DIAGNOSTIC AND THERAPEUTIC APPLICATIONS OF GROWTH HORMONE RELEASING FACTORS

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Growth hormone-releasing hormone (GHRH) is a 44-amino acid peptide which stimulates release and synthesis of growth hormone (GH). The 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 diagnostic utility of GHRH testing; and c) and to explore the potential utility of GHRH for the treatment of GH deficiency. (a) During this year we have demonstrated that the GH response to continuous GHRH exposure declines after an acute rise, with a period of desensitization to subsequent GHRH exposure. This reponse occurs even when release of GH is prevented, indicating that the response is mediated at least in part by receptor occupancy and not only through depletion of releasable GH stores. (b) We have studied the normal range of GHRH responses in healthy aging men, and in boys and girls throughout pubertal development. Despite a decrease in spontaneous GH secretion, GHRH responses are maintained in older adults. Responses also vary little during puberty. This permits adult normative data to be used as a reference for studies in children. In obesity, where spontaneous GH secretion is decreased, responsivity to GHRH is also reduced. By contrast, when GH secretion is increased, as in malnutrition, anorexia nervosa, and Laron type dwarfism, responses to GHRH are not increased over normal. This suggests that responses to GHRH are near-maximal under normal conditions. GH deficient children have lower mean responses than normal children, but the majority do respond to GHRH, and many responses overlap the normal range. Thus, GHRH testing is not reliable for diagnosing GHD; but demonstrates that most GHD is due to a deficiency fo GHRH, and not to a pituitary lesion. Thus GHRH could be used to treat these GHD children if given repeatedly. (c) In an initial test of this hypothesis, a group of GHD children were treated with GHRH, placebo, and GH. In the majority, GHRH restored GH secretion, elevated somatomedin C, and accelerated linear growth. The response was comparable to the effects of GH. Currently patients are being treated with a range of GHRH doses and frequencies to determine the optimun treatment regimen.