DIAGNOSTIC AND THERAPEUTIC APPLICATIONS OF GROWTH HORMONE RELEASING FACTORS

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Growth hormone-releasing hormone (GHRH) is the hypothalamic peptide which stimulates the release and synthesis of growth hormone (GH). The long-term aims of this project are a) to define the role of GHRH in the regulation of GH secretion; b) to study the modulation of GHRH responses in altered physiologic states and the possible utility of GHRH testing; and c) to explore the efficacy of GHRH and analogs for the treatment of GH deficiency and excess. (a) We have characterized the effect of sex steroids on GHRH responses and episodic GH secretion. Short-term sex steroid treatment increases GH secretion, SmC levels, and responses to GH provocative tests, but does not alter the response to GHRH. Chronic therapy of hypogonadal men increases the amplitude of GH pulsatile secretion. In a comparison of patterns of GH secretion in young and old men and women, the strongest predictor of spontaneous GH secretion is plasma levels of estradiol. (b) We have determined the patterns of response to GHRH during normal aging and during pubertal development. Responses are similar at all these life stages, permitting adult normative data to be used as standards for pediatric studies. Most children with GH deficiency (GHD) respond to GHRH injections with an increase in GH, suggesting that GH deficiency is largely a hypothalamic GHRH deficiency. Among non-responding GHD patients, the majority convert to responders with repeated GHRH priming, indicating that their initial lack of responsivity is due to atrophy of unstimulated somatotrophs rather than to intrinsically abnormal pituitaries. Thus GHRH could be used as therapy for the majority of GHD patients. (c) After demonstration of the efficacy of GHRH for acceleration of growth in a short-term study, we have begun two chronic therapy trials to determine the dose and pattern of GHRH needed for therapy. It appears that GHRH need not be given by frequent pulsatile injections and can restore normal growth rates even when given as a single daily injection. Characterization of even longer-acting GHRH preparations and of ways to enhance the response to a given GHRH dose is now in progress.