The overall objective is to understand the role of prenatal androgens and estrogens in the programming of feedback systems that control GnRH secretion. Our hypothesis is that exposures to androgens and estrogens before birth decrease the sensitivities of the feedback control of GnRH secretion and that this is facilitated by postnatal exposure to estrogens.
The specific aims are to determine: 1) the roles of prenatal androgens and estrogens in programming adult steroid feedback control of GnRH secretion; 2) if prenatal exposure to sex steroids exacerbates the actions of postnatal estrogen to modify steroid feedback control of GnRH secretion; 3) if early exposure to androgens and estrogens programs type, number and distribution of hypothalamic steroid receptors and the type or number of synaptic and glial associations with GnRH neurons. We have extensive experience with unraveling how prenatal exposure to sex steroids alters postnatal sensitivity to steroid negative feedback and the timing of the pubertal rise in GnRH secretion. We will extend our inquiry into postpubertal timing mechanisms that underlie the ovulatory cycle. We will focus on four feedback controls of GnRH. We propose that these feedback controls are inherent in the female and that they are abolished or desensitized by testosterone and its metabolites to result in the single GnRH feedback control system of the male. In the female, selective pathophysiologic programming of these feedback controls early in development by excess testosterone should prevent or disrupt ovarian cyclicity. We will continue our complementary integrative physiological and anatomical investigations. We will create novel neuroendocrine phenotypes experimentally to test hypotheses about the differentiation of the function of, and neuroanatomical organization and activation of GnRH secretion. Our strategy will be to expose the developing female to various steroids and determine their effect on the four major controls of GnRH secretion in the ovulatory cycle. These same well-characterized females will then be used for testing hypotheses about prenatal programming of presynaptic input to GnRH neurons and functionality of GnRH feedback. The results have relevance to our understanding of how the prenatal hormonal environment influences normal and abnormal postnatal activation and function of the reproductive neuroendocrine system. Inappropriate early programming can predictably lead to abnormal onset and maintenance of ovarian cyclicity.
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