The overall objective of the proposal is to investigate interactions between two major endocrine axes, the hypothalamo-pituitary-adrenal (HPA) and the hypothalamo-pituitary-gonald (HPG) axes in a non human primate model, the rehesus monkey, which is known for its similarity to the human in regard to the control of the menstrual cycle. More specifically in the first 3 aims, we will study the mechanisms by which stressful stimuli may interfer with the normal reproductive process. Our previous studies in the ovariectomized (OVX) monkey support the classical concept that stress, by activating HPA and the release of central HPA neuropeptides, suppresses pulsatile gonadotropin secretion. Yet, these studies also clearly indicate that the response to stress is modulated by the ovarian steroids. Thus, our first 2 aims will compare effects of an immune/inflammatory-like stress challenge on gonadotropin release at different stages of the menstrual cycle and the mechanisms which differentiate the acute and the chronic response. A pilot study has demonstrated surprising responses to the stress challenge, in that under specific ovarian endocrin conditions the challenge becomes stimulatory rather than inhibitory to gonadotropin secretion. The long term effects of these responses to the stress challenge on the menstrual cycle will then be investigated. In aim 3, we will examine the role of HPA in the genesis of the stress related hypothalamic amenorrhea syndrome and determine whether the use of specific antagonists may activate the return to cyclicity. In the final aim, we will focus on HPA-HPG interactions during the follicular phase, in the absence of stress. Pilot studies in OVX-estrogen replaced monkeys suggest that HPA, in its unstimulated state, may play a small but relevant role in support of tonic gonadotropin secretion. The relevance of this process to folliculogenesis will be studied in the intact monkey. Overall, the data will provide information about novel mechanisms by which HPA and stress influence themenstrual cycle and may suggest new therapeutical approaches to the problem of hypothalamic amenorrhea.