Embryotoxicity of sex steroidal hormones in nonhuman primates: II. Hydroxyprogesterone caproate, estradiol valerate

Abstract

Two sex steroid compounds which have been used clinically for parenteral supportive therapy of pregnancy were examined for embryotoxic effects in rhesus and cynomolgus macaques. Hydroxyprogesterone caproate (HPC) alone or in combination with estradiol valerate (EV) were administered intramuscularly (i.m.) to pregnant monkeys at 7-day intervals between 20 and 146 days of gestation and fetuses were examined following cesarean section at 150 +/- 2 days. HPC alone was tested in both species at doses ranging from 0.01 X to 10 X the human dose equivalent (HDE); only rhesus monkeys were exposed to the HPC + EV combination at 0.1 X to 10 X HDE. Total embryolethality resulted following the administration of HPC alone and combined with EV at 1 X and 10 X HDE in rhesus monkeys; the level of abortions in cynomolgus monkeys exposed to HPC (0.1 X to 1 X HDE) was comparable to controls. A small number of nonspecific malformations and developmental variations observed in cynomolgus fetuses after HPC exposure were considered to be incidental findings. No anomalies were found in surviving rhesus monkey fetuses treated with HPC + EV. The results indicate that long-term in utero exposure to the progestin, HPC, alone or in combination with EV in rhesus and cynomolgus monkeys, is embryolethal but not teratogenic at doses up to ten times the human therapeutic dose.

Metabolism of 17α-Hydroxyprogesterone Caproate, an Agent for Preventing Preterm Birth, by Fetal Hepatocytes

“…17-OHPC has been reported to have a clinical signal for embryofetal toxicity in the human trials conducted to date (Christian et al, 2007), and a similar signal has been observed in rhesus monkeys (Hendrickx et al, 1987). However, in the absence of elaborate reproductive toxicology and pharmacokinetic studies in animals and humans, the data are inconclusive to address the embryo-fetal toxicity issues vis-à-vis 17-OHPC and/or its metabolites.…”

Drugs in infertility and fetal safety

“…Early mouse studies demonstrated teratogenicity of estradiol salts, including cleft palate with estradiol benzoate (64) and eyelid and mammary defects with estradiol dipropionate (65). However, studies in monkeys using estradiol salts in combination with hydroxyprogesterone caproate failed to show a relationship between estrogen and congenital anomalies (66).…”

Guidelines for the management of spontaneous preterm labor: identification of spontaneous preterm labor, diagnosis of preterm premature rupture of membranes, and preventive tools for preterm birth

“…Furthermore, in a recent very large preterm birth prevention study of singleton pregnancies, no cases of miscarriage associated with the use of micronized natural progesterone were observed [102]. On the other hand, 17-OHP-C is associated with an increase in resorption (miscarriage) in pregnant rats [96], total embryo-lethality in pregnant rhesus monkeys [103], a signal for a 30% increase in miscarriage in a meta-analysis of 17-OHP-C clinical studies [81], as well as an imbalance in miscarriage associated with 17-OHP-C in the largest placebo controlled randomized trial published to date [83]. In a study by Rebarber et al [104], patients who received prophylactic treatment with 17-OHP-C had a higher incidence of gestational diabetes (odds ratio 2.9 [95% CI: 2.1-4.1]) than those who were not treated.…”