Fetal Ovarian Maturation by Estrogen-- Impact on Adult

描述(申请人提供)：不孕不育/卵巢功能障碍继续对很大一部分女性人口造成不利影响。众所周知，正常成人生殖功能的基础发生在胎儿时期，因此卵巢在宫内成熟的障碍可能导致成年后生殖细胞、内分泌功能和生殖潜力的不可修复的损失。然而，由于在人类妊娠期进行体内研究的困难，人们对胎儿卵巢在宫内发育的调节及其对成人卵巢功能的影响知之甚少。在之前的资助期间，我们证明了雌激素受体α和β在胎儿卵巢中表达，在怀孕后半段服用芳香酶抑制剂导致雌激素耗竭的狒狒胎儿，原始卵泡的数量减少了50%，其中一些卵泡看起来不健康。此外，卵泡间巢的数量增加，并伴随着与颗粒前细胞相关但不被颗粒前细胞包裹的卵母细胞。 α-抑制素表达上调。这些发现，再加上观察到雌激素水平恢复的胎儿卵巢发育正常，支持了雌激素调节灵长类动物胎儿卵巢发育的假设。因此，在接下来的研究期间，我们建议进行三项研究，以阐明雌激素调节胎儿卵巢卵泡发生的机制，并确定卵巢在子宫内的雌激素编程是否影响成年后的生殖功能和生育能力。研究一将验证这样一种假设，即在狒狒胎儿体内，雌激素通过其结构蛋白Ezrin和Ezrin结合蛋白调节卵母细胞微绒毛的发育，从而促进健康原始卵泡的形成。研究1和研究2的目标交织在一起，以检验这样一种假设：雌激素通过下调抑制素的表达，从而增加激活素与卵母细胞的比率，来调节生殖细胞索中颗粒前卵泡对卵母细胞的包裹。 抑制素，促进新形成的卵泡中卵母细胞微绒毛的形成。研究1和研究2是 在研究3中转化为生理/临床相关性，该研究将检验这样的假设，即灵长类动物胎儿卵巢在子宫内依赖雌激素的成熟决定成年后的生殖功能和生育能力。从这些实验中得出的结果有望转化并提高我们对人类女性生殖生物学和生育能力的了解。

Description (provided by applicant): Infertility/ovarian dysfunction continues to adversely affect a large segment of the female population. It is well established that the foundation for normal adult reproductive function occurs during fetal life and thus impairment of ovarian maturation in utero may result in irreparable loss of germ cells, endocrine function and reproductive potential in adulthood. Because of the difficulty in conducting in vivo studies during human pregnancy, however, little is known about the regulation of fetal ovarian development in utero and its impact on adult ovarian function. During the previous funding period, we demonstrated that estrogen receptors alpha and beta were expressed in the fetal ovary, and in baboon fetuses in which estrogen had been depleted by administration of an aromatase inhibitor during the second half of gestation, the number of primordial follicles was reduced by 50% with several of the follicles appearing unhealthy. Moreover, the number of interfollicular nests comprised of oocytes associated with but not enveloped by pregranulosa cells was increased and accompanied by upregulation of alpha-inhibin expression. These findings, plus the observation that ovarian development was normal in fetuses in which estrogen levels were restored, support the hypothesis that estrogen regulates fetal ovarian development in the primate. Therefore, during the upcoming study period, we propose three studies to elucidate the mechanisms by which estrogen regulates fetal ovarian folliculogenesis and determine whether reproductive function and fertility in adulthood is impacted by estrogen programming of the ovary in utero. Study 1 will test the hypothesis that estrogen in utero in the baboon fetus promotes formation of healthy primordial follicles by regulating development of oocyte microvilli via their structural proteins ezrin and ezrin-binding protein. The goals of Study 1 and 2 are interwoven to test the hypothesis that estrogen regulates the envelopment of oocytes by pregranulosa in germ cell cords by down-regulating expression of inhibin and thereby increasing the ratio of activin to inhibin, and enhances oocyte microvillus formation in newly formed follicles. Studies 1 and 2 are translated into physiologic/clinical relevance in Study 3, which will test the hypothesis that the estrogen-dependent maturation of the primate fetal ovary in utero determines reproductive function and fertility in adulthood. The results to be derived from these experiments are expected to translate to and improve our knowledge of human female reproductive biology and fertility.