Fetal Ovarian Maturation by Estrogen-- Impact on Adult

描述（由申请方提供）：不孕症/卵巢功能障碍继续对大部分女性人群产生不利影响。已经确定的是，正常成年生殖功能的基础发生在胎儿期，因此子宫内卵巢成熟受损可能导致生殖细胞、内分泌功能和成年生殖潜力的不可挽回的损失。然而，由于在人类妊娠期间进行体内研究的困难，人们对子宫内胎儿卵巢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，并且在狒狒胎儿中，雌激素在妊娠后半期通过给予芳香酶抑制剂而耗尽，原始卵泡的数量减少了50%，其中几个卵泡出现不健康。此外，由与前颗粒细胞相连但不被前颗粒细胞包裹的卵母细胞组成的卵泡间巢数量增加， α-腺苷二酸表达的上调。这些发现，再加上观察到，卵巢发育是正常的胎儿中，雌激素水平恢复，支持的假设，雌激素调节胎儿卵巢发育的灵长类动物。因此，在即将到来的研究期间，我们提出了三项研究来阐明雌激素调节胎儿卵巢卵泡发生的机制，并确定成年后的生殖功能和生育能力是否受到子宫内卵巢雌激素编程的影响。研究1将检验这一假设，即雌激素在狒狒胎儿子宫内通过其结构蛋白ezrin和ezrin结合蛋白调节卵母细胞微绒毛的发育，促进健康原始卵泡的形成。研究1和2的目的是交织在一起，以检验雌激素通过下调激活素的表达，从而增加激活素与卵母细胞的比率，调节生殖细胞索中前颗粒层对卵母细胞的发育的假设。 在新形成的卵泡中促进卵母细胞微绒毛的形成。研究1和2是 在研究3中转化为生理/临床相关性，该研究将检验灵长类动物胎儿卵巢在子宫内的雌激素依赖性成熟决定成年后的生殖功能和生育力的假设。从这些实验中得到的结果有望转化为并提高我们对人类女性生殖生物学和生育力的认识。

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.