Inhibition and augmentation of progesterone production during pregnancy: effects on parturition in rhesus monkeys

Abstract

Objectives: Uterine quiescence during mammalian pregnancy is attributed to progesterone. However. systemic progesterone levels remain elevated in primates before parturition. Epostane, a selective 3beta-hydroxysteroid dehydrogenase inhibitor, and progesterone (with or without epostane) were administered to late pregnant rhesus monkeys to clarify the role of progesterone in primate parturition.

Study design: On days 122 to 132 of gestation (term 167 days), 11 rhesus monkeys (Macaca mulatta) with timed pregnancies were divided into three treatment groups: (1) epostane alone (10 mg/kg subcutaneously), (2) epostane with progesterone subcutaneously in Silastic silicone rubber capsules, and (3) progesterone implants only with no surgical instrumentation. Maternal and fetal blood and amniotic fluid were sampled for progesterone, estrone, estradiol, cortisol, testosterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and amniotic fluid was sampled for prostaglandins E2 and F2alpha. Uterine activity was monitored continuously by electromyography and intraamniotic pressure. Cervical status was assessed by a modified Bishop's score. Production of prostaglandins E2 and F2alpha by amnion was determined by tissue superfusion. The group of three noninstrumented monkeys, which received only progesterone Silastic silicone rubber implants subcutaneously at 146 to 148 days, were observed until spontaneous vaginal delivery.

Results: Epostane reduced maternal and fetal progesterone levels by 75% and 50%, respectively, followed by increased uterine activity and cervical ripening within 24 hours and vaginal delivery within 48 hours. Amniotic fluid progesterone decreased to undetectable levels. Progesterone implants prevented the epostane-induced decrease in maternal and fetal progesterone levels and the associated myometrial and cervical changes until the implants were removed. Alterations in other steroid hormones were consistent with inhibition of 3beta-hydroxysteroid dehydrogenase. Amniotic prostaglandin E2 production was increased sixfold by epostane (p < 0.05) but did not reach the high levels normally seen at spontaneous parturition. Animals that received progesterone implants alone had markedly elevated circulating progesterone concentrations yet were delivered spontaneously at term (range 163 to 167 days).

Conclusions: Progesterone withdrawal induces preterm labor and delivery (which can be blocked by progesterone substitution) but exogenous progesterone, even in substantial quantities, does not prevent parturition at term.