ACUTE ADMINISTRATION OF A 3-BETA-HYDROXYSTEROID DEHYDROGENASE INHIBITOR TO RHESUS-MONKEYS AT THE MIDLUTEAL PHASE OF THE MENSTRUAL-CYCLE - EVIDENCE FOR POSSIBLE AUTOCRINE REGULATION OF THE PRIMATE CORPUS-LUTEUM BY PROGESTERONE

Colocalization of progesterone receptors and 3 beta-hydroxysteroid dehydrogenase (3 beta HSD), a key enzyme in progesterone biosynthesis, in macaque luteal cells suggests that progesterone has an autocrine role in the regulation of primate luteal function. To test this hypothesis, we administered trilostane, a 3 beta HSD inhibitor, to rhesus macaques at the midluteal phase of spontaneous menstrual cycles to rapidly and reversibly reduce progesterone production. Animals received trilostane (600 mg/dose; treated group; n = 5) or vehicle (control group; n = 4) orally on days 6-7 of the luteal phase. Trilostane significantly (P < 0.05) elevated pregnenolone levels within 1 h of treatment compared to those in vehicle-treated animals; after 1 day of treatment, the mean pregnenolone level (173 nmol/L) was 86-fold greater than the control value. Pregnenolone levels dropped after cessation of drug administration and became indistinguishable from control levels by day 13. Trilostane significantly reduced serum progesterone levels within 3 h of initial administration (P<0.01), and levels remained near baseline (1.0 nmol/L) throughout the 2 days of treatment. Progesterone levels also remained low after cessation of trilostane treatment in four of five monkeys, and trilostane-treated animals experienced a shorter luteal phase than vehicle-treated animals (7.8 +/- 0.2 us. 16 +/- 1 days; P < 0.01). Histological analysis (n = 3/group) revealed indexes of premature structural luteolysis by 4 days after the onset of trilostane administration. Exposure to trilostane had no effect on the percentage of luteal cells expressing progesterone receptors, as determined by immunocytochemistry. Serum LH levels were not different between treatment and control groups throughout the experimental period. As trilostane dramatically reduced serum progesterone and induced premature menses without a major concurrent alteration in serum cortisol, we conclude that trilostane is an effective, rapidly acting inhibitor of 3 beta HSD in the macaque corpus luteum during the midluteal phase of the menstrual cycle. Progesterone production did not typically resume after cessation of trilostane treatment despite continuing gonadotropin support, and exposure to trilostane was associated with premature structural luteolysis. Thus, progesterone or a related metabolite may be required to maintain the function and structural integrity of the primate corpus luteum during the normal menstrual cycle.