NEUROENDOCRINOLOGY OF PUBERTY

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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.