NEUROENDOCRINOLOGY OF PUBERTY

当营养不足或能量消耗很大时，成年人的生育能力就会降低，发育中的个体的青春期就会延迟。这种对生殖活动的抑制在机制上还没有得到理解。我们认为，在这个研究阶段，这是一个综合性的问题，需要生理学和药理学的方法来回答有关大脑如何区分营养状况和身体成熟程度的广泛问题。我们的广泛目标是了解营养和代谢变化控制生殖的生理机制，特别是血液传播信息调节GnRH分泌的信号，传感器和途径。为了进一步了解发育过程中生长、代谢和高频率GnRH脉冲产生之间的关系，我们必须首先确定能量代谢如何调节GnRH分泌。为了进一步了解发育过程中生长、代谢和高频率GnRH脉冲产生之间的关系，我们必须首先确定能量代谢如何调节成年人的GnRH分泌。因此，我们将首先评估葡萄糖利用率和瘦素的变化如何改变成年期的GnRH分泌，然后确定这种机制是否可能是生长期间青春期的时间。将使用绵羊，因为它的大尺寸和长寿命允许个体通过其发育进行纵向研究，并允许在成年人中进行详细研究。重要的是，它非常适合于垂体促激素模式的表征。具体目标1将确定后脑和肝脏是否含有传感器，将葡萄糖可用性的信息传递给受调节的GnRH分泌。我们将增加和减少每个站点的本地可用性，以建立它们的功能和相互关系。具体目标2将确定瘦素作为调节GnRH脉冲分泌的信号的作用。这将通过在急性禁食和慢性低营养期间集中施用瘦素来实现。虽然在摄食行为中被广泛研究，但我们对其在调节GnRH分泌中的生理作用了解甚少。具体目标3将通过监测垂体门静脉循环中的应激肽以及通过拮抗急性禁食和慢性低营养期间的应激肽作用，评估“营养应激”作为促性腺激素功能减退症的原因，即GnRH分泌减少。具体目标4将通过使用我们的大型动物模型的能力来确定葡萄糖可用性乘以青春期GnRH是否增加，在该模型中，我们可以长期给予代谢重要信号，如胰岛素和瘦素。了解GnRH分泌的代谢控制对生长和成熟以及其他生理条件都有广泛的应用，在这些生理条件下，由于能量代谢的改变，GnRH分泌减少可能导致不育。这些包括饮食失调引起的饮食营养不良;在高能量消耗期间，如运动引起的闭经和哺乳期无排卵;在1型糖尿病引起的不孕症。

When nourishment is inadequate or energy expenditure is great, fertility is reduced in the adult, and puberty is delayed in the developing individual. This suppression of reproductive activity is not understood mechanistically. We believe this to be an integrative problem at this stage of inquiry that requires both physiologic and pharmacologic approaches to answer broad questions about how the brain discriminates how well nourished and how mature the body is. Our broad objective is to understand the physiological mechanisms by which changes in nutrition and metabolism control reproduction, specifically the signals, sensors, and pathways whereby blood-borne information regulates GnRH secretion. To progress further in understanding the relationship between growth, metabolism and production of high frequency GnRH pulses during development, we must first determine how energy metabolism regulates GnRH secretion. To progress further in understanding the relationship between growth , metabolism and production of high frequency GnRH pulses during development, we must first determine how energy metabolism regulates GnRH secretion in the adult. Thus, we will first evaluate how changes in glucose availability and leptin modify GnRH secretion during adulthood and then determine if such a mechanism might be timing puberty during growth. The sheep will be used because its large size and long lifespan permits individuals to be studied longitudinally through their development and permits detailed studies in adults. Importantly, it is well suited for the characterization of hypophysiotrophic hormone patterns. Specific Aim 1 will determine if the hindbrain and the liver contain sensors that transmit information about glucose availability to regulated GnRH secretion. We will both increase and decrease availability locally in each site to establish their function and their interrelationships. Specific Aim 2 will determine the role of leptin as a signal to regulate the pulsatile secretion of GnRH. This will be achieved through central administration of leptin during both acute fasting and chronic low nutrition. Although widely studied in feeding behavior, we have little understanding of its physiologic role in regulating GnRH secretion. Specific Aim 3 will assess "nutritional stress" as a cause hypogonadotropism through reduced GnRH secretion by monitoring of stress peptides in the pituitary portal circulation and by antagonizing their action during acute fasting and chronic low nutrition. Specific Aim 4 will determine if glucose availability times the pubertal GnRH increase by using the power of our large animal model in which we can chronically administer metabolically important signals such as insulin and leptin. Understanding the metabolic control of GnRH secretion has broad application both to growth and maturation and to other physiologic conditions in which reduced GnRH secretion may contribute to infertility because of altered energy metabolism. These include dietary malnutrition from eating disorders; during high-energy expenditure, as in exercise- induced amenorrhea and lactational anovulation; during type 1-diabetes- induced infertility.