THE IMPACT OF SUBCHRONIC HYPERCORTISOLEMIA ON PROGESTERONE METABOLISMAND THE LUTEINIZING HORMONE-PROGESTERONE AXIS IN THE CYNOMOLGUS MONKEY

The purpose of the study was to assess the impact of subchronic hyperc ortisolemia on progesterone (P) metabolism and production and on perip heral LH levels in a nonhuman primate using a repeated measures experi mental design. Osmotic pumps that released hydrocortisone phosphate (H P) at a dose of 15 mg/day were implanted sc in seven cynomolgus monkey s for two menstrual cycles. The pumps were filled with saline for the two control cycles, which either preceded (three animals) or followed (four animals) HP infusion. P metabolism, P production, and episodic s ecretion of LH were determined 8 +/- 1 days after the serum estradiol peak in the second control cycle and in the second cycle of HP infusio n in each monkey, after iv bolus administration of 50 mu Ci [H-3]P, fo llowed by a 6-h blood sampling period. HP infusion elevated serum cort isol levels 1.6-fold. Serum P levels were decreased throughout the lut eal phase by 58% (P < 0.01). The MCR of P and the volume of distributi on at steady state of P were increased by 200% during HP infusion (bot h P < 0.005). The production rate of P was increased by HP treatment i n five of seven monkeys. HP infusion increased the ratio of 20 alpha-[ H-3]dihydroprogesterone to [H-3]P in serum from 0.5 to 1.0 (P < 0.05) while decreasing the fraction of [H-3]P and its metabolites excreted i n urine from 20% to 11% (P < 0.05). Serum LH levels, determined over a 5.25-h period in the luteal phase, were elevated by 200% during HP tr eatment (P < 0.05). Episodic secretion of LH during treatment was char acterized by a 660% increase in the pulse amplitude (P < 0.05) and an apparent decrease in the pulse frequency. The results of this study pr ovide evidence that moderate elevation of serum cortisol levels for tw o menstrual cycles in primates 1) increases the MCR of P, which may be the cause of the observed decrease in serum P levels; and 2) elevates serum LH levels by amplifying its pulse amplitude, which may result i n a compensatory rise in the production rate of P.