Because the aging pituitary remains responsive to stimulation by growth hormone (GH) secretagogues - GHRH, ghrelin, and their mimetics - these compounds could potentially be used instead of GH itself to increase GH secretion in aging. The factors contributing to the age-related decline in GH secretion are largely extrapituitary, and with repeated or continuous administration GHS's can significantly increase GH secretion and elevate levels of insulin-like growth factor-I (IGF-I) to the young adult normal range. Treatment with GHS's has both theoretical and practical potential advantages over GH - preserving feedback regulation by IGF-I to buffer against overtreatment, and yielding a more physiologic pulsatile pattern of GH secretion. Nonpeptide GHS's can also be administered orally. This review focuses primarily on results using GHRH; studies with ghrelin agonists are reviewed in detail in other articles from this symposium. We and others have shown that GHRH stimulates the brisk release of GH in healthy seniors, and that repeated administration of GHRH elevates IGF-I in a dose-dependent manner. In two 6-month treatment studies in healthy older women and men, subcutaneous injections of GHRH(1-29)NH2, self-administered once nightly, chronically increased nighttime GH secretion and produced sustained elevations of IGF-I levels. IGF-I increases were greatest in men, averaging 30%. Women not taking estrogen showed somewhat lesser increases (23%), and women taking oral estrogen replacement had no significant increase despite the greatest increments in GH secretion. Lean body mass increased; body fat was reduced by an average of 5-8%, with greatest effect on abdominal visceral fat; and again this effect was blunted in estrogenized women. Effects on physical function varied by group. In nonestrogenized women, physical function deteriorated in those receiving placebo; some measures were stabilized in women receiving GHRH. These changes were not significant in estrogenized subjects. GHRH appeared to improve cognitive function, especially in domains sensitive to changes in processing speed. The formulation of GHRH used in these studies is short-acting, with effects ending within a few hours. Perhaps for this reason, late-night GH secretion decreased after the initial GHRH-stimulated surge, and sleep quality was not improved. Side effects were those of fluid retention and were generally mild. The duration of these studies do not allow inferences to be drawn on prevention of the onset of clinical features of frailty. Thus, 6-month treatment with once-daily GHRH can elevate GH secretion and IGF-I, and improve body composition in a manner similar to the effects of GH. Effects on physical function are equivocal. Effects on cognition are encouraging but preliminary. The current GHRH formulation is too short-acting to provide optimal effects.
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