Effects of subchronic implantation of hydrocortisone phosphate-releasing osmotic pumps on peripheral gonadotropin levels and estradiol feedback to gonadotropin secretion in the cynomolgus monkey

The purpose of our study was to investigate subchronic effects of moderate hypercortisol- emia on serum gonadotropin and estradiol (E₂) levels in the primate using a repeated- measures experimental design. Osmotic pumps which released hydrocortisone 21-phosphate (HP) at a dose of 5 mg/day were implanted subcutaneously (s.c.) in each of five cynomolgus monkeys for one menstrual cycle. The pumps were filled with saline for the two control cycles, one of which preceded and one of which followed hormone infusion. Subsequently, osmotic pumps which released HP at a higher dose of 15 mg/day were implanted s.c. in four of the initial five monkeys for the longer period of two menstrual cycles. The pumps were filled with saline for the two additional control cycles, one of which preceded and one of which followed HP infusion at 15 mg/day. The control cycle which followed HP infusion at 5 mg/day and the control cycle which preceded HP infusion at 15 mg/day were separated by at least one menstrual cycle. Administration of HP at the lower dose elevated serum cortisol levels 1.4-fold and decreased serum adrenal androgens to 0.6 of the pretreatment baseline. The higher dose of HP elevated serum cortisol levels 1.7-fold and suppressed serum adrenal androgens to 0.4 of the baseline. In the menstrual cycle following HP infusion serum cortisol levels were depressed to 0.8 and 0.6 of the pretreatment levels after the lower and the higher dose of HP, respectively. Serum levels of adrenal androgens returned to the baseline after the lower dose of HP. but were still suppressed to 0.5 of the baseline after the higher treatment dose. Implantation of pumps which released 5 mg/day of HP did not affect gonadotropin levels in the serum, either in the follicular phase (FP) or the luteal phase (LP) of the menstrual cycle. Serum E;levels were increased by 77% in the FP during HP infusion at 5 mg/day (p < 0.001), but returned to control values in the LP. Implantation of pumps which released 15 mg/day of HP raised serum luteinizing hormone (LH) levels throughout the two menstrual cycles of treatment, by 111 and 96% in FPs (p < 0.001), and by 84 and 70% in LPs (p < 0.001). Conversely, serum follicle-stimulating hormone (FSH) levels were decreased by 45 and 50% in FPs (p < 0.05), and by 54 and 50% in LPs(p < 0.001). The higher dose of HP also resulted in an increase in serum E₂levels by 97 and 118% in FPs (p < 0.05), and by 89 and 81% in LPs (p < 0.05). The lengths of menstrual cycles, FPs and LPs were not significantly affected during or after treatment with either dose of HP. These results provide evidence that moderate elevation of serum cortisol levels for periods equivalent to a maximum of two menstrual cycles in primates:(1) increases circulating LH levels, unlinked to changes in serum E₂ or adrenal androgen levels, and may be dose dependent;(2) decreases circulating FSH levels, which could be explained by increased negative E;feedback on FSH, and (3) may interfere under some conditions with negative E₂feedback on FSH.