The overall goal of this new grant proposal is to elucidate the physiological mechanisms by which undernutrition leads to a suppression of reproductive function in primate species. All studies in this proposal will utilize adult male rhesus monkeys that are fasted for one day. We have previously shown that this short period of fasting leads to a decrease in the frequency of pulsatile LH and testosterone secretion, which appears to result from a decrease in the frequency of GnRH secretion. Thus the locus of dysfunction in the reproductive axis during both chronic and acute periods of undernutrition appears to be at the level of the GnRH pulse generator, however use of the short-term fasting model will allow us to study how nutrition affects reproductive function without ill effects on the health and well-being of the experimental animals. Two specific hypotheses will be tested by the projects in this proposal: (1) that metabolic changes occurring as a direct result of the state of undernutrition suppress GnRH neuronal activity, and (2) that a general stress response occurring during undernutrition suppresses GnRH neuronal activity. Projects 1-4 are designed to identify """"""""signals"""""""" that are leading to the suppressed activity of the GnRH pulse generator in undernourished states. Project 1 will determine whether the slowing of LH pulse frequency during short-term fasting can be reversed by (a) administering nutrients intravenously to provide nutrition without relieving the psychological stress of withholding food, and (b) providing noncaloric pellets to relieve the psychological stress of food deprivation without increasing nutrient intake. Projects 2-4 are designed to isolate signals which serve to link GnRH neuronal activity to the nutritional state of the body by (a) examining the ability of the GnRH neuronal system to respond to short-term fasting when it has been surgically disconnected from other neuronal input, (b) measuring neuronal and metabolic changes occurring in the vicinity of the GnRH neurons using push-pull perfusion techniques, and (c) determining whether administration of specific pharmacological agonists and antagonists can reverse the effects of short-term fasting on pulsatile LH secretion. Project 5 will involve measurement of GnRH and POMC mRNA levels during short-term fasting to begin to determine whether changes in neuropeptide synthesis are involved in the slowing of the GnRH neuronal activity, but that they will also increase our understanding of the general mechanisms leading to quiescence of the GnRH neuronal system in other physiological and pathological conditions (i.e., during normal childhood, anorexia nervosa, spontaneous hypothalamic-hypophyseal dysfunction, stress, and participation in chronic vigorous exercise programs).

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD026888-02
Application #
3328478
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1990-04-01
Project End
1993-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Grimes, Michael A; Cameron, Judy L; Fernstrom, John D (2009) Cerebrospinal fluid concentrations of large neutral and basic amino acids in Macaca mulatta: diurnal variations and responses to chronic changes in dietary protein intake. Metabolism 58:129-40
Mancini, Fulvia; Loucks, Tammy L; Cameron, Judy L et al. (2005) Sex steroid milieu does not alter the impact of fasting on leptin levels in women. Fertil Steril 84:1768-71
Cameron, Judy L (2004) Interrelationships between hormones, behavior, and affect during adolescence: complex relationships exist between reproductive hormones, stress-related hormones, and the activity of neural systems that regulate behavioral affect. Comments on part III. Ann N Y Acad Sci 1021:134-42
Berga, S L; Loucks, T L; Cameron, J L (2001) Endocrine and chronobiological effects of fasting in women. Fertil Steril 75:926-32
Grimes, M A; Cameron, J L; Fernstrom, J D (2000) Cerebrospinal fluid concentrations of tryptophan and 5-hydroxyindoleacetic acid in Macaca mulatta: diurnal variations and response to chronic changes in dietary protein intake. Neurochem Res 25:413-22
Tang-Christensen, M; Havel, P J; Jacobs, R R et al. (1999) Central administration of leptin inhibits food intake and activates the sympathetic nervous system in rhesus macaques. J Clin Endocrinol Metab 84:711-7
Larsen, P J; Tang-Christensen, M; Stidsen, C E et al. (1999) Activation of central neuropeptide Y Y1 receptors potently stimulates food intake in male rhesus monkeys. J Clin Endocrinol Metab 84:3781-91
Caston-Balderrama, A L; Cameron, J L; Hoffman, G E (1998) Immunocytochemical localization of Fos in perfused nonhuman primate brain tissue: fixation and antisera selection. J Histochem Cytochem 46:547-56
Schreihofer, D A; Cameron, J L; Verbalis, J G et al. (1997) Cholecystokinin induces Fos expression in catecholaminergic neurons of the macaque monkey caudal medulla. Brain Res 770:37-44
Cameron, J L (1996) Nutritional determinants of puberty. Nutr Rev 54:S17-22

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