GnRH antagonist on primordial follicle survival primate

描述(申请人提供)：哺乳动物卵巢中原始卵泡池的形成、存活和生长是由各种自分泌、旁分泌和内分泌信号调节的动态过程。虽然原始毛囊通常被认为是一个相对静止和休息的种群，但它极易受到环境和化学因素的破坏和破坏。这也是一个很难研究的种群，因为原始毛囊捐赠在个体之间存在显著的变异性，即使在给定的物种内也是如此。在已确定的许多卵巢功能的自分泌/旁分泌调节中，GnRH/GnRH受体系统在卵巢中的作用重新引起了人们的兴趣。现在很明显，包括灵长类在内的许多哺乳动物的卵巢中都存在两种形式的促性腺激素释放激素及其同源受体。促性腺激素释放激素激动剂对卵巢的直接作用已得到证实，尽管较新，但促性腺激素释放激素拮抗剂也被证明直接调节卵巢功能。我们最近证明了用促性腺激素释放激素拮抗剂的短期治疗可以快速而显著地破坏小鼠卵巢中的原始卵泡。我们推测，目前临床使用的新的、高效的GnRH拮抗剂可能对灵长类卵巢中的原始卵泡储备有类似的不良影响。因此，本提案的主要目标是确定GnRH拮抗剂是否破坏了人类生殖的灵长类动物模型中的原始卵泡。为了验证这一假设，我们建议确定GnRH拮抗剂治疗对食蟹猴原始卵泡数量的影响。此外，为了确定GnRH在灵长类卵巢中的潜在细胞靶点(和来源)，我们将使用激光捕获显微切割和实时定量PCR来测量GnRH/GnRH受体系统的表达。这些实验将首次提供有关GnRH拮抗剂对灵长类卵巢原始卵泡存活的影响的详细信息。此外，GnRH/GnRH受体系统在灵长类动物卵巢中的细胞定位将为了解GnRH及其类似物潜在的卵巢作用机制提供重要的信息。随着新的和更有效的GnRH拮抗剂进入临床应用，特别是在治疗其他健康的生育妇女时，必须确定它们对原始卵泡存活和卵巢衰老的潜在影响。

DESCRIPTION (provided by applicant): The formation, survival, and growth of the primordial follicle pool in the mammalian ovary are dynamic processes regulated by a variety of autocrine, paracrine, and endocrine signals. Although often considered to be a relatively quiescent and resting population, primordial follicles are nevertheless unusually susceptible to destruction and damage by environmental and chemical agents. It is also a difficult population to study given the marked variability that exists in primordial follicle endowment between individuals, even within a given species. Among the many autocrine/paracrine regulators of ovarian function that have been identified, the role of the GnRH/GnRH receptor system in the ovary has received renewed interest. It is now evident that 2 forms of GnRH and their cognate receptors are present in the ovaries of many mammals including primates. Direct effects of GnRH agonists on the ovary are well established, and although newer, GnRH antagonists have also been demonstrated to directly modulate ovarian function. We have recently demonstrated a rapid and pronounced destruction of primordial follicles in the mouse ovary by short-term treatment with GnRH antagonists. We hypothesize that new, highly potent GnRH antagonists currently in clinical use may have similar adverse effects on the primordial follicle reserve in the primate ovary. As such, the primary goal of the present proposal is to determine whether GnRH antagonists destroy primordial follicles in a primate model of human reproduction. To test this hypothesis, we propose to determine the effects of GnRH antagonist treatment on the number of primordial follicles in the cynomolgus monkey. In addition, to identify the potential cellular targets (and sources) of GnRH in the primate ovary, we will measure the expression of the GnRH/GnRH receptor system using laser capture micro-dissection and real-time PCR. These experiments will provide the first detailed information on the effects of GnRH antagonists on primordial follicle survival in the primate ovary. In addition, cellular localization of the GnRH/GnRH receptor system in the primate ovary will provide important insight into the potential ovarian mechanisms of action of GnRH and its analogs. As newer and more potent GnRH antagonists enter clinical use, especially for the treatment of otherwise healthy fertile women, their potential effects on primordial follicle survival and ovarian senescence must be identified.