Chronic hyperestrogenemia: lack of positive feedback action on gonadotropin-releasing hormone-induced luteinizing hormone release and dual site of negative feedback action

Abstract

To test whether sustained midfollicular estrogen concentrations sensitize the pituitary response to GnRH in the continued presence of a GnRH stimulus, six female monkeys with regular menstrual cycles were administered hourly pulses of GnRH in the presence or absence of an sc estrone implant. Three were studied in a sequence of 2- to 8-week blocks of 1) control, 2) hourly pulses of exogenous GnRH (6 micrograms/1 min), 3) hourly GnRH pulses plus an estrone (E1) implant, and 4) the E1 alone. In the other three animals the sequence was 1) control, 2) E1, 3) E1 implant plus hourly GnRH pulses, and 4) GnRH pulses only. E1 increased mean estradiol concentrations from 55 pg/ml to 100 pg/ml and the corresponding E1 concentrations from 95 pg/ml to 160 pg/ml. LH concentrations, excluding midcycle surges, were 10.9 +/- 2.2 (SEM) ng/ml, 12.6 +/- 1.5 ng/ml, 11.7 +/- 1.5 ng/ml, and undetectable (less than 6 ng/ml) for the control, GnRH, GnRH plus E1, and E1-treatment periods, respectively. Of note was the suppression of LH concentrations to undetectable levels by midfollicular concentrations of estrogen during the E1-alone treatment period, and the return of LH concentrations to normal follicular phase levels by the application of exogenous GnRH support. This observation suggested that an estrogen negative feedback signal can suppress endogenous GnRH. To further examine this hypothesis we applied the same protocol to two hypogonadal female monkeys. E1 capsule placement increased the mean estradiol concentration from 22 to 61 pg/ml and suppressed LH and FSH to undetectable levels. When hourly pulses of GnRH (6 micrograms/1 min) were supplied, mean LH and FSH increased to 29.8 and 14.9 ng/ml, respectively. These studies demonstrate that elevation of estrogen concentrations to midfollicular levels does not sensitize the pituitary to GnRH stimulation, and pituitary sensitization is therefore unlikely to be important as a cause of elevated LH secretion in anovulatory states, such as the polycystic ovaries syndrome. In the hypogonadal monkeys, a 5-fold decrease in gonadotropin concentrations occurred in spite of full exogenons GnRH support, consistent with a hypophyseal site of estrogen negative feedback action. However, the GnRH clamp did prevent the complete suppression of LH and FSH noted when only estrogen was applied, consistent with an additional negative feedback effect on the hypothalamus. Although this same phenomenon is observed in the eugonadal monkeys, it appears unlikely that a hypothalamic site of estrogen inhibition plays a significant role during the menstrual cycle, otherwise the progressive rise in follicular phase estrogen concentrations would, by arresting GnRH secretion, abort folliculogenesis.