Significant progress has been made during the last 5 years in elucidating the complex mechanisms involved in the stimulatory and inhibitory effects of progesterone on gonadotropin secretion. From these studies, a multifactorial hypothesis explaining regulation of gonadotropin secretion by progesterone has been proposed which includes progesterone regulation of estrogen receptor dynamics, modulation of opioid tone, and modulation of GABA and glutamate neurotransmission of the positive and negative feedback effects of progesterone. This renewal application will further elucidate mechanisms involved with the initiation and termination of the gonadotropin surge and has 4 specific aims. SPECIFIC AIM 1 will determine the mechanism of an increase in estrogen receptors of the pituitary associated with the termination of the preovulatory gonadotropin surge. The study will include measurement of pituitary ER mRNA transcription and translation along with ER binding and degradation. The role of a hypothalamic factor will also be investigated by using hypothalamic-lesioned rats, a GnRH antagonist and NPY. SPECIFIC AIM 2 will determine the role of estrogens and progesterone on the regulation of the opioid tone during the gonadotropin surge. The studies will include the measurement of hypothalamic beta-endorphin, opioid receptors and POMC mRNA levels and their correlation with gonadotropin secretion. SPECIFIC AIM 3 will determine the role of GABA in progesterone-induced inhibition and stimulation of gonadotropin secretion in the hypothalamus and the pituitary. The study will use in vitro hypothalamic GnRH release and pituitary FSH and LH release in the presence and absence of GABA agonists and antagonists and intraventricular injection of GABA antagonists. GABA receptors will also be measured. SPECIFIC AIM 4 will determine the role of glutamic acid decarboxylase (GAD) in the stimulation and suppression of gonadotropin secretion by progesterone. The study will include measurement of hypothalamic GnRH, GABA, glutamic acid, GAD activity and GAD mRNA levels during progesterone induced stimulation and suppression of gonadotropin secretion. These studies will provide new information on the neuroendocrine regulation of gonadotropin secretion by progesterone.