Prenatal Programming of Postnatal GNRH Feedback Controls in The Female

总体目标是了解产前雄激素和雌激素在控制GnRH分泌的反馈系统编程中的作用。我们的假设是，出生前暴露于雄激素和雌激素会降低GnRH分泌反馈控制的敏感性，而产后暴露于雌激素会促进这一点。具体目的是确定：1)产前雄激素和雌激素在编程成人激素反馈控制GnRH分泌中的作用；2)产前暴露于性类固醇是否会加剧产后雌激素的作用，从而改变激素对GnRH分泌的反馈控制；3)如果早期暴露于雄激素和雌激素计划，下丘脑类固醇受体的类型、数量和分布以及与GnRH神经元相关的突触和神经胶质的类型或数量。我们在揭示产前暴露于性类固醇如何改变出生后对类固醇负反馈的敏感性和青春期GnRH分泌上升的时间方面有丰富的经验。我们将扩展我们对青春期后排卵周期的计时机制的调查。我们将重点介绍GnRH的四种反馈控制。我们认为这些反馈控制是女性固有的，确实如此

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.