Prevention of preterm birth with vaginal progesterone or 17-alpha-hydroxyprogesterone caproate: a critical examination of efficacy and safety.

Progestogens are the first drugs to demonstrate reproducibly a reduction in the rate of early preterm birth. The efficacy and safety of progestogens are related to individual pharmacologic properties of each drug within this class of medication and characteristics of the population that is treated. The synthetic 17-hydroxyprogesterone caproate and natural progesterone have been studied with the use of a prophylactic strategy in women with a history of preterm birth and in women with a multiple gestation. Evidence from a single large comparative efficacy trial suggests that vaginal natural progesterone is superior to 17-hydroxyprogesterone caproate as a prophylactic treatment in women with a history of mid-trimester preterm birth. Progestogen therapy is indicated for women with this highest risk profile based on evidence from 2 trials. A therapeutic approach based on the identification of a sonographic short cervix has been studied in several phase III trials. Independent phase III trials and an individual patient metaanalysis suggest that vaginal progesterone is efficacious and safe in women with a singleton and a short cervix. Two trials that tested 17-hydroxyprogesterone caproate in women with a short cervix showed no benefit. No consistent benefit for the prophylactic or therapeutic use of progestogens has been demonstrated in larger trials of women whose pregnancies were complicated by a multiple gestation (twins or triplets), preterm labor, or preterm rupture of membranes. Unfortunately, several large randomized trials in multiple gestations have identified harm related to 17-hydroxyprogesterone caproate exposure, and the synthetic drug is contraindicated in this population. The current body of evidence is evaluated by the Grading of Recommendations Assessment, Development, and Evaluation guidelines to derive the strength of recommendation in each of these populations. A large confirmatory trial that is testing 17-hydroxyprogesterone caproate exposure in women with a singleton pregnancy and a history of preterm birth is near completion. Additional study of the efficacy and safety of progestogens is suggested in well-selected populations based on the presence of biomarkers.

Population pharmacokinetics of 17α-hydroxyprogesterone caproate in singleton gestation.

AIMS: 17α-hydroxyprogesterone caproate (17-OHPC) reduces the rate of preterm birth in women with a prior preterm birth. Limited data exist on the pharmacokinetics (PK) of 17-OHPC or the plasma concentrations achieved during therapy. In this study, we evaluated the population PK of 17-OHPC in pregnant subjects with singleton gestation and also evaluated intrinsic and extrinsic factors that may potentially affect 17-OHPC PK in this patient population. METHODS: Sixty-one women with singleton pregnancies participated in this trial. Subjects received weekly intramuscular injections of 250 mg 17-OHPC in 1 ml castor oil from the time of enrolment (16 0/7 weeks - 20 6/7 weeks) up to 35 weeks gestation or until delivery. Blood samples were obtained between 24 and 28 weeks, between 32 and 35 weeks and over a 28-day period beyond the last injection. Maternal and/or cord blood were obtained at delivery. Data analysis was performed by nonlinear mixed effects modelling (NONMEM(®) ). RESULTS: The 17-OHPC PK were best described by a model with one maternal compartment and one fetal compartment, with first-order absorption and elimination from the maternal compartment. Maternal body weight was a significant covariate for both clearance (CL/F) and volume of distribution (Vmaternal /F). The final population mean estimates were: CL/F 1797 l/d, Vmaternal /F 32 610 l and mother to cord rate constant 0.005 day(-1) . This report describes for the first time the population PK of 17-OHPC in singleton pregnancy. CONCLUSIONS: The population PK study reported here represents the initial steps in understanding and optimizing 17-OHPC therapy for preventing preterm birth.

Route of administration and formulation dependent pharmacokinetics of 17-hydroxyprogesterone caproate in rats.

1. Weekly intramuscular injections of (250 mg/week) of 17-hydroxyprogesterone caproate (17-OHPC) are the only treatment option for prevention of preterm birth in women with a prior history of preterm delivery. 2. The objective of the current study was to evaluate the use of an alternate formulation and the feasibility of an alternate route of administration of this agent. 17-OHPC was administered to adult female SD rats, as marketed oily formulation intramuscularly, or as a solution IV, IM, or PO. 3. Plasma concentrations of 17-OHPC were measured by LC-MS-MS and pharmacokinetic parameters were calculated by non-compartmental analysis, using WinNonLin (Certara, St. Louis, MO). 4. After IV or IM administration as a solution, the mean half-life of 17-OHPC was around 11 h. The bioavailability was nearly 100% after IM administration, but was very low (<3%) after PO administration of a solution dosage form. 5. Intramuscular injection of the oily formulation resulted in low levels of 17-OHPC that were sustained for a prolonged time period with a projected bioavailability close to 100%. 6. The pharmacokinetics of 17-OHPC is dependent on the formulation and the route of administration. 7. The low bioavailability after oral administration indicates that oral administration of 17-OHPC may not be feasible with simple formulations of this drug.

Pharmacology and placental transport of 17-hydroxyprogesterone caproate in singleton gestation.

OBJECTIVE: The purpose of this study was to estimate pharmacokinetic parameters and to evaluate placental transport of 17-hydroxyprogesterone caproate (17-OHPC) in singleton gestation. STUDY DESIGN: Sixty-one women who received weekly injections of 17-OHPC underwent 2 pharmacokinetic studies at 20 + 0 to 24 + 6 weeks' gestation (study 1) and 31 + 0 to 34 + 6 weeks' gestation (study 2); daily blood samples were obtained between injections. In 18 women, blood samples were obtained over a 28-day period beyond the last injection (extended study). Maternal and/or cord blood were obtained at delivery. RESULTS: The half-life (median ± SD) of 17-OHPC was 16.2 ± 6 days. Concentrations of 17-OHPC were higher during study 2 than during study 1. Body mass index affected maternal 17-OHPC concentrations. Cord:maternal 17-OHPC concentration ratios averaged 0.2; 17-OHPC was detectible in cord plasma 44 days after the last maternal injection. CONCLUSION: The apparent half-life of 17-OHPC is long, and pharmacokinetic parameters vary widely between subjects and are affected by maternal body mass index. The drug crosses the placental barrier.

Pharmacokinetics of 17-hydroxyprogesterone caproate in multifetal gestation.

OBJECTIVE: The purpose of this study was to define the pharmacokinetic parameters of 17-hydroxyprogesterone caproate (17-OHPC) in multifetal gestation. STUDY DESIGN: Blood was obtained at 24-28 weeks' gestation and at 32-35 weeks gestation in 97 women with twin and 26 women with triplet gestation who were receiving 17-OHPC. Six of the women with twins had daily blood sampling for 7 days between 24 and 28 weeks' gestation, and pharmacokinetic parameters were estimated with the use of noncompartmental analysis. Modeling was applied to estimate the population parameters and to simulate various treatment scenarios. RESULTS: The apparent half-life of 17-OHPC was 10 days. Body mass index significantly impacted 17-OHPC concentrations, but fetal number and parity did not. Apparent clearance was significantly greater in African American than in white women (P = .025). CONCLUSION: This is the first pharmacokinetic analysis of 17-OHPC in pregnant women. Determination of half-life, covariates that affect plasma 17-OHPC concentrations, and the modeling of drug behavior provide insights into this drug's pharmacologic properties during multifetal pregnancy.

Comparative Bioavailability of Hydroxyprogesterone Caproate Administered via Intramuscular Injection or Subcutaneous Autoinjector in Healthy Postmenopausal Women: A Randomized, Parallel Group, Open-label Study.

PURPOSE: The purpose of this study was to evaluate the bioavailability of hydroxyprogesterone caproate (HPC) administered as a subcutaneous injection in the back of the upper arm using a prefilled autoinjector syringe with a 27-gauge needle compared with standard intramuscular injection in the gluteus maximus using a 21-gauge needle. METHODS: Healthy postmenopausal women 50 to 75 years old were randomized in a parallel group design to receive a single SC injection of 1.1 mL (275-mg total dose) of preservative-free HPC administered using an autoinjector in the back of the upper arm or a single IM injection of 1 mL (250-mg total dose) of preservative-free HPC administered in the gluteus maximus. Blood samples were collected through 1008 hours (42 days) after injection. The primary measures were the Cmax, AUC0-t, and AUC0-∞. Secondary measures were Tmax, ke, t½, and injection site reactions captured as a treatment-emergent adverse event. FINDINGS: The pharmacokinetic population consisted of 90 individuals; 45 received subcutaneous administration and 45 received intramuscular administration. Geometric mean whole blood concentrations of HPC were comparable between administration regimens. Subcutaneous administration resulted in a higher geometric mean Cmax than intramuscular administration (7.88 vs 6.91 ng/mL), but median Tmax values were comparable (48.1 vs 49.7 hours). The least square geometric mean ratios for AUC0-168), AUC0-t, and AUC0-∞ were 102.89%, 110.25%, and 113.51%, respectively, with all 90% CIs within the 80.0% to 125.0% window that defined bioequivalence. The ratio for Cmax was 113.95% with a 90% CI of 91.94% to 141.23% but with substantial overlap of individual values between administration regimens. The geometric mean t½ of HPC was 212 hours for the subcutaneous administration and 188 hours for the intramuscular administration. The most common treatment-emergent adverse event was injection site pain (subcutaneous, 37.3%; intramuscular, 8.2%), described as mild (85%) to moderate (15%). IMPLICATIONS: Administration of HPC by SC injection of 1.1 mL (275 mg) via autoinjector is bioequivalent to IM injection of 1.0 mL (250 mg). ClinicalTrials.gov identifier: NCT02940522.

Pharmacodynamic effects of once-a-month combined injectable contraceptives.

The pharmacology and clinical assessment of existing first generation once-a-month combined injectable contraceptives, mainly Deladroxate and Chinese Injectable No. 1, are reviewed. Although these two types of monthly injectables have been used in some million women in China and Latin America, Deladroxate needs indepth re-evaluation of its long-term toxicity and possible accumulation. For injectable No. 1, its disadvantage of being administered on an erratic schedule will cause significant confusion in family planning practice. When used in a strict once-a-month schedule, it is not sufficiently effective for contraception. In order to attain predictable menstrual cycle control as well as high efficacy with a 30-day injection schedule, two improved once-a-month injectable formulations, Cyclofem and Mesigyna, were developed. Pharmacokinetic/pharmacodynamic study on estrogenic components suggested that estradiol valerate and cypionate were suitable estrogen esters to give elevated plasma estrogen levels for 7 to 11 days. After a single injection of Cyclofem and Mesigyna, both formulations showed equal contraceptive effect with inhibition of follicle maturation for some 30 days and ovulation, corpus luteum formation for some 60 days. Multicentre studies on the optimization of dosages of progestogens and estrogens in once-a-month injectables confirmed that the full doses of Cyclofem (DMPA 25 mg/estradiol cypionate 5 mg) and Mesigyna (NET-EN 50 mg/estradiol valerate 5 mg) are suitable for large scale clinical trials. Pharmacodynamics and progestogen/estrogen ratio study indicated the importance of not only the absolute amounts of the progestogen and estrogen but also of their ratio. Reduction of estrogen dose resulted in breakthrough ovulation with both Cyclofem and Mesigyna. Also, it is important to note that the second part of the injection cycle is dominated by the progestogen component of both monthly formulations. A longitudinal study indicated that there is no accumulation of norethisterone after 12 months of treatment with NET-EN 50 mg and estradiol valerate 5 mg.

PIP: About 1 million women in Latin America and China have used the 1st generation once-a-month combined injectable contraceptives Deladroxate and Chinese Injectable No. 1. Animal toxicity studies of Deladroxate found pituitary hyperplasia in rats, breast tumors in beagles, and accumulation of estradiol enanthate in the body. Thus, long-term toxicity and accumulation of Deladroxate need to be reevaluated. The erratic schedule of the Injectable No. 1 (initially administered on day 5 with 2 ampoules or 1 dose on day 5 and 1 dose on day 12; subsequent administration on the 10-12th day of the cycles) will confuse acceptors and family planning providers. Yet, a strict once-a-month cycle of Injectable No. 1 does not adequately protect against conception. Researchers have developed 2 improved once-a-month injectable formulations, Cyclofem and Mesigyna, to achieve good menstrual cycle control and high efficacy. The estrogen components of both formulations (estradiol valerate and cypionate) sufficiently elevate plasma estrogen levels for 7-11 days. One injection of both formulations inhibits follicle maturation for about 30 days and ovulation and corpus luteum formation for about 60 days. The doses of Cyclofem (25 mg depot-medroxyprogesterone acetate + 5 mg estradiol cypionate) and Mesigyna (50 mg norethindrone acetate + estradiol valerate) have been found to be optimal for use in large scale clinical trials. Not only are the absolute amounts of the progestogen and estrogen important, but also the progestogen/estrogen ratio. A lower estrogen dose in both Cyclofem and Mesigyna effects breakthrough ovulation. The progestogen component predominates the 2nd part of the injection cycle in both formulations. Norethindrone does not accumulate in the body after 12 months of treatment with Mesigyna.

17-alpha-Hydroxyprogesterone caproate and natural progesterone in assisted reproduction: a comparative study.

The use of luteal phase support has been demonstrated in patients undergoing an IVF/ET procedure. This study was designed to compare the absorption and the efficacy of two different luteal supports: 17-alpha-hydroxyprogesterone caproate (Lentogest, AMSA, Italy) and natural Progesterone (Prontogest, AMSA, Italy). A total of 80 patients received luteal supplementation with 50 mg of natural P/day intramuscularly, until beta-hCG evaluation. Then, in case of positive beta-hCG, patients were randomly divided into two groups (A and B) in order to compare two different protocols: Group A, 17-OHPc (341 mg once a week) and Group B, natural P (50 mg/day) both intramuscularly and extended for 10-12 weeks. Our study showed that the treatment with 17-OHPc results in a higher percentage of pregnancy rate compared to natural P, but the differences are not statistically significant. Thus, we emphasize that 17-OHPc preparation for better acceptance appears to be the most suitable and comfortable method for luteal phase support.

17α Hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth.

Use of 17-alpha-hydroxyprogesterone caproate for the prevention of spontaneous preterm birth in women at risk is reviewed. Early studies regarding this topic reached contradicting conclusions, however recent studies showed that weekly injections of 17-alpha-hydroxyprogesterone caproate beginning at 16-20 weeks' gestation resulted in a substantial reduction in the rate of spontaneous recurrent preterm birth. Long-term follow-up of children exposed in-utero to the drug has shown normal growth and development and normal scores for gender specific roles. In conclusion, 17-alpha-hydroxyprogesterone caproate is currently the only drug with sufficient evidence to support its use for prevention of spontaneous recurrent preterm birth.

17 α-Hydroxyprogesterone caproate (Makena™): in the prevention of preterm birth.

17 α-hydroxyprogesterone caproate is a synthetic progestin of which there is now a US FDA-approved formulation available for intramuscular administration (Makena™) to reduce the risk of preterm birth. Intramuscular 17 α-hydroxyprogesterone caproate (identical in formulation and manufacturing process to Makena™, thus hereafter referred to as Makena™) 250 mg once weekly, initiated at 16-20 weeks' gestation, was effective in reducing the risk of preterm birth in women with a singleton pregnancy at high risk of delivering preterm in a large, well designed, placebo-controlled trial (n = 463 randomized). Rates of delivery before 37 (primary endpoint), 35, or 32 weeks' gestation were significantly lower with Makena™ than with placebo, corresponding to relative risk reductions of 34%, 33%, and 42%, respectively. The benefit of the drug in reducing the risk of preterm birth was observed when deliveries were spontaneous (but not when indicated because of complications) and regardless of maternal race. In addition, there was a significantly lower rate of several adverse fetal/neonatal outcomes among infants of women who received Makena™ than among infants of placebo recipients, including necrotizing enterocolitis, need for supplemental oxygen, birth weight of <2500 g, and intraventricular hemorrhage. Makena™ was generally well tolerated in pregnant women in this trial. Moreover, fetal exposure to the drug appeared to be safe according to a 2- to 5-year follow-up of the study, with no evidence of a detrimental effect of the drug on child neurodevelopment and a low overall incidence (≈2%) of reproductive or genital abnormalities that was not significantly different from placebo.

Detection of 17alpha-hydroxyprogesterone caproate in equine plasma by gas chromatography/tandem mass spectrometry.

A method was developed for the analysis of the synthetic progestin 17alpha-hydroxyprogesterone caproate in equine plasma following its administration by intramuscular injection. The method employed a reversed-phase solid-phase extraction followed by enol-trimethylsilylation and analysis by gas chromatography/tandem mass spectrometry. The intact ester was detectable in the plasma for up to 2 weeks after a single therapeutic dose, and was found to be stable in equine whole blood for at least 2 months.

The in vitro metabolism of 17-hydroxyprogesterone by ovaries of the goldfish, Carassius auratus, is affected by substrate concentration.

Ovaries of mature goldfish (Carassius auratus) were incubated with 17-[3H]hydroxyprogesterone and 0, 0.01, 0.1, 1, 10, and 100 micrograms/ml 17-hydroxyprogesterone (17P). The major products were quantified after separation by thin-layer and high-performance chromatography. The results show that substrate concentration markedly affects the pattern of metabolites. Glucuronides and sulfates decreased from 7.2 +/- 2.0 and 28.5 +/- 4.4% of recovered radioactivity, respectively, in the absence of added 17P to insignificant yields at 10 micrograms/ml 17P. 7 alpha-Tetrols were the major products (36-52%) with 0-1 microgram/ml substrate, but at 10 and 100 micrograms/ml 17,20 alpha-dihydroxy-4-pregnen-3-one (17,20 alpha P) was the major metabolite and there were low yields of other products. 11-Deoxycortisol was produced in significant amounts only at low substrate concentrations. The results support the hypothesis that 5 alpha-reduced-7 alpha-hydroxylated metabolites are formed by enzymes of high activity but low capacity and serve to limit secretion of 17,20 alpha P and its 20 beta epimer to the period of maximum GtH stimulation.

[Comparison of the kinetics of the response of salivary and plasma 17-hydroxyprogesterone to the administration of HCG in men]. / Comparaison de la cinétique de la réponse de la 17-hydroxyprogestérone salivaire et plasmatique à l'administration de hCG chez l'homme.

17-hydroxyprogesterone (17-OHP) time course response to hCG (5,000 IU) was studied simultaneously in the saliva and the plasma of 12 adult healthy men. In both fluids, 17-OHP was determined by radioimmunossay after chromatography on Sephadex LH-20 columns of diethyl ether extracts. The use of an iodinated tracer has greatly increased the sensitivity of the technique. Baseline levels in plasma and saliva were: 1.0 +/- 0.1 ng/ml (mean +/- SEM) and 24 +/- 2 pg/ml respectively. After hCG, a biphasic pattern was observed in both fluids with a similar early response but the peak elicited at 33 h in plasma was not observed in saliva where the levels were lower than those recorded at 24 h. At 48 h saliva 17-OHP increased again to levels similar to those at 24 h. Thus the 17-OHP pattern in saliva was the mirror image of that found in plasma. Since saliva steroids are believed to reflect the plasma non-protein bound fraction, this difference was assumed to be due to the decrease of the unbound fraction of plasma 17-OHP in the late afternoon as a consequence of the increase of the CBG-bound fraction since at that time cortisol levels are low. Indeed the ratios of saliva to plasma 17-OHP levels were found to be significantly correlated with plasma cortisol levels: r = 0.44 (p less than 0.01; n = 140). Thus the absence of the secondary peak at 33 h may be due to cortisol circadian rhythm. However the similar response in saliva at 24 and at 48 h after hCG was enough important to make reliable the evaluation of the endocrine testicular function so that saliva may be collected instead of plasma in the hCG stimulation test protocol.

The role of hormones in the acquisition of sperm motility in salmonid fish.

In salmonid fish, spermatozoa taken from the testes are immotile, but acquire motility during their passage through the sperm duct. Using male masu salmon (Oncorhynchus masou), we found that gonadotropin-induced testicular production of 17 alpha, 20 beta-dihydroxy-4-pregnen-3-one (17 alpha, 20 beta-DP), the oocyte maturation-inducing hormone of salmonid fish, is responsible for the acquisition of sperm motility. However, neither testosterone (T) nor 11-ketotestosterone (11-KT), the two major androgens in teleost fish, were effective. We also present evidence that 17 alpha, 20 beta-DP action is mediated through an increase in sperm duct pH, which in turn increases the cAMP content of sperm allowing the acquisition of motility.

Fetal lamb 3 beta, 20 alpha-hydroxysteroid oxidoreductase: dual activity at the same active site examined by affinity labeling with 16 alpha-(bromo[2'-14C]acetoxy)progesterone.

3 beta,20 alpha-Hydroxysteroid oxidoreductase was purified to homogeneity from fetal lamb erythrocytes. The Mr 35,000 enzyme utilizes NADPH and reduces progesterone to 4-pregnen-20 alpha-ol-3-one [Km = 30.8 microM and Vmax = 0.7 nmol min-1 (nmol of enzyme)-1] and 5 alpha-dihydrotestosterone to 5 alpha-androstane-3 beta, 17 beta-diol [Km = 74 microM and Vmax = 1.3 nmol min-1 (nmol of enzyme)-1]. 5 alpha-Dihydrotestosterone competitively inhibits (Ki = 102 microM) 20 alpha-reductase activity, suggesting that both substrates may be reduced at the same active site. 16 alpha-(Bromoacetoxy)progesterone competitively inhibits 3 beta- and 20 alpha-reductase activities and also causes time-dependent and irreversible losses of both 3 beta-reductase and 20 alpha-reductase activities with the same pseudo-first order kinetic t1/2 value of 75 min. Progesterone and 5 alpha-dihydrotestosterone protect the enzyme against loss of the two reductase activities presumably by competing with the affinity alkylating steroid for the active site of 3 beta,20 alpha-hydroxysteroid oxidoreductase. 16 alpha-(Bromo[2'-14C]acetoxy) progesterone radiolabels the active site of 3 beta,20 alpha-hydroxysteroid oxidoreductase wherein 1 mol of steroid completely inactivates 1 mol of enzyme with complete loss of both reductase activities. Hydrolysis of the 14C-labeled enzyme with 6 N HCl at 110 degrees C and analysis of the amino acid hydrolysate identified predominantly N pi-(carboxy[2'-14C]methyl)histidine [His(pi-CM)].(ABSTRACT TRUNCATED AT 250 WORDS)

Different absorption behaviors among steroid hormones due to possible interaction with P-glycoprotein in the rat small intestine.

The intestinal absorption of ten steroid hormones was evaluated in the rat small intestine, especially focusing on the interaction with intestinal P-glycoprotein (P-gp). Hydrocortisone, prednisolone, 6alpha-methylprednisolone, and dexamethasone (adrenocortical steroid hormones) all disappeared in a regional-dependent manner (duodenum>jejunum>ileum). The decreased rate of disappearance in the lower small intestine seemed to be due to the involvement of absorption barriers like P-gp. In contrast, all sex hormones including progesterone exhibited very high absorbability in the entire small intestine (duodenum=jejunum=ileum), possibly demonstrating the absence of restricted absorption by intestinal P-gp. Progesterone enhanced the rate of disappearance of vinblastine but did not affect 6alpha-methylprednisolone. In the presence of vinblastine and verapamil, on the other hand, the rate of disappearance of 6alpha-methylprednisolone increased significantly. It was demonstrated that there was a plural P-gp family, which had different substrate specificities, in the rat intestine and that steroid hormones interacted with them as substrates or inhibitors in a very complex manner.

In vitro metabolism of progesterone, 17-hydroxyprogesterone, and 17,20 beta-dihydroxy-4-pregnen-3-one by ovaries of the common carp Cyprinus carpio: production rates of polar metabolites.

[14C]Progesterone, 17-[3H]hydroxyprogesterone, and 17,20 beta-[3H]dihydroxy-4-pregnen-3-one (17,20 beta P) were incubated for 1, 3, 6 or 24 hr with ovaries from carp which had received injections of either carp pituitary extract or saline. All three substrates were very rapidly metabolized to polar products, but 17,20 beta P was not detected as a metabolite of either progesterone or 17-hydroxyprogesterone. The major metabolite in all incubations was very similar, but not identical, in chemical and chromatographic properties to 5 beta-pregnane-3 alpha, 6 alpha, 17,20 beta-tetrol. A compound isopolar with 5 beta-pregnane-3 alpha, 6 alpha, 17,20 alpha-tetrol was isolated only in incubations of progesterone and 17-hydroxyprogesterone. It is suggested that hydroxylation and reduction may be a deactivation mechanism allowing 17,20 beta P to build up as an intermediate, and active maturation inducing steroid, only in response to the ovulatory gonadotrophin surge, thus assisting in synchrony of oocyte maturation.