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-LUTEUMBY PROGESTERONE

Colocalization of progesterone receptors and 3 beta-hydroxysteroid deh ydrogenase (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 macaqu es at the midluteal phase of spontaneous menstrual cycles to rapidly a nd reversibly reduce progesterone production. Animals received trilost ane (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 compare d to those in vehicle-treated animals; after 1 day of treatment, the m ean pregnenolone level (173 nmol/L) was 86-fold greater than the contr ol value. Pregnenolone levels dropped after cessation of drug administ ration and became indistinguishable from control levels by day 13. Tri lostane 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 p hase than vehicle-treated animals (7.8 +/- 0.2 us. 16 +/- 1 days; P < 0.01). Histological analysis (n = 3/group) revealed indexes of prematu re structural luteolysis by 4 days after the onset of trilostane admin istration. Exposure to trilostane had no effect on the percentage of l uteal cells expressing progesterone receptors, as determined by immuno cytochemistry. Serum LH levels were not different between treatment an d control groups throughout the experimental period. As trilostane dra matically reduced serum progesterone and induced premature menses with out 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 cessatio n of trilostane treatment despite continuing gonadotropin support, and exposure to trilostane was associated with premature structural luteo lysis. Thus, progesterone or a related metabolite may be required to m aintain the function and structural integrity of the primate corpus lu teum during the normal menstrual cycle.