Inhibition of ovulation by progestin analogs (agonists vs antagonists): Preliminary evidence for different sites and mechanisms of actions

Abstract Continuous administration of the antiprogesterone RU486 inhibits ovulation in women and in monkeys; in this regard RU486 may act as a progestin agonist rather than as an antagonist. We compared the site(s) and mechanism(s) of RU486-induced ovulation inhibition with those of levonorgestrel (LNG). Six regularly menstruating cynomolgus monkeys each received placebo, RU486 (1 mg/kg/d) or LNG (2 g/kg/d) im between days (cd) 2–22 of three separate menstrual cycles. Serum levels of estradiol (E 2 ), progesterone (P 4 ), androstenedione, LH and FSH were analyzed by RIAs in daily blood samples. Basal and GnRH-stimulated (1 and 50 g of GnRH iv 2 h apart) secretion of LH and FSH was assessed using serial blood samples collected for 12 h on cd 10. Mean cycle length was prolonged by RU486 and LNG treatments from 32 d to 70 d and 52 d, respectively (p 2 levels were similar to those of the control cycle; despite peaks of E 2 secretion, no LH peaks were seen. In contrast, E 2 concentrations were profoundly suppressed during LNG treatment (p 2 was accompanied by lower levels of androstenedione, and suppressed ratio of E 2 /androstenedione (p