The etiology of polycystic ovary syndrome is uncertain, though excess LH stimulation of the ovaries is involved in the majority of patients (PCOS type 1). The concept that polycystic ovarian syndrome may reflect an abnormality in the set point of the hypothalamic feedback of E2 and P on the GnRH pulse generator will be explored. This will be tested by a comparison of dose response curves of suppression of GnRH pulse frequency after varying P concn in normal control and PCOS type 1 women. Preliminary data suggest that slowing the frequency of GnRH secretion required a higher progesterone concentration in PCOS women compared to normal controls. Hyperandrogenemia and hyperinsulinemia are features of PCOS.
In specific aim 2, studies will delineate the potential roles of hyperandrogenemia and hyperinsulinemia in the maintenance of LH hypersecretion in PCOS. GnRH pulse secretion after androgen blockade with flutamide on PCOS and normal women and subsequently the effect of flutamide on E2 and P suppression of LH frequency will be examined. The effects of metformin on insulin sensitivity and LH pulsatility will be examined, and after plasma insulin has been reduced for 5 weeks, delineate if E2 and P suppression of LH frequency is more effective. The results of these studies will provide some insights into the hypothalamic mechanisms involved in maintaining elevated LH plasma levels in PCOS type 1.
