REGULATION OF FETAL OVARIAN MATURATION BY ESTROGEN--IMPACT ON ADULT FERTILITY

不孕不育/卵巢功能障碍继续对 女性人口的一部分。在人类和非人类灵长类动物中， 为成人正常生殖功能奠定了基础 胎儿的生命。因此，卵巢在子宫内成熟的障碍可能 导致无法修复的生殖细胞、内分泌功能和 成虫的生殖潜力。因此，对 胎儿卵巢正常发育的机制是一个先决条件 对成人卵巢的合理处理 功能障碍/不孕症。因为对女性的活体研究不可能 出于明显的道德原因，我们对过程的理解 调节胎儿卵巢功能和随后的生殖功能 成年人是不完整的。因此，使用动物模型进行的研究 胎儿可以在子宫中进行研究/治疗，然后作为成年人进行检查。 需要阐明胎儿卵巢的潜在机制 成年后的发育/生育情况，并将这一信息转化为 人类。在狒狒(Papio Anubis)中， 胎儿器官系统的发育与人类相似。此外，我们 已经证明雌激素在调节中起着中心的综合作用 胎盘-胎儿功能与胎儿器官系统发育。雌激素 也调节成人的卵巢功能和我们的初步研究 提示狒狒胎儿卵巢表达雌激素受体。 因此，本提案将采用活体实验范式。 来检验雌激素调节胎儿卵巢的假说 发育，从而决定成年后的生殖功能。在……里面 研究1，胎儿卵巢成熟(卵原细胞、卵母细胞、 原始、初级和次级卵泡)和功能生化 分化(雌激素受体的表达和定位； 类固醇生成酶；α-抑制素；卵泡刺激素 受体)将在未经处理的狒狒的早期、中期和 妊娠晚期和足月期雌激素产生的动物 在怀孕过程中的特定时间内耗尽。要测试 假设胎儿卵巢的成熟依赖于雌激素 决定成年后的生育能力，子宫内雌激素的影响 剥夺成人卵巢功能(卵巢组织学.对 促性腺激素)和生育力将在4岁时确定。 在雌激素耗尽/补充的情况下交付给母亲。结果是 从拟议的研究中得出的结论将为我们提供新的见解 对胎儿卵巢发育调控的认识及临床意义 雌激素依赖性卵巢印迹改变对小鼠卵巢功能的影响 子宫对成人生育力的影响。

Infertility/ovarian dysfunction continues to adversely affect a large segment of the female population. In humans and non-human primates, the foundation for normal adult reproductive function is established during fetal life. Consequently, impairment of ovarian maturation in utero may result in irreparable loss of germ cells, endocrine function and reproductive potential in the adult. Thus, an understanding of the mechanisms underlying normal fetal ovarian development is a prerequisite to a rational approach to the management of adult ovarian dysfunction/infertility. Because in vivo studies in women cannot be performed for obvious ethical reasons, our understanding of the processes regulating fetal ovarian function and subsequent reproductive function as an adult is incomplete. Therefore, studies using an animal model in which the fetus can be studied/treated in utero and then examined as an adult are required to elucidate the mechanisms underlying fetal ovarian development/fertility in adulthood and to translate this information to the human. In the baboon (Papio anubis) the nature and timing of development of fetal organ systems parallels that in humans. Moreover, we have shown that estrogen play a central integrative role in regulating placental-fetal function and development of fetal organ systems. Estrogen also regulates ovarian function in the adult and our preliminary studies indicate that the baboon fetal ovary expresses the estrogen receptor. Therefore, the present proposal will employ in vivo experimental paradigms in the baboon to test the hypothesis that estrogen regulates fetal ovarian development and thus determines reproductive function as an adult. In Study 1, fetal ovarian maturation (development of oogonia, oocytes, primordial, primary and secondary follicles) and functional biochemical differentiation (expression and localization of estrogen receptor; steroidogenic enzymes; alpha-inhibin; follicle stimulating hormone receptor) will be determined in untreated baboons during early, mid and late gestation and in term animals in which estrogen production is depleted at select times during the course of gestation. To test the hypothesis that the estrogen-dependent maturation of the fetal ovary determines fertility as an adult, the effect of in utero estrogen deprivation on adult ovarian function (ovarian histology; responsivity to gonadotrophins) and fertility will be determined at age 4 in baboons delivered to mother in which estrogen was depleted/repleted. The results to be derived from the proposed study will provide new insight into our understanding of the regulation of fetal ovarian development and the impact of alterations in the estrogen-dependent imprinting of the ovary in utero on fertility in the adult.