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

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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.