REPRODUCTIVE AGING AND THE HUMAN HYPOTHALAMUS

我们的总体目标是描述和理解这些事件 发生在人类中枢神经系统对卵巢的反应 绝经失败。在上一个资助期，显著 在描述下丘脑的剧烈变化方面取得了进展。 绝经后女性。下丘脑速激肽升高 绝经后妇女的基因表达，并伴有细胞 肥大。此外，LHRH mRNA的细胞水平是 在内侧基底节内神经元的重排内增加 下丘脑。我们假设这些变化是次要的 是卵巢功能衰竭，而不是年龄本身。目前的建议 通过确定激素停用的影响来检验这一假说 和替换对灵长类神经肽基因表达的影响 下丘脑。在第一个具体目标中，我们将确定是否 幼年食蟹猴的卵巢切除模拟了卵巢指数的增加 LHRH和速激肽基因在绝经后的表达 女人。如果是这样，这将提供令人信服的证据，证明 我们在绝经后妇女身上观察到的变化是由于 卵巢衰竭。在具体目标2和3中，我们将研究 去卵巢的幼猴的下丘脑 治疗方案中的类固醇替代疗法 复制那些给人类开出的处方。在具体目标4中，我们将 经治疗的绝经后妇女的下丘脑检查 激素替代疗法。将使用原位杂交技术 确定激素替代是否能降低LHRH和速激肽 猴和人下丘脑中基因表达的预测 来自我们之前的研究。我们还将确定长期的 持续的雌激素替代产生神经毒性的迹象 人和猴的弓状核。这些研究将提供一个确定的 为了解在中国发生的重要事件奠定基础 绝经后妇女的下丘脑和提供第一 激素替代疗法的神经解剖效应研究进展 灵长类下丘脑的治疗。数百万女性目前 接受激素替代治疗，但对其影响知之甚少 这些治疗方法对中枢神经系统有影响。

Our overall objective is to characterize and understand the events that occur in the human central nervous system in response to the ovarian failure of menopause. In the previous funding period, significant progress was made in describing dramatic changes in the hypothalamus of postmenopausal women. There is increased hypothalamic tachykinin gene expression in postmenopausal women, accompanied by cellular hypertrophy. In addition, cellular levels of LHRH mRNA are increased within a subpoplation of neurons within the medial basal hypothalamus. We have hypothesized that these changes are secondary to ovarian failure and not due to age per se. The present proposal tests this hypothesis by determining the effects of hormone withdrawal and replacement on neuropeptide gene expression in the primate hypothalamus. In the first specific aim, we will determine if ovariectomy of young cynomolgus monkeys mimics the increase in LHRH and tachykinin gene expression that occurs in postmenopausal women. If so, this would provide compelling evidence that the changes we have observed in postmenopausal women are due to ovarian failure. In specific aims 2 and 3, we will examine the hypothalamus of young ovariectomized monkeys that have received steroid replacement therapy in treatment regimens designed to duplicate those prescribed to humans. In specific aim 4, we will examine the hypothalamus of postmenopausal women treated with hormone replacement therapy. In situ hybridization will be used to determine if hormone replacement reduces LHRH and tachykinin gene expression in the monkey and human hypothalamus as predicted from our previous studies. We will also determine if long-term continuous estrogen replacement produces signs of neurotoxicity in the human and monkey arcuate nucleus. These studies will provide a firm foundation for understanding the important events that occur in the hypothalamus of postmenopausal women and provide the first information on the neuroanatomic effects of hormone replacement therapy in the primate hypothalamus. Millions of women are currently receiving hormone replacement but little is known about the effects of these treatments on the central nervous system.