This proposal seeks to gain insights into the dynamic interplay between neuroendocrine and metabolic factors underlying two common dysfunctional states of chronic anovulation and the long-term consequences in women with functional hypothalamic amenorrhea (FHA) and polycystic ovary syndrome (PCO). We propose that the insulin/IGFBP-1/IGF-1 system serves as a circadian metabolic marker. We postulate that the centrally initiated alteration of the reproductive axis in FHA is associated with peripheral alterations of the insulin-IGFBP-1-IGF-1 relationship, while PCO represents defects of the hypothalamic-pituitary-ovarian (H-P-O) axis exerted by changes in the insulin-IGF system secondary to tissue specific insulin resistance - hyperinsulinemia with alterations nascent during peripubertal years. Experiments are designed to delineate both the maintenance and reversal of these chronic anovulatory states. In FHA, mechanisms that govern multiple neuroendocrine-metabolic aberrations observed in recent years will be explored such as the metabolic basis of hypoinsulinemia as related to the IGF system and nutritional states; the role of increased CRF drive in the development of hypercortisolism and reduced GnRH/LH pulsatility; the role of altered thyroid hormone binding proteins in reduced serum concentrations of T4 and T3 and the role of adrenergic mechanisms and/or altered photosensitivity in the development of nocturnal hypermelatoninemia. In PCO, studies will be made to define the role of insulin and IGF-1 on the hypersecretion of LH and ovarian hyperandrogenism and effects of fasting and weight reduction on the insulin-IGF system as related to the functional status of the reproductive axis. The paracrine/autocrine role of the insulin-IGF system and inhibin/activin system will be characterized by in situ hybridization, immunocytochemistry and Rnase protection assay in ovarian follicles obtained from PCO patients and from normal women. Finally, longitudinal studies will be conducted to ascertain the natural history, its reversal, and long-term impacts of neuroendocrine and metabolic aberrations in FHA and PCO. In addition, peripubertal hyperandrogenic girls will be studied longitudinally to affirm the hypothesis of peripubertal onset of PCO. Results generated from these studies should provide new insights in the understanding of chronic anovulation in these conditions and afford rational approaches to their management.
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