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.
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