Immune stressors markedly stimulate the hypothalamic-pituitary-adrenal (HPA) axis and can also profoundly inhibit the hypothalamic-pituitary- gonadal (HPG) axis. The suppressive effects on reproductive neuroendocrine function induced by immune stressors are manifest in many ways: 1) inhibited tonic pulsatile secretion of hypothalamic gonadotropin-releasing hormone (GnRH) and pituitary luteinizing hormone (LH) secretion; 2) blockage of the preovulatory surges of these same hormones; 3) and disruption of pregnancy. Knowing that immune stressors activate the HPA axis and that HPA hormones can inhibit reproductive neuroendocrine function, we propose to test the unifying hypothesis that activation of the neuroendocrine stress axis following immune challenge causes suppression of reproductive neuroendocrine hormonal output, and this suppression disrupts the normal follicular phase and cyclicity in females. Toward this hypothesis, we propose four specific aims, each addressing a specific question: 1) Does endotoxin stimulate corticotropic-releasing hormone (CRH) and arginine vasopressin (AVP) secretion into the hypothalamic-pituitary portal blood coincident with its inhibition of pulsatile GnRH secretion? 2) Can the suppressive effects of endotoxin on pulsatile GnRH secretion be prevented by blocking the actions of CRH and/or AVP? 3) Does the hypothalamic distribution of receptors for CRH and AVP suggest these molecules can impact GnRH neurons indirectly or directly? and 4) Does endotoxin disrupt the normal follicular phase of the estrous cycle by suppressing pulsatile GnRH/LH secretion, by inhibiting estradiol secretion, and/or by blocking the mechanism by which estradiol induces the preovulatory GnRH/LH surges?
