Stress Increases Gonadotropin Inhibitory Hormone Cell Activity and Input to GnRH Cells in Ewes

Stress reduces GnRH and gonadotropin secretion in sheep, but the central mechanism for this suppressive effect is unknown. Gonadotropin-inhibitory hormone (GnIH) negatively regulates GnRH neurons and gonadotropes. Here, we measured activity of GnIH neurons and contact of GnIH fibers on GnRH neurons during either chronic "pseudostress" or acute stress in sheep. We also measured GnIH secretion into hypophysial portal blood during pseudostress and acute stress. The pseudostress was daily im injections (0.5 mg) of Synacthen Depot (adrenocorticotropin) or vehicle for 4 weeks, which increased the GnIH cell number and gene expression/cell in the hypothalamus, measured by in situ hybridization. Double label immunohistochemistry showed that Synacthen Depot treatment increased the percentage of GnRH cells in close contact with GnIH fibers but did not alter GnIH levels in hypophysial portal blood. Acute stress protocols were either sequential audiovisual predator stress, followed by insulin-induced hypoglycemia, or a single challenge with lipopolysaccharide (iv). Both of these acute stressors activated a c-Fos response in GnIH cells and increased the contacts of GnIH fibers to GnRH cells. Neither acute stress protocol increased GnIH secretion into hypophysial portal blood. These data show that chronic pseudostress and acute stressors increase the function of GnIH cells as well as the degree to which GnIH cells may provide input to GnRH cells. Thus, GnIH cells may provide a central mechanism whereby stress compromises reproduction. Neither chronic pseudostress nor acute stress elevates secretion of GnIH into portal blood, but stress effects mediated by GnIH cells are directed towards GnRH cell bodies.