Effect of GnRH antagonist on primordial follicle survival in the primate ovary

描述（由申请人提供）：哺乳动物卵巢中原始卵泡池的形成、存活和生长是受多种自分泌、旁分泌和内分泌信号调节的动态过程。虽然原始卵泡通常被认为是一个相对静止和休息的群体，但它对环境和化学物质的破坏和损害异常敏感。这也是一个很难研究的群体，因为个体之间的原始卵泡禀赋存在显著的差异，即使在给定的物种内。 在许多已被确定的卵巢功能的自分泌/旁分泌调节剂中，GnRH/GnRH受体系统在卵巢中的作用已重新引起人们的兴趣。现在很明显，2种形式的GnRH及其同源受体存在于许多哺乳动物（包括灵长类动物）的卵巢中。GnRH激动剂对卵巢的直接作用已得到充分证实，尽管较新，但GnRH拮抗剂也已被证明可直接调节卵巢功能。我们最近已经证明了一个快速和明显的破坏原始卵泡在小鼠卵巢的短期治疗与GnRH拮抗剂。我们推测，目前临床使用的新型高效GnRH拮抗剂可能对灵长类动物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拮抗剂是否破坏人类生殖灵长类动物模型中的原始卵泡。为了检验这一假设，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，为了确定灵长类动物卵巢中GnRH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PCR测量GnRH/GnRH受体系统的表达。这些实验将首次提供有关GnRH拮抗剂对灵长类动物卵巢原始卵泡存活影响的详细信息。此外，GnRH/GnRH受体系统在灵长类动物卵巢中的细胞定位将为GnRH及其类似物的潜在卵巢作用机制提供重要的见解。随着更新和更有效的GnRH拮抗剂进入临床使用，特别是用于治疗其他健康的生育妇女，必须确定其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.