FEMALE REPRODUCTIVE AGING-- THE ROLE OF ESTROGEN

生殖功能的停止是女性生命中最剧烈和相当迅速的内分泌变化之一，并产生深刻和广泛的影响。曾有一段时间，人们认为由于卵泡耗竭导致雌二醇浓度下降导致绝经。现在，很明显，许多因素相互作用，导致生殖功能下降和生殖周期停止。此外，我们开始意识到，最具生殖能力的状态影响着传统生殖轴之外的多种功能。越来越多的妇女和越来越多的妇女比例将在绝经后状态下度过她们生命中的大部分时间。因此，我们必须加深对调节向非周期性过渡的因素的理解，以及相反地，向非周期性过渡对多系统功能的影响。该计划分为五个研究项目，由一个核心支持。这些项目被整合和协调，以测试以下假设：（1）在衰老过程中，雌激素反应性的变化控制着卵泡的健康和功能，（2）卵巢金属蛋白酶及其抑制剂表达模式的年龄相关和雌二醇依赖性改变导致卵泡发育和排卵异常，（3）衰老和/或雌二醇的累积暴露调节生长激素和催乳激素功能的变化。（4）GnRH神经元的β-肾上腺素能和β-肾上腺素能调节的改变引起它们诱导LH峰的能力改变。和（5）雌二醇在脑中起关键的保护作用;因此，降低雌二醇浓度导致对脑损伤和神经变性的易感性增加。行政/动物中心支持所有项目，提供组织规划，将每个项目的结果整合到更全面的概述中，并维护所有动物记录并协调其光学内分泌治疗和使用。我们提交这个项目提案，因为我们在生殖衰老的相互依赖方面有共同的利益。贯穿所有项目的一个共同威胁是我们对雌二醇在衰老中的作用的兴趣。最后，这种支持机制将使我们能够以最佳方式使用老龄动物，使我们能够比较数据并节省老龄动物的成本。

The cessation of reproductive function is one of the most dramatic and fairly rapid endocrine changes in the life of a female and carries profound and broad repercussions. At one time, it was thought that decreasing estradiol concentration, resulting from exhaustion of ovarian follicles, caused the menopause. Now, it is clear that many factors interact to bring about declining reproductive function and the cessation of reproductive cycles. Furthermore, we are beginning to appreciate the most- reproductive state affects multiple functions that extend beyond the traditional reproductive axis. An increasing number and an increasing proportion of women will liver a larger fraction of their lives in the postmenopausal state. Therefore, it is critical that we deepened our understanding of the factors that regulate the transition to acyclicity and, conversely, the impact of transition to acyclicity on the function of multiple systems. The program is organized into five research projects that are supported by one Core. The projects are integrated and coordinated to test the following hypotheses (1) changing estrogen responsiveness governs the health and function of ovarian follicles during aging, (2) age-related and estradiol-dependent alterations in the pattern of expression in the ovarian metalloproteinases and their inhibitors result in abnormalities in follicular development and ovulation, (3) aging and/or the cumulative exposure to estradiol regulate changes in somatotroph and lactotroph function, (4) alterations in glutamatergic and adrenergic regulation of GnRH neurons cause changes in their ability to induce LH surges; and (5) estradiol plays a critical protective role in the brain; therefore, declining estradiol concentrations lead to an increased vulnerability to brain injury and neurodegeneration. An Administrative/Animal ore supports all of the projects, providing organizational planning, integrating results from each project into a more comprehensive overview, and maintaining all animal records and coordinating their optical endocrine treatments and use. We submit this program project proposal because we share interests in interdependent aspects of reproductive aging. A common threat that weaves through all of the projects is our interests in the role of estradiol in aging. Finally, this mechanism of support will permit us to use aging animals in the most optimal manner, allowing us to compare data and economize on the costs of aging animals.