Low serum GH and IGF-1 levels appear to be significant factors involved in the development of physical frailty in normal older men and women via effects on muscle, bone and physical morbidity as well as sense of well-being. The first specific aim of this study will be to further understand the pathophysiology of decreased GH secretion in these subjects in order to distinguish when GH secretion is decreased because of a specific hypothalamic hormonal deficiency compared to normal aging. The hypothesis to be investigated is whether decreased GH secretion in some older men and women primarily results from a deficiency of the putative hypothalamic GHRP-like hormone and secondarily from a decreased secretion of the endogenous GHRH or an increased secretion of Somatostatin (SRIF). A combined quantitative and qualitative pituitary GH release approach will be utilized in which the GH responses are determined after the acute administration of GHRP-2, GHRH and GHRP-2+GHRH. GHRPs administered chronically to short stature children with various degrees of GH deficiency or to obese subjects have produced anabolic effects by increasing the rate of body growth in children and increasing fat-free mass as determined by analysis of body composition with dual photon x-ray absorptiometry (DEXA) in obese subjects. GHRPs in certain dosages and by specific routes of administration slightly and transiently raise serum cortisol levels. Also, GHRP may transiently impair glucose homeostasis which over time becomes negligible possibly because lean body mass in increased. The matter may represent increased skeletal muscle and perhaps an added route for glucose disposal. The studies by Veldhuis et al on pulsatile GH secretion indicate a dual defect on GH secretion and clearance in GH deficient adults. These investigators have defined the differential impact of age, sex steroid hormones and obesity on basal versus pulsatile GH secretion. Low euglycemic dosages of recombinant IGF-1 rapidly suppress the fasting enhanced pulsatile release of GH. The second specific aim of this study will be to determine the 24 normal older men and women with decreased secretion of GH. Because of its physiological significance, pulsatile GH secretion will be emphasized. In addition, effects on the following parameters will be studied: body composition, thyroid, adrenal function, serum PRL, cortisol, serum lipoproteins, glucose-insulin levels after an oral glucose tolerance test, PTH, osteocalcin, Prolagen-C, and leptin. These shorter chronic GHRP-2 studies are considered of sufficient time to optimize the GHRP-2 approach in terms of dosage, GH axis and various metabolic responses to become a basis for longer term studies.
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