Endocrine and Paracrine Regulation of FSH Action in the Primary Ovary

在了解促卵泡激素和促黄体生成素在生长和发育中的作用方面取得了重大进展。 灵长类动物排卵前卵泡的分化。从这些研究中获得的信息迅速被 被临床医学同化为诱导排卵的新策略。一个仍然存在的主要问题 尚未解决的是对控制卵泡发育早期阶段的控制机制的阐明，如 以及这些早期卵泡对FSH产生反应的机制。因为排卵前 卵泡必须来自发育早期的卵泡池，了解腔前和早期的生理学知识 有腔卵泡对于我们进一步理解和控制卵巢周期是必不可少的。 由于它们在啮齿动物早期卵泡发育中的重要作用和已有的表达 在灵长类动物卵泡发生的相似阶段，这些因素及其信号转导途径，我们 选择研究卵母细胞产品GDF-9和颗粒细胞产品激活素对早期 猕猴的卵泡发育。我们将使用一种新的药物输送系统来传递GDF-9和 激活素B在体内直接进入卵巢，结合我们之前开发的促性腺激素钳夹模型， 这使得我们能够将自分泌/旁分泌药物的局部卵巢活动从这些药物的全身影响中分离出来 促性腺激素分泌药物。因此，这一独特的系统将允许我们确定局部卵巢的影响 这些因素与系统效应无关，这些系统效应混淆了先前研究的结果。 这一修订项目的具体目标是： 具体目的1.制备和鉴定重组GDF-9和激活素B，用于猴体内研究。 具体目的2.检测重组激活素B对腔前卵泡生长和卵泡发育的影响。 卵巢对卵泡刺激素和促黄体生成素的反应性。 具体目的3.检测重组GDF-9对腔前卵泡生长的影响及对卵泡功能的影响。 卵巢对卵泡刺激素和促黄体生成素的反应性。 对灵长类动物早期卵泡的调节和发育的了解将导致这种可能性 旨在提高距排卵几个周期的卵泡队列的治疗方法。尤其是在女性中 他们对我们目前的排卵诱导疗法反应不佳，这是一个更大、更健康的早期队列 促性腺激素治疗时的有腔卵泡可能会改善成熟卵泡的数量和质量。 排卵前卵泡。另一方面，了解控制早期卵泡生长的因素将 促进开发控制生育的新方法。

Significant progress has been made in understanding the roles of FSH and LH on the growth and differentiation of the preovulatory follicle in primates. Information gained from these studies has rapidly been assimilated into new strategies for ovulation induction in clinical medicine. A major question that remains unsolved is the elucidation of the control mechanisms that govern the early stages of follicular development, as well as the mechanisms by which these early follicles become responsive to FSH. Because preovulatory follicles must come from the pool of early developing follicles, knowledge of the physiology of preantral and early antral follicles is essential to further the understanding and our ability to manipulate the ovarian cycle. Because of their important roles in early follicular development in rodents and the documented expression of these factors and their signal transduction pathways at comparable stages of folliculogenesis in primates, we have chosen to study the effects the oocyte product, GDF-9, and the granulosa cell product, activin, on early follicular development in macaque monkeys. We will use a novel drug delivery system to deliver GDF-9 and activin B directly to ovaries in vivo in combination with our previously developed "gonadotropin clamp" model, which allows us to isolate local ovarian actions of autocrine/paracrine agents from systemic effects of these agents on gonadotropin secretion. This unique system will thus permit us to determine the local ovarian effects of these factors independently of systemic effects that have confused the results from previous studies. The Specific Aims of this revised project are: Specific Aim 1. To prepare and characterize recombinant GDF-9 and activin B for in vivo studies in monkeys. Specific Aim 2. To determine the effects of recombinant activin B on preantral follicular growth and on the responsiveness of the ovary to FSH and LH. Specific Aim 3. To determine the effects of recombinant GDF-9 on preantral follicular growth and on the responsiveness of the ovary to FSH and LH. An understanding of the regulation and development of early follicles in primates will lead to the possibility of therapies aimed at enhancing a cohort of follicles several cycles away from ovulation. In particular, in women who are "poor responders" to our current ovulation induction therapies, a larger and healthier cohort of early antral follicles at the time of gonadotropin treatment would likely improve both the quantity and quality of mature preovulatory follicles. On the other hand, knowledge of the factors that govern early follicular growth would facilitate the development of novel methods of fertility control.