Nutritional deprivation is associated with reproductive dysfunction and can lead to functional hypothalamic chronic an ovulation (FHCA). Even though this is a frequent cause of infertility, the exact metabolic clues that signal the brain remain to be determined. Our main objective is to investigate whether recently discovered energy-related peptides, such as the peripherally-secreted ghrelin and the centrally-secreted agouti-related peptide (AGRP), may function as clues that modulate the gonadotropin-releasing hormone (GnRH) pulse generator, the pacemaker for the hypothalamic-pituitary-gonadal (HPG) axis. Since these peptides are orexigenic and are upregulated during fasting, our central research hypothesis is that administration of these peptides in a normal animal will mimic the under-fed state and result in the inhibition of the GnRH pulse generator.
Aims 1 and 2 will investigate whether AGRP or ghrelin infusion can inhibit pulsatile LH release, a reflection of GnRH pulse activity. Because AGRP is co-located with neuropeptide Y (NPY) in arcuate neurons, we will also investigate synergy between these 2 peptides. Since both AGRP and ghrelin activate the hypothalamic-pituitary-adrenal (HPA) axis, additional protocols will document the role of functional central pathways, including that of HPA, in mediating the action of these energy-related peptides on the GnRH pulse generator.
In aims 3 and 4, we will extend our studies to the role of energy-related peptides in 2 physiopathological models which modify GnRH/LH pulsatility, one evoking food restriction, the other a psychogenic stress, and investigate whether direct or indirect antagonism of energy-related peptides or an infusion of leptin, an anorexigenic peptide, can restore normal pulsatile activity. Our studies will be performed in the rhesus monkey, a non-human primate which mimics well the physiology and physiopathology of the human reproductive system. Overall, our data will provide novel information in support of a role of new orexigenic peptides in nutrition-related and perhaps also psychogenic stress-related reproductive dysfunction and infertility. ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD046715-04
Application #
7247874
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Lamar, Charisee A
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$348,813
Indirect Cost
Name
Columbia University (N.Y.)
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032