The metabolic modulation of GnRH secretion and the timing of puberty in sheep.

The timing of puberty is profoundly influenced by growth, but how the brain monitors somatic development to increase gonadotropin-releasing hormone (GnRH) secretion remains a major question. My working hypothesis is that the ability to increase GnRH secretion is dependent on growth-related changes in energy metabolism, in particular the availability of glucose. My animal model was the gonadectomized male lamb. My approach was to monitor circulating luteinizing hormone (LH) concentrations during three conditions that impair energy metabolism: diabetes, pharmacologic glucoprivation, and altered nutrition. I determined that insulin modulates LH pulse frequency. My findings in diabetic sheep that acute insulin withdrawal decreased LH pulse frequency and that acute re-supplementation with insulin restored LH pulse frequency suggest that insulin or insulin-dependent changes in energy metabolism modulate GnRH secretion. I determined that glucose availability modulates LH pulse frequency. My finding that a glucose antagonist (2-deoxyglucose, 2DG) given either peripherally (jugular vein) or centrally (lateral cerebral ventricle) acutely blocked LH pulses, suggests that neural mechanisms controlling GnRH secretion are glucose dependent. My finding that either GnRH or a GnRH secretagogue (N-methyl-D,L-aspartate, NMA) sustained LH pulse frequency after 2DG treatment, suggests that reducing glucose availability does not impair the GnRH neuron, per se. However, my finding that LH pulse amplitude was not normalized by GnRH treatment, suggests that decreasing glucose availability may reduce the responsiveness of the anterior pituitary. I determined that both chronic and acute changes in level of nutrition modulate glucose concentrations and LH pulse frequency. My finding that LH secretion was positively associated with changes in circulating glucose and insulin is consistent with the hypothesis that changes in glucose availability are responsible for the maintenance of GnRH secretion. However, my finding that neither circulating glucose nor insulin concentrations increase when LH secretion begins, raises the possibility that mechanisms controlling the initial rise of GnRH secretion may differ from those regulating its maintenance. Collectively, my results support the concept that intrinsic changes in the availability of glucose interface energy metabolism with GnRH secretion in the developing sheep. The role of glucose availability as a metabolic factor timing puberty remains an open issue.Ph.D.Animal PhysiologyBiological SciencesNeurosciencesVeterinary scienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/132310/2/9963747.pd