Modeling Hormonal Regulation of the Reproductive Cycle of Women with an Emphasis on Changes that Occur from the Late Reproductive Years into the Menopausal Transition

模拟女性生殖周期的激素调节，重点关注从生育后期到更年期过渡期间发生的变化

• 批准号: 1225607
• 负责人: James Selgrade
• 金额: $ 46.19万
• 依托单位: North Carolina State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1225607&HistoricalAwards=false
• 关键词: Modeling; Hormonal; Regulation; Reproductive; Cycle

Regulation of the reproductive cycle in adult women is a dual control system involving at least eight hormones produced by the brain and the ovaries. This research project develops and analyzes differential equation models for the number of follicles (eggs) and blood levels of reproductive hormones during a woman's reproductive years from age 20 until menopause. The investigators' models already predict hormone levels that agree with data in the literature for normally cycling women, and the models have other solutions reflecting characteristics of polycystic ovarian syndrome (PCOS), a leading cause of female infertility. Building on this work, the researchers will develop more complex, mechanistic models to describe a woman's cycling throughout her reproductive life and to track the "primordial pool" of follicles with which a woman is born and that continually decreases as she ages. Ad hoc techniques will be devised to estimate model parameters using data sets from multiple age groups. Model simulations will be used to predict and to study age-related and pathological changes in cycling. These include a decrease in serum inhibins, which is one of the earliest signs of reproductive aging, and erratic luteal levels of estrogen and progesterone, which may occur in women in their 40's. Tools from numerical analysis and dynamical systems, e.g., parameter identification methods, sensitivity analysis, stability theory, and bifurcation techniques, will be used to develop and to study these models. A woman's peak fertility occurs between the ages of 20 and 30. However, in North America and Europe more women are postponing childbearing until their 30's and must deal with the consequences of reduced natural fertility due to a decreasing number of follicles and changes in reproductive hormones. In addition, women with polycystic ovarian syndrome (PCOS) often exhibit hormonal imbalances and insulin insensitivity. A goal of this research project is to model and study the interplay between PCOS, excess androgens, and glucose metabolism. A lifelong model for hormonal control of the female reproductive cycle may be used to predict optimal types, doses, and durations of hormonal therapies for young and aging women. In turn, given the broad consensus that hormone therapies be used at lowest doses for the shortest intervals necessary to achieve specific therapeutic aims, the impact of these modeling studies on women's health should be beneficial. This research also may advance our understanding of several types of increasingly prevalent diseases, including PCOS, infertility in general, diabetes, and other metabolic disorders.

成年女性生殖周期的调节是一个双重控制系统，涉及大脑和卵巢产生的至少八种激素。该研究项目开发并分析了女性从20岁到更年期的生育期内卵泡（卵子）数量和生殖激素血液水平的微分方程模型。研究人员的模型已经预测了与文献中正常骑自行车的女性数据一致的激素水平，并且模型还有其他反映多囊卵巢综合征（PCOS）特征的解决方案，PCOS是女性不孕症的主要原因。在这项工作的基础上，研究人员将开发出更复杂的机械模型来描述女性在整个生殖过程中的周期，并跟踪女性出生时的卵泡“原始池”，随着年龄的增长，卵泡会不断减少。特设技术将被设计来估计模型参数，使用多个年龄组的数据集。模型模拟将用于预测和研究与年龄相关的和病理变化的自行车。这些包括血清中的雌激素减少，这是生殖老化的最早迹象之一，以及不稳定的雌激素和孕酮水平，这可能发生在40多岁的女性中。来自数值分析和动力系统的工具，例如，将使用参数识别方法、敏感性分析、稳定性理论和分叉技术来开发和研究这些模型。女性的生育高峰期在20岁到30岁之间。然而，在北美和欧洲，越来越多的妇女推迟生育到30多岁，并且必须应对由于卵泡数量减少和生殖激素变化而导致的自然生育能力降低的后果。此外，患有多囊卵巢综合征（PCOS）的女性通常表现出激素失衡和胰岛素不敏感。该研究项目的目标是建立模型并研究PCOS，过量雄激素和葡萄糖代谢之间的相互作用。女性生殖周期激素控制的终身模型可用于预测年轻和老年女性激素治疗的最佳类型，剂量和持续时间。反过来，考虑到广泛的共识，即激素治疗应在最低剂量下使用，以达到特定的治疗目标所需的最短间隔，这些建模研究对女性健康的影响应该是有益的。这项研究也可能促进我们对几种日益流行的疾病的理解，包括PCOS，一般不孕症，糖尿病和其他代谢紊乱。