REPRODUCTIVE AGING AND THE HUMAN HYPOTHALAMUS

我们的总体目标是描述和理解 发生在人类中枢神经系统，以响应卵巢 更年期的失败 在上一个供资期间， 在描述下丘脑的巨大变化方面取得了进展 绝经后的妇女。下丘脑速激肽增加 绝经后妇女的基因表达，伴随着细胞 肥厚此外，LHRH mRNA的细胞水平是 在内侧基底节内的神经元亚群内增加 下丘脑我们假设这些变化是次要的 而不是因为年龄本身。现时的建议 通过确定激素戒断的影响来验证这一假设 灵长类神经肽基因表达的变化 下丘脑在第一个具体目标中，我们将确定 年轻食蟹猴的卵巢切除术模拟了 绝经后妇女LHRH和速激肽基因表达的研究 妇女 如果是这样，这将提供令人信服的证据， 我们在绝经后妇女中观察到的变化是由于 卵巢衰竭在具体目标2和3中，我们将审查 切除卵巢的年轻猴子的下丘脑， 类固醇替代疗法的治疗方案设计， 复制给人类的处方。具体目标4： 检查绝经后妇女的下丘脑， 激素替代疗法 原位杂交将用于 确定激素替代是否减少LHRH和速激肽 猴子和人类下丘脑中的基因表达与预测一致 我们之前的研究。我们还将确定是否长期 持续的雌激素替代会产生神经毒性的迹象， 人和猴弓状核。这些研究将提供一个公司 了解发生在世界上的重要事件的基础 绝经后妇女的下丘脑，并提供第一个 关于激素替代的神经解剖学影响的信息 灵长类动物下丘脑的治疗。目前，数百万妇女 接受激素替代治疗，但对激素替代治疗的影响知之甚少。 这些治疗对中枢神经系统的影响

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.