NEUROENDOCRINOLOGY OF PUBERTY

总体目标是通过以下方式了解生理机制： 营养和生长的变化会影响性生活的时间， 成熟 本研究将以发育中的绵羊作为动物模型进行试验 当能量有限时，葡萄糖可以作为 GnRH神经分泌系统的重要调节剂。 我们进一步建议 葡萄糖对GnRH分泌的代谢控制是有效的 葡萄糖在成年人中的功能可能类似， 能量是有限的。 具体目标是：1）确定影响 葡萄糖利用率对GnRH分泌的影响; 2）确定 葡萄糖利用率的变化被传递到中枢神经系统 调节GnRH分泌的系统; 3）确定葡萄糖可用性 影响成年人的GnRH分泌，如发育中的个体; 4） 以确定营养和生长对抑制的影响， 性类固醇对GnRH分泌的反馈控制。 将使用几种实验方法和手段。 在我们 在动物模型中，控制GnRH分泌的机制对 营养水平的变化（分钟-小时）。 初步研究 表明葡萄糖调节作用，我们已经建立了方法学 测量GnRH分泌（垂体门静脉采血）。 目标1将 评估GnRH对药物阻断葡萄糖代谢的反应 将确定增加中枢葡萄糖是否能逆转禁食诱导的 促性腺激素减退症，并将确定葡萄糖的急性变化是否会改变 GnRH脉冲频率或脉冲幅度。 目标2将决定该地区是否 尾侧脑干中的最后肌作为化学传感器来监测葡萄糖 浓度的 我们亦会研究 营养/代谢的外周检测器及其相对重要性 用于调节GnRH分泌的脑葡萄糖检测器。 目标3将 确定葡萄糖是否是代谢控制中的重要信号， 成年个体的GnRH分泌与未成熟个体的GnRH分泌基本相同。 我们将比较对葡萄糖或其竞争性拮抗剂的剂量反应， 两个年龄段都是2D。 目标4将测试是否营养生长迟缓 个体对抑制性类固醇反馈保持高度敏感， 延缓青春期GnRH分泌的增加。 这项研究将导致 关于葡萄糖在青春期发育中的作用的未来研究 当能量有限时，对抑制性类固醇的敏感性降低。 这项关于GnRH分泌代谢控制的基础研究， 广泛的应用。 它也与生长和成熟有关 与其他生理条件有关，其中GnRH分泌减少可能 导致不孕症的原因是能量代谢的改变。 这些 包括饮食性营养不良，如厌食症等饮食失调 和贪食症;高能量消耗，例如在运动引起的 闭经和哺乳期无排卵; 1型糖尿病引起 不孕

The overall objective is to understand the physiological mechanisms by which changes in nutrition and growth influence the timing of sexual maturation. The developing sheep will be used as the animal model to test the hypothesis that when energy is limited, glucose can serve as an important modulator of the GnRH neurosecretory system. We further propose that this metabolic control of GnRH secretion by glucose is operative throughout life and that glucose may function similarly in the adult when energy is limited. The specific aims are; 1) to determine the influence of glucose availability on GnRH secretion; 2) to determine sites where changes in glucose availability are transduced to the central nervous system to modulate GnRH secretion; 3) to determine if glucose availability influences GnRH secretion in the adult, as in the developing individual; 4) to determine the influence of nutrition and growth on the inhibitory feedback control of sex steroids on GnRH secretion. Several experimental approaches and methodologies will be used. In our animal model, the mechanism governing GnRH secretion is very sensitive to changes in level of nutrition (within minutes-hours). Preliminary studies suggest a regulatory role for glucose, and we have established methodology to measure GnRH secretion (pituitary portal blood collection). Aim 1 will asses the GnRH response to pharmacological blockade of glucose metabolism will determine if increasing glucose centrally can reverse fasting-induced hypogonadotropism, and will determine if acute changes in glucose alter GnRH pulse frequency or pulse amplitude. Aim 2 will determine if the area postrema in the caudal brainstem serves as a chemosensor to monitor glucose concentrations. We will also examine the possible involvement of peripheral detectors of nutrition/metabolism and their relative importance to brain glucodetectors for modulation of GnRH secretion. Aim 3 will determine if glucose is an important signal in the metabolic control of GnRH secretion in the adult much the same as in the immature individual. We will compare the dose-response to glucose or its competitive antagonist, 2DG at both ages. Aim 4 will test if nutritionally growth-retarded individuals remain hypersensitive to inhibitory steroid feedback thereby delaying their pubertal increase in GnRH secretion. This study will lead to future research about the role of glucose in timing the pubertal decrease in sensitivity to inhibitory sex steroids when energy is limited. This fundamental research on the metabolic control of GnRH secretion has broad application. It is relevant both to growth and maturation, as well s to other physiologic conditions in which reduced GnRH secretion may contribute to infertility because of altered energy metabolism. These include dietary malnutrition such as during eating disorders like anorexia and bulimia; high energy expenditure, for example as in exercise induced amenorrhea and lactational anovulation; type 1 diabetes-induced infertility.