Prenatal Programming of Reproductive Health and Disease

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DESCRIPTION (provided by applicant): The susceptibility of the reproductive system to early exposure to steroid hormones has become a major concern in our modern societies. At risk is the fetus whose mother has been exposed to exogenous steroids for a variety of reasons: she has had failed contraception and continued exposure to contraceptive steroids, she is on anabolic steroids, or she is inadvertently being exposed to environmental compounds that have estrogenic or androgenic activity. Experimental manipulation of the prenatal steroid environment provides a powerful investigative tool for unraveling mechanisms that underlie programming of the reproductive axis. Findings from the current funding period found prenatal testosterone (T) excess disrupts the developmental trajectory of the fetus culminating in reproductive neuroendocrine, ovarian, metabolic and behavioral perturbations and implicates ovarian hyperandrogenism and hyperinsulinemia in the development of the pathology. This proposal aims to capitalize on this recently validated sheep model to test a novel, unifying hypothesis for the developmental origins of infertility disorders namely "Hyperinsulinemia and functional hyperandrogenism resulting from metabolic perturbations and/or increased steroid drive to the fetal neuroendocrine-ovarian system plays a key role in prenatal T-induced reproductive dysfunctions". The specific goals of the P01 proposal are to 1) use an insulin-sensitizing agent postnatally to ameliorate hyperinsulinemia and determine if it rescues reproductive function in prenatal T-treated sheep, 2) use an anti-androgen postnatally and determine if it rescues reproductive function in prenatal T-treated sheep, 3) determine if co-treatment with T and an androgen antagonist during fetal life will prevent metabolic and reproductive pathology from developing in the adult, and 4) determine the neuroanatomical, neuroendocrine, ovarian, behavioral and metabolic mechanisms underlying restoration of function. The proposal targets key elements of strategic plans that emanated from workshops convened by the NICHD in 2000-01 "From Cells to Selves" and focuses on the following areas: fetal antecedents of disease, reproductive health for the 21st Century, developmental biology and biobehavioral development.