Consistent features ofpolycystic ovarian syndrome (PCOS) include anovulation and hyperandrogenemia. In different individuals, these may be associated with hyperinsulinemia, obesity and associated disorders such as dyslipidemia. LH levels are elevated in up to 90% of patients when recent ovulation (and transient suppression of LH) has been excluded. The elevated LH reflects a persistently rapid frequency of GnRH secretion, enhancing LH synthesis, secretion and consequent androgen production by the ovary. An important aspect of normal ovulatory cycles is the differential synthesis and secretion of FSH and LH at different cycle stages. The ability to differentially secrete LH or FSH relates in part to changes in GnRH pulse frequency (slow frequency favors FSH) and slowing the GnRH pulse generator is effected by luteal progesterone (P). In PCOS, sensitivity to P is reduced by hyperandrogenemia and GnRH pulse frequency remains persistently rapid, leading to excess LH, normal or low FSH, excess androgen production and acyclicity. In SA1, we aim to pursue the primacy of P as the regulator of the GnRH pulse generator in normal women, in support of a thesis that elevation of P inhibits the rapid GnRH (1 pulse/h) secretion present after sexual maturation in adolescents. We also examine if excess androgens impair P induction of increased hypothalamic opioid activity, as a mechanism for reduced inhibition of GnRH pulse secretion. SA2 seeks to examine hypothalamic abnormalities in hyperandrogenemic adolescents, where hyperandrogenemia and abnormal LH secretion is documented and thought to be the forerunner of adult PCOS. We plan to determine ifhyperandrogenemia exerts similar inhibitory actions on P suppression of GnRH in adolescents prior to and after menarche. We will also study nocturnal LH, FSH and steroid secretion in eu- and hyperandrogenemic adolescent girls, to determine ifP effects the daytime suppression of GnRH pulse secretion during early pubertal maturation. If so, pubertal exposure to excess androgens may have similar actions to those seen in adults, leading to persistent 24 h GnRH secretion. In SA3, we aim to examine the efficacy of anti-androgens in enhancing the ability of P to inhibit GnRH pulse secretion, in efforts to enhance subsequent selective FSH secretion and follicular maturation upon steroid withdrawal. Our goal is to use physiologic principles to design protocols, which will inhibit the production of excess androgens and allow induction of cyclical follicular maturation and ovulation.
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