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，出生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类固醇反馈控制GnRH分泌中的作用; 2）产前暴露于性类固醇是否加剧了出生后雌激素改变类固醇反馈控制GnRH分泌的作用; 3）如果早期暴露于雄激素和雌激素程序类型，下丘脑类固醇受体的数量和分布以及与GnRH神经元的突触和神经胶质关联的类型或数量。我们有丰富的经验来阐明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分泌增加的时间。我们将把我们的调查深入到排卵周期的基础青春期后的定时机制。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， 被睾酮及其代谢产物消除或脱敏，导致男性的单一GnRH反馈控制系统。在女性中，这些反馈控制的选择性病理生理程序在发展早期过量睾酮应防止或破坏卵巢周期。我们将继续我们的互补性综合生理和解剖研究。我们将通过实验创造新的神经内分泌表型，以检验关于GnRH分泌功能分化、神经解剖学组织和激活的假设。我们的策略是将发育中的女性暴露于各种类固醇，并确定它们对排卵周期中GnRH分泌的四个主要控制的影响。这些特征良好的雌性动物将被用来检验关于 突触前输入到GnRH神经元的产前编程和GnRH反馈的功能。这些结果与我们了解产前激素环境如何影响正常和异常的产后生殖神经内分泌系统的激活和功能有关。不适当的早期程序可以预见导致卵巢周期的异常发生和维持。

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.