Gonadotropin-releasing hormone (GnRH) is the ultimate regulator of the hypothalamic-pituitary-gonadal axis, and therefore of reproductive function. Pulsatile secretion of this neuropeptide from hypothalamic GnRH neurons regulates the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gonadotrope. LH and FSH, in turn, act on the gonads and stimulate the production of gonadal steroid hormones, which feedback to regulate the hypothalamus and the pituitary. Despite the importance of the steroid hormone feedback loop in hypothalamic control of the estrus cycle, the mechanisms of estrogen and progesterone regulation of GnRH synthesis and secretion remain to be fully elucidated. The role of progesterone in the regulation of GnRH secretion from GnRH neurons will be investigated, both in a GnRH-expressing neuronal cell line and in vivo using transgenic mice as outlined in the following specific aims. Specific Aim 1: Determine the effect of progesterone on GnRH secretion, in the presence or absence of estrogen, in GT1-7 cells. Specific Aim 2: Determine the mechanism of progesterone regulation of GnRH secretion. Specific Aim 3: Determine whether neuronal PR is required normal fertility in vivo using a central nervous system neuron-specific PR knock-out mouse model. PUBLIC HEALTH RELVANCE: Proper regulation of GnRH expression and pulsatile secretion by neurons in the hypothalamus is important for a number of physiological processes, including puberty, the menstrual cycle, pregnancy, and menopause. Malfunction of the hypothalamic-pituitary-gonadal axis results in pathophysiological states, including infertility. Therefore, understanding the mechanisms of GnRH regulation is critical for developing our knowledge of reproduction in mammals, including humans.