Rhythmic bursts of gonadotropin-releasing hormone (GnRH) from hypothalamic neurons are essential for initiation and maintenance of secretion of the gonadotropins. The frequency and amplitude of these neural and pituitary events are regulated, in turn, by circulating levels of estradiol-17 beta (E2) and progesterone (P). One of these ovarian steroids, E2, inhibits luteinizing hormone (LH) release, whereas it enhances GnRH release; the second steroid (P) slows pulsatile LH release, in part, by increasing central opioid inhibition of GnRH secretion. The identify of other neuropeptides and catecholamines and their mode of actions and interactions of GnRH secretion in the ovulatory process and the normal menstrual cycle remain unclear. We propose to measure the patterns of GnRH in push-pull perfusion (PPP) samples from the hypothalamus and to compare these GnRH patterns with those of peripheral gonadotropins, E2, and P during the menstrual cycle in rhesus macaques and in the periovulatory period in rabbits. We will examine the roles of selected neuropeptides (neuropeptide Y, endorphins, corticotropin-releasing factor, and substance P) and that of norepinephrine in control of GnRH release by one or more of three methods: ( 1) measure their endogenous release rates in PPP samples, (2) infuse the test compound intrahypothalamically and measure changes in GnRH release, and (3) give specific antagonists or antibodies to a peptide and record these effects on endocrine and post-coital behavioral parameters. We will then study the influence of E2, P, and cortisol on the release of selected peptides and catecholamines in PPP samples and relate these findings to those on GnRH release. We propose also to measure GnRH release after intrahypothalamic infusion of pituitary hormones and inhibin and after unilateral ovariectomy for direct evidence on shortloop feedback and on hypothalamic laterality in feedback signaling. To explore these hypothalamo- hypophyseal interactions, we will use specific radioimmunoassays for peptides and steroids and a radioenzymatic assay for the catecholamines. Blood and/or PPP samples will be collected during superfusion of hypothalamic tissues (in vitro) and hypothalamic PPP in freely-moving females (in vivo). These findings will provide insight into how the hypothalamus influences the normal reproductive process, and hence may be useful in treating certain causes of infertility, anorexia nervosa, and obesity.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD016631-06
Application #
3313785
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1982-09-01
Project End
1992-11-30
Budget Start
1987-09-01
Budget End
1988-11-30
Support Year
6
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Oregon Regional Primate Research Center
Department
Type
DUNS #
City
Beaverton
State
OR
Country
United States
Zip Code
97006
Smith, Jeremy T; Shahab, Muhammad; Pereira, Alda et al. (2010) Hypothalamic expression of KISS1 and gonadotropin inhibitory hormone genes during the menstrual cycle of a non-human primate. Biol Reprod 83:568-77
Pau, K Y; Hess, D L; Kohama, S et al. (2000) Oestrogen upregulates noradrenaline release in the mediobasal hypothalamus and tyrosine hydroxylase gene expression in the brainstem of ovariectomized rhesus macaques. J Neuroendocrinol 12:899-909
Pau, C Y; Pau, K Y; Spies, H G (1998) Putative estrogen receptor beta and alpha mRNA expression in male and female rhesus macaques. Mol Cell Endocrinol 146:59-68
Pau, K Y; Yu, J H; Lee, C J et al. (1998) Topographic localization of neuropeptide Y mRNA in the monkey brainstem. Regul Pept 75-76:145-53
Urbanski, H F; Pau, K Y (1998) A biphasic developmental pattern of circulating leptin in the male rhesus macaque (Macaca mulatta). Endocrinology 139:2284-6
Pau, K Y; Spies, H G (1997) Neuroendocrine signals in the regulation of gonadotropin-releasing hormone secretion. Chin J Physiol 40:181-96
Spies, H G; Pau, K Y; Yang, S P (1997) Coital and estrogen signals: a contrast in the preovulatory neuroendocrine networks of rabbits and rhesus monkeys. Biol Reprod 56:310-9
Pau, K Y; Berria, M; Hess, D L et al. (1996) Opiatergic influence on gonadotropin-releasing hormone and luteinizing hormone release during the macaque menstrual cycle. Biol Reprod 55:478-84
Pau, K Y; Berria, M; Hess, D L et al. (1995) Hypothalamic site-dependent effects of neuropeptide Y on gonadotropin-releasing hormone secretion in rhesus macaques. J Neuroendocrinol 7:63-7
Pau, K Y; Berria, M; Hess, D L et al. (1993) Preovulatory gonadotropin-releasing hormone surge in ovarian-intact rhesus macaques. Endocrinology 133:1650-6

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