The broad objective of this research proposal is to determine the mechanisms by which changes in nutritional intake modify the activity of the hypothalamic-pituitary-gonadal axis. The acutely undernourished male rat provides an excellent model for studying the mechanisms and signals mediating nutritional influences on the reproductive system because gonadotropin secretion diminishes rapidly after the onset of food deprivation (within 48 hours), reducing the complications of chronic undernutrition and stress. In the rat, decreased nutrient intake appears to impair reproductive function primarily by increasing the sensitivity of the hypothalamic-pituitary branch of the reproductive axis to the negative feedback actions of gonadal steroids.
The first aim of this proposal is to determine whether the change in sensitivity occurs at the level of the hypothalamus or pituitary. This question will be addressed by exmaining the response of the pituitary to testosterone negative feedback in the presence of a constant GnRH stimulus and by determining the changes in the amplitude and frequency of pulsatile LH release during undernutrition. Studies to further characterize the changes that occur at the level of the hypothalamus and pituitary during undernutrition include 1) determining whether changes occur in the post-translational processing of gonadotropins within pituitary gonadotrophes, 2) determining whether undernutrition changes the ability of various neurotransmitters (NE, E, DA, 5-HT and -endorphin) to modify GnRH release, and 3) determining whether agonists or antogonists of these neurotransmitters can stimulate gonadotropin secretion in undernourished rats. Additional studies are designed to identify the physiological signal which links the activity of the reproductive axis to nutrient intake by examining the ability of various nutrients (e.g., specific amino acids, fatty acids, glucose) and hormones (e.g., insulin, T3, and T4), whose levels change during undernutrition, to prevent the decrease in gonadotropin secretion caused by undernutrition. Together, the studies in this proposal will increase our understanding of 1) the physiological regulation of gonadotropin secretion, 2) the mechanisms involved in changing the sensitivity to gonadal steroid negative feedback (a phenomenon which occurs in many species, including primates, during pubertal maturation), 3) why reproductive function occurs in states of undernutrition, and 4) the general question of how changes in the nutritional status of the body affect brain function.
