHPC appears to be metabolized primarily by the cytochrome P450 enzymes CYP3A4 and CYP3A5.[1] It may also be metabolized by CYP3A7 in fetal liver and the placenta.[1] Unlike progesterone, OHPC is not metabolized by traditional steroid-transforming enzymes and does not form similar metabolites.[16] The metabolism of OHPC is by reduction, hydroxylation, and conjugation, including glucuronidation, sulfation, and acetylation.[16] The caproate ester of OHPC is not cleaved during metabolism, so 17α-hydroxyprogesterone is not formed from OHPC.[16][49] As such, OHPC is not a prodrug of 17α-hydroxyprogesterone, nor of progesterone.[16][49]

OHPC has been found to have a terminal half-life of 7.8 days when given by intramuscular injection in an oil-based formulation to non-pregnant women.[6] 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).[46] In pregnant women, the terminal half-life of OHPC appears to be longer, about 16 or 17 days.[1][7] However, in women pregnant with twins rather than a singlet, the terminal half-life of OHPC was found to be shorter than this, at 10 days.[7]

Elimination[edit]

OHPC 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]

Routes[edit]

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

Chemistry[edit]

OHPC, 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.[70][19] It is specifically a derivative of 17α-hydroxyprogesterone with a hexanoate (caproate) ester at the C17α position.[70][19] Analogues of OHPC include other 17α-hydroxyprogesterone derivatives such as algestone acetophenide (dihydroxyprogesterone acetophenide), chlormadinone acetate, cyproterone acetate, gestonorone caproate (norhydroxyprogesterone caproate), hydroxyprogesterone acetate, hydroxyprogesterone heptanoate, medroxyprogesterone acetate, and megestrol acetate.[70][19]

History[edit]

Along with hydroxyprogesterone acetate, OHPC was developed by Karl Junkmann of Schering AG in 1953 and was first reported by him in the medical literature in 1954.[17][71][72][73][74] It was reportedly first marketed in Japan in 1954 or 1955,[18] and was subsequently introduced as Delalutin in the United States in 1956. After decades of use, Squibb, the manufacturer, voluntarily withdrew the brand, however, physicians continued to use OHPC "off-label". Renewed interest was sparked with a large NIH-sponsored study in 2003 that found that OHPC 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 drug, as sponsored by KV Pharmaceutical as Makena, 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.[75] The drug is not effective in preventing premature birth in women with multiples. With the arrival of Makena as an orphan drug, the price of the drug was to increase from $15 to $1,500 per dose meaning a typical treatment would cost $25,000 to $30,000 – a pricing strategy that was strongly criticized. The FDA then announced that pharmacies could continue to compound the drug at their usual cost of $10~20 per dose without fear of legal reprisals.,[22] and KV reduced its price to $690 per dose.[76]

Society and culture[edit]

Generic names[edit]

Hydroxyprogesterone caproate is the generic name of OHPC and its INN, USAN, BANM, and JAN, while hydroxyprogesterone hexanoate was its former BANM.[70][19][38]

Brand names[edit]

OHPC is marketed throughout the world under a variety of brand names including Proluton, Proluton Depot, and Makena (US), among many others.[70][19][38] It was also formerly marketed under brand names including Delalutin, Prodrox, and Hylutin among others, but these formulations have since been discontinued.[70][19]

Availability[edit]

OHPC is marketed in the United States and throughout Europe, Asia, and Central and South America.[19][38] It is notably not available in Canada, the United Kingdom, New Zealand, or South Africa, and only veterinary formulations are available in Australia.[19][38] OHPC 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.[38][10]

Controversy[edit]

A 2011 decision by the U.S. FDA was going to result in driving "up the [U.S.] cost of an available medication from about $300 to $30,000 – about a 100-fold increase – with minimal added clinical benefit".[21] However, the U.S. FDA said that it would not go after compounding pharmacies that filled prescriptions, and KV Pharmaceutical announced a lower price.[21]

See also[edit]

References[edit]

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z Deeks ED (2011). "17 α-Hydroxyprogesterone caproate (Makena™): in the prevention of preterm birth". Paediatr Drugs. 13 (5): 337–45. doi:10.2165/11208140-000000000-00000. PMID 21888448. 
  2. ^ a b c Krop J, Kramer WG (2017). "Comparative Bioavailability of Hydroxyprogesterone Caproate Administered via Intramuscular Injection or Subcutaneous Autoinjector in Healthy Postmenopausal Women: A Randomized, Parallel Group, Open-label Study". Clin Ther. 39 (12): 2345–2354. doi:10.1016/j.clinthera.2017.10.020. PMID 29191450. 
  3. ^ a b c d e Shaik, Imam H.; Bastian, Jaime R.; Zhao, Yang; Caritis, Steve N.; Venkataramanan, Raman (2015). "Route of administration and formulation dependent pharmacokinetics of 17-hydroxyprogesterone caproate in rats". Xenobiotica. 46 (2): 169–174. doi:10.3109/00498254.2015.1057547. ISSN 0049-8254. PMC 4809632Freely accessible. 
  4. ^ a b Mickelson 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. PMID 7306509. 
  5. ^ a b Dunn 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". J. Clin. Endocrinol. Metab. 53 (1): 58–68. doi:10.1210/jcem-53-1-58. PMID 7195404. 
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  12. ^ a b Ralph I. Dorfman (5 December 2016). Steroidal Activity in Experimental Animals and Man. Elsevier Science. pp. 398–. ISBN 978-1-4832-7299-3. 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). 
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  60. ^ Benign Prostatic Hypertrophy. Springer Science & Business Media. 6 December 2012. pp. 266–. ISBN 978-1-4612-5476-8. 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. 
  61. ^ J.E. Castro (9 March 2013). The Treatment of Prostatic Hypertrophy and Neoplasia. Springer Science & Business Media. pp. 39–. ISBN 978-94-015-7190-6. 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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  71. ^ WIED GL, DAVIS ME (1958). "Comparative activity of progestational agents on the human endometrium and vaginal epithelium of surgical castrates". Ann. N. Y. Acad. Sci. 71 (5): 599–616. doi:10.1111/j.1749-6632.1958.tb46791.x. PMID 13583817. 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. 
  72. ^ 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 
  73. ^ Ralph Isadore Dorfman (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, [...] 
  74. ^ Norman Applezweig (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. 
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