Although physiologic and pharmacologic states of glucocorticoid excess, including stress, have been consistently correlated with diminished reproductive endocrine function in the rat and other species, the mechanism(s) and site(s) of glucocorticoid inhibition of the hypothalamic- pituitary luteinizing hormone (LH) axis are not clearly understood. While few studies have investigated the possibility that glucocorticoids may suppress LH release via a neuroendocrine mechanism, specific receptors for these hormones have been identified in discrete neural sites within the rat brain, and have been localized recently within specific hypothalamic nuclei already implicated in the control of pituitary LH release. Results from preliminary data studies indicate that intracerebroventricular (icv) administration of a potent glucocorticoid receptor agonist can promote a dose-proportionate decline in circulating LH levels in intact adult male rats. These data indicate that central glucocorticoid receptors mediate a suppressive effect upon LH release, and suggest that such receptors may exist within neural pathways that influence neuroendocrine regulation of pituitary LH. The studies outlined in the following proposal will seek to identify the type(s) of central glucocorticoid receptor that serves to inhibit LH release. Studies will be undertaken to investigate the effects of icv administration of graded doses of highly selective agonists of the high affinity type I and the low affinity type II glucocorticoid receptor on peripheral plasma LH levels in the male rat. Parallel studies will evaluate the significance of these receptor subtypes to the physiological regulation of hormone release through investigation of the effects of specific receptor blockade on basal and stress-stimulated LH release. Based upon observed results of global pharmacologic manipulation of glucocorticoid receptor populations, we will utilize published information concerning the microdistribution of glucocorticoid receptor subtypes in the rat brain to administer selective receptor agonists to discrete brain sites, in an effort to characterize the neuroanatomical distribution of glucocorticoid receptors that mediate a decline in pituitary LH release. Lastly, immunocytochemical analyses will be carried out to determine whether glucocorticoid receptors within the preoptic area and hypothalamus bind to receptors present within immunodemonstrable luteinizing hormone- releasing hormone (LHRH)-containing neuronal elements.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK041919-02
Application #
3242881
Study Section
Reproductive Biology Study Section (REB)
Project Start
1992-02-01
Project End
1995-01-31
Budget Start
1993-02-01
Budget End
1994-01-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Washington State University
Department
Type
Schools of Veterinary Medicine
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164