Quantitative Assessment of the Effects of Aging on the Female Reproductive Axis

描述（由申请人提供）：人类女性怀孕的可能性随着年龄的增长而减少，但其潜在机制尚不清楚。这提出了一个主要的临床问题，因为许多妇女推迟生育，直到第四和第五个几十年的生活（例如，建立职业生涯后）和现有的诊断工具不能可靠地预测卵巢储备，而卵巢储备反过来又被用来帮助确定是否应该治疗与年龄相关的生殖潜力降低的妇女。我们以前已经表明，与年轻和年长的同龄人相比，老年绝经前妇女的垂体生殖激素分泌特征发生了改变。这支持了我们的总体假设，即除了卵母细胞耗竭和/或异常卵母细胞/卵泡相互作用外，正常衰老与下丘脑-垂体和卵巢激素之间关系的可检测变化有关，这可能预示着卵巢储备减少。我们建议进一步解决这一假设与年轻和老年绝经前妇女的临床和数学研究相结合。我们将研究衰老对卵巢激素分泌模式的影响，垂体和卵巢激素之间的剂量反应相互作用，以及卵巢对神经内分泌功能的反馈。此外，我们将估计在何种程度上可以预测这些影响，利用现有的一些诊断工具。为此，我们将测试特定的假设，老年绝经前妇女相比，他们的年轻同龄人：1。卵巢激素分泌特性和时间关系的改变; 2.降低卵巢对神经内分泌信号的反应性; 3.增强的性腺激素反馈作用于神经内分泌信号。此外，我们还将测试假设，即：4。与正常衰老相关的垂体-卵巢内分泌轴的改变不能用大多数现有的评估卵巢储备的诊断工具可靠地检测出来。与现有的研究相比，我们将首次使用跨学科的方法来定义衰老如何影响生殖轴组件之间的关系。确定这种关系，表现出最强大的变化将指导未来的干预性研究，以执行这些改变的机制的详细分析。最终，我们的长期目标是开发新的诊断工具和治疗方法，使临床医生能够合理决定哪些女性应该或不应该接受与年龄相关的生殖潜力降低相关的各种治疗方案。公共卫生相关性：预计这些研究将阐明指导生殖系统功能的复杂内分泌机制中与年龄有关的变化。他们将使未来的研究集中在这些知识的应用，以开发新的诊断和治疗方法，以年龄相关的生殖潜力下降。

DESCRIPTION (provided by applicant): The likelihood of conceiving diminishes with aging in the human female, but the underlying mechanisms are not understood. This presents a major clinical problem since many women delay childbearing until the 4th and 5th decades of life (e.g., after establishing a career) and existing diagnostic tools cannot reliably predict ovarian reserve which, in turn, is utilized to help determine whether a woman should be treated given her age- associated reduction in reproductive potential. We have previously shown that the pituitary reproductive hormones in older premenopausal women have altered secretory characteristics when compared to younger and older peers. This supports our overall hypothesis that in addition to oocyte depletion and/or abnormal oocyte/follicular interactions, normal aging is associated with detectable changes in the relationships between hypothalamic-pituitary and ovarian hormones, which may be predictive for reduction in ovarian reserve. We propose to further address this hypothesis with a combination of a clinical and mathematical study in younger and older premenopausal women. We will study the effect of aging on the secretion patterns of the ovarian hormones, on the dose-response interactions between pituitary and ovarian hormones and on ovarian feedback on neuroendocrine function. In addition, we will estimate the extent to which these effects can be predicted utilizing some of the existing diagnostic tools. To this end, we will test the specific hypotheses that older premenopausal women compared to their young peers have: 1. Altered secretion characteristics and temporal relationships of the ovarian hormones; 2. Reduced ovarian responsivity to neuroendocrine signaling; 3. Enhanced gonadal hormones feedback exerted on the neuroendocrine signaling. In addition, we will also test the hypothesis that: 4. Alterations in the pituitary-ovarian endocrine axis associated with normal aging cannot be detected reliably with most of the existing diagnostic tools for estimating ovarian reserve. In contrast to existing studies we will for the first time use interdisciplinary methods to define how aging affects the relationships between the components of the reproductive axis. Identification of such relationships which demonstrate the most robust changes will guide future interventional studies to perform a detailed analysis of the mechanisms of these alterations. Ultimately, our long-term goal is to develop novel diagnostic tools and therapeutic approaches to allow clinicians to make rational decisions regarding which women should or should not be subjected to the various treatment options in connection to age-associated reductions in reproductive potential. PUBLIC HEALTH RELEVANCE: The studies are expected to illuminate the age-related changes in the complex endocrine mechanisms directing the function of the reproductive system. They would allow future studies to focus on the application of this knowledge to develop novel diagnostic and therapeutic approaches to age-associated reductions in reproductive potential.