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

成年女性生殖周期的调节是一个双重控制系统，至少涉及大脑和卵巢产生的八种激素。这项研究项目开发并分析了女性从20岁到更年期的生殖年份中卵泡(卵子)数量和血液生殖激素水平的微分方程式模型。研究人员的模型已经预测了与文献中正常周期女性的激素水平一致的数据，并且模型有其他反映多囊卵巢综合征(PCOS)特征的解决方案，PCOS是女性不孕的主要原因。在这项工作的基础上，研究人员将开发更复杂、更机械的模型，以描述女性在整个生殖生命中的骑行过程，并跟踪女性出生时携带的毛囊池，该池随着年龄的增长而不断减少。将设计特别技术，使用来自多个年龄段的数据集来估计模型参数。模型模拟将用于预测和研究自行车运动中与年龄相关的病理变化。其中包括血清抑制素水平下降，这是生殖老化的最早迹象之一，以及黄体雌激素和孕酮水平不稳定，这可能发生在40岁的S。来自数值分析和动力学系统的工具，如参数识别方法、灵敏度分析、稳定性理论和分叉技术，将被用来开发和研究这些模型。女性的生育高峰出现在20岁到30岁之间。然而，在北美和欧洲，越来越多的女性将生育推迟到30岁的S，她们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力下降的后果。此外，患有多囊卵巢综合征(PCOS)的女性经常表现出激素失衡和胰岛素不敏感。这项研究项目的一个目标是模拟和研究PCOS、过量雄激素和葡萄糖代谢之间的相互作用。一个荷尔蒙控制女性生殖周期的终生模型可以用来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，鉴于广泛的共识是，激素治疗应在实现特定治疗目标所需的最短时间内以最低剂量使用，这些模拟研究对妇女健康的影响应该是有益的。这项研究还可能促进我们对几种日益流行的疾病的理解，包括多囊卵巢综合征、一般不孕不育、糖尿病和其他代谢紊乱。

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.