A B S T R A C r To evaluate gonadotropin release in polycystic ovary syndrome (PCO), one or more of the following hypothalamic-pituitary function tests were performed on 24 patients with the syndrome. These tests included (a) the pulsatile pattern and day-to-day fluctuation of gonadotropin release; (b) effects of exogenous estrogen and antiestrogen (clomiphene) administration on gonadotropin release; and (c) pituitary responsiveness to maximal (150 i'g) and submaximal (10 Ag) luteinizing hormone-releasing factor (LRF) injections. In 10 of the 14 patients sampled frequently (15 min) for 6 h, luteinizing hormone (LH) levels were elevated above the concentration seen in normal cycling women (except the LH surge). These high LH concentrations appeared to be maintained by and temporally related to the presence of exaggerated pulsatile LH release, either in the form of enhanced amplitude or increased frequency. In all subjects, levels of folliclestimulating hormone (FSH) were low or low normal, and a pulsatile pattern was not discernible. In four patients, daily sampling revealed marked day-to-day fluctuation of LH but not FSH. That the elevated LH levels were not related to a defect in the negative-feedback effect of estrogen was suggested by the appropriate fall of LH in four patients given an acute intravenous infusion of 17fi-estradiol. This infusion had no effect on FSH levels. In addition, clomiphene elicited rises of both LH and FSH that were comparable to the ones observed in normal women given the same treatment. The clomiphene study also suggested that the positive-feedback mechanism of estrogen on LH release was intact when the preovulatory rises of 179-estradiol induced appropriate LH surges. The elevated LH levels appeared to be related to a heightened pituitary responsiveness to the LRF. This was found in the 11 and 2 patients given maximal (150 sg) and submaximal (10 /Ag) doses of LRF, respectively. The augmented pituitary sensitivity for LH release correlated with the basal levels of both estrone (P <0.025) and 17j8-estradiol (P < 0.02). The net increase in FSH was significantly greater (P < 0.001) in the PCO patients than the normal women with maximal doses of LRF. With the smaller dose study, none of the injections had a discernible effect on FSH concentrations in either subject. The disparity between LH and FSH secretion could be explained by the preferential inhibitory action of estrogen on FSH release, coupled with a relative insensitivity of FSH release.These data indicate that in these PCO patients the abnormalities of the hypothalamic-pituitary regulation of gonadotropin secretion was not an inherent defect but represented a functional derangement consequent to inappropriate estrogen feedback, which led to a vicious cycle of chronic anovulation and inappropriate gonadotropin secretion.

The influence of endogenous estradiol (E2) levels on gonadotropin and PRL sensitivity to dopamine (DA) infusion (4 micrograms/kg/min) was assessed at different stages of the follicular phase of the menstrual cycle. Basal LH and FSH levels were comparable in day 2 and day 12 subjects, and despite a 4-fold increase in E2 concentration, the inhibition of LH by DA was small and quantitatively similar and there was no discernible effect on FSH in either group. In marked contrast, day 14 subjects with an elevated basal LH level exhibited a dramatic increase in the sensitivity of LH and FSH to DA inhibition. Further, a remarkable rebound release for LH but not FSH occurred on the termination of DA infusion. There was a significant correlation between basal LH and response to DA (r = 0.979). This unique increase in response to DA at a time when hypothalamic LRF secretion is assumed to be elevated suggests that DA may exert its effect by inhibiting LRF release. The inhibition of PRL release by DA is correlated with endogenous E2 levels (r equal 0.685) as well as basal PRL levels (r = 0.878). Rebound release of PRL occurs in all three groups of women on termination of the DA infusion, but the magnitude was greatest in Day 14 subjects with the highest endogenous E2 levels. These data suggest that while E2 seems to augment the sensitivity of PRL inhibition by DA, its does not seem to directly influence gonadotropin sensitivity to DA inhibition. The selective hypersensitivity of both LH and FSH to DA observed on the day before midcycle LH peak is consistent with a reduction in LRF neuronal inhibition by tuberoinfundibular DA neurons at this time.

The elevated LH secretion in 8 patients with the polycystic ovarian syndrome (PCO) was promptly suppressed by the infusion of dopamine (DA; 4 microgram/kg.min for 4 h). Compared to normal women studied during the early follicular phase, the maximal LH suppression due to DA infusion was significantly greater in PCO patients when expressed as either the net or percent decrease. This enhanced LH sensitivity to DA inhibition in PCO patients with chronically elevated estrogens, suggests that the inappropriately elevated LH release and the exaggerated LH pulses may be causally related, in part, to a reduction of endogenous DA inhibition of LH secretory activity.

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