NEUROENDOCRINE METABOLIC CONTROL OF THE MENSTRUAL CYCLE

本提案旨在深入了解以下方面之间的动态相互作用： 神经内分泌和代谢因素的基础上两个常见的功能失调 慢性无排卵状态及其对女性的长期影响 功能性下丘脑性闭经与多囊卵巢综合征 （PCO）。 我们建议胰岛素/IGFBP-1/IGF-1系统作为一个 昼夜代谢标志物 我们假设， FHA中生殖轴的改变与外周 胰岛素-IGFBP-1-IGF-1关系的改变，而PCO代表 下丘脑-垂体-卵巢（H-P-O）轴的缺陷 继发于组织特异性胰岛素的胰岛素-IGF系统的变化 抵抗-高胰岛素血症伴青春期初期改变 年 实验的目的是描绘维护和 逆转这些慢性无排卵状态。 在FHA中， 近年来观察到的多种神经内分泌代谢异常 年将探索，如低胰岛素血症的代谢基础， 与胰岛素样生长因子系统和营养状态相关;慢性肾功能衰竭增加的作用 促使皮质醇增多症和GnRH/LH降低 甲状腺激素结合蛋白改变在 降低血清T4和T3浓度以及肾上腺素能受体的作用 机制和/或改变的光敏性在夜间发展 高褪黑素血症 在公署方面，我们会进行研究， 胰岛素和IGF-1对LH分泌过多和卵巢高雄激素血症的影响 以及禁食和减肥对胰岛素-IGF系统的影响， 与生殖轴的功能状态有关。 的 胰岛素-IGF系统的旁分泌/自分泌作用和胰岛素样生长因子/激活素 系统将通过原位杂交、免疫细胞化学 PCO患者卵泡中RNA酶和RNA酶保护试验 和正常女性的。 最后，将进行纵向研究， 确定自然历史，其逆转，以及长期影响 FHA和PCO中的神经内分泌和代谢畸变。 此外，本发明还提供了一种方法， 将对围青春期高雄激素女孩进行纵向研究， PCO的青春期发病假说。 从这些产生的结果 研究应该提供新的见解，在理解慢性 在这些条件下不排卵，并提供合理的方法， 管理

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.