FSH, Estradiol and Inhibin in Female Reproduction

该项目的总体目标是继续研究女性生殖的神经内分泌和性腺调节，重点研究FSH、雌二醇和抑制素之间的复杂相互关系。现在有证据表明，雌二醇和抑制素都有助于女性卵泡刺激素的负反馈控制。然而，在正常月经周期的卵泡期和黄体期，它们在精确控制卵泡刺激素中的相对作用尚未明确。在两种独特的情况下，我们已经证明雌二醇和抑制素的协调分泌被改变了：在生殖衰老中，雌二醇水平在抑制素水平较低的情况下增加，而在非裔美国妇女中，正常生殖周期的特征是雌二醇相对于白人妇女在面对相同水平的抑制素时增加。确定导致这些变化的机制将为我们了解抑制素、雌二醇和促性腺激素在正常生殖生理中的相互作用提供重要的见解。目的1将确定雌二醇和抑制素对正常月经周期卵泡期和黄体期FSH分泌负反馈调节的相对贡献，使用正常和gnrh缺乏的女性，其中雌激素分泌被芳香酶阻断改变。目的2将通过研究抑制素和雌二醇分泌在固定FSH刺激下的反应，以及确定颗粒细胞数量、抑制素亚基表达和芳香化酶功能以及在窦腔和排卵前卵泡中的表达作为生殖衰老的功能，试图阐明雌二醇和抑制素分泌二分法在生殖衰老中的机制。目的3将确定FSH、雌二醇和抑制素之间的反馈和前馈相互作用，这些相互作用导致非裔美国妇女在正常生殖周期中雌二醇水平升高。反馈将使用雌激素输注方案进行检查，而前馈将检查排卵前卵泡中雌二醇和抑制素分泌的控制。了解生殖系统的下丘脑-垂体和卵巢组成部分的反馈和前馈动力学对于理解生殖疾病的病理生理学至关重要。最终需要这些信息来设计包括不孕症在内的生殖疾病患者的治疗方案。

The broad goal of this project is to continue to investigate the neuroendocrine and gonadal regulation of reproduction in women, focusing on the complex interrelationships between FSH, estradiol and the inhibins. There is now evidence that both estradiol and the inhibins contribute to the negative feedback control of FSH in women. However, their relative roles in the precise control of FSH during the follicular and luteal phases of the normal menstrual cycle have not been delineated. There are two unique circumstances in which we have shown that the coordinated secretion of estradiol and the inhibins is altered: in reproductive aging, estradiol levels are increased in the presence of low levels of inhibin while in African-American women, normal reproductive cycles are characterized by increased estradiol relative to Caucasian women in the face of identical levels of inhibin. Determining the mechanisms responsible for these changes will provide us with important insights into the interactions of inhibin, estradiol and gonadotropins in normal reproductive physiology. Aim 1 will determine the relative contributions of estradiol and the inhibins to the negative feedback regulation of FSH secretion during the follicular and luteal phases of the normal menstrual cycle using normal and GnRH-deficient women in whom estrogen secretion is altered by aromatase blockade. Aim 2 will seek to elucidate the mechanisms underlying the dichotomy between estradiol and inhibin secretion in reproductive aging by investigating inhibin and estradiol secretion in response to fixed FSH stimulation and by determining the number of granulosa cells and inhibin subunit expression and aromatase function and expression in antral and preovulatory follicles as a function of reproductive aging. Aim 3 will determine the feedback and feed-forward interactions between FSH, estradiol and the inhibins that result in an increase in estradiol levels across normal reproductive cycles in African- American women. Feedback will be examined using an estrogen infusion protocol while feed-forward will examine the control of estradiol and inhibin secretion in preovulatory follicles. Understanding the feedback and feed-forward dynamics of the hypothalamic-pituitary and ovarian components of the reproductive system is critical to an appreciation of the pathophysiology of reproductive disorders. This information is ultimately required for the design of therapeutic options for patients with reproductive disorders including infertility.