NEUROENDOCRINOLOGY OF PUBERTY

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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.