Genital and nongenital teratogenesis of prenatal progestogen therapy: the effects of 17 alpha-hydroxyprogesterone caproate on embryonic and fetal development and endochondral ossification in the C57B1/6J mouse.

Abstract

The current study assesses the effects of 17 alpha-hydroxyprogesterone caproate on embryo-fetal development, with a particular focus placed on intrauterine endochondral bone development and growth. Primigravid C57 BI/6J mice were administered 17 alpha-hydroxyprogesterone caproate by means of subdermal pellets designed to deliver doses of 0.5, 5.0, and 50.0 mg/kg/day on gestational days 7 through 19. Assuming a dosage regimen of 250 mg per 50 kg per week in humans for the treatment of threatened spontaneous abortion, the doses used were 0.7, 7.0, and 70.0 times the human dose equivalent. The time course of exposure encompassed the period of organogenesis through the late fetal period. No maternal toxicity was noted throughout the course of 17 alpha-hydroxyprogesterone caproate administration. Fetal weight at term and the percentage of resorptions, dead fetuses, male fetuses, and malformations at term were not significantly affected at any evaluated dose when compared with control group values. The steroid did not exert a significant influence on any assessed parameter of endochondral bone development or growth, even at a dosage concentration that far exceeded the human therapeutic dose equivalent. As would be expected, fetal weight was directly correlated with diaphyseal length and also influenced the relationship of cartilage to osseous tissue in both the humeri and femora. There were no 17 alpha-hydroxyprogesterone caproate dose and fetal sexual phenotype interactive effects noted with regard to any developmental or bone growth parameter measured, thus discounting any sexual phenotype-related toxic or teratogenic sensitivities. The data indicate that 17 alpha-hydroxyprogesterone caproate administered at doses of up to 70 times the human dose equivalent did not induce increases in the frequency of genital and, importantly, nongenital teratogenesis in spite of exposure during the critical period of organogenesis. Additionally, the steroid did not affect limb morphogenesis or endochondral ossification.