Summary Future Directions

GHRH is a physiologic replacement for patients with reduced GH secretion owing to hypothalamic causes. Its range of potential clinical applications is thus almost as broad as the potential applications of GH treatment, except for patients with pituitary lesions— both the traditional indication of idiopathic GH deficiency, and the nontraditional indications such as wasting illness, wound and fracture healing, and aging, which largely remain to be clarified. Compared to GH, it has several physiologic advantages. It stimulates an episodic pattern of GH secretion that may produce different responses from the broad elevation in GH levels seen with GH treatment, and it preserves feedback at the pituitary level to help buffer against overtreatment. This latter effect is not an absolute protection, since the patients with GHRH-producing tumors manifest GH excess; but it may help in settings with the lower levels of GHRH used in treatment. Older patients in particular appear to be sensitive to the side effects of GH in doses which are well tolerated in children.

GHRH antagonists are in early clinical trials; they will provide a helpful physiologic probe, but whether they will be useful in any but the small fraction of cases of acromegaly owing to GHRH overproduction remains doubtful. Despite intensive study, a long-acting superagonist analog of GHRH in man has not yet become available. Native GHRH is rapidly inactivated by proteolysis at the N terminal, and thus the response to acute GHRH administration is very brief, falling short of the goal of recreating a normal pattern of pulsatile overnight secretion (Fig. 10). Since GHRH is less well suited to oral or nasal administration than secretagogues in the GHRP family, development of a long-acting analog or formulation of GHRH is critical if it is to have a major role in clinical treatment. The recognition that an endogenous substance binding to the GHRP receptor(s) probably also plays a major role in the physiologic regulation of GH means that a full physiologic replacement program for hypothalamic GH deficiency may entail substitution with both classes of secretagogues.

Thus the challenges for future studies with GHRH are threefold. On a technical level, a long-acting preparation is acutely needed. The number of patients even with classical GH deficiency who have been treated with GHRH is still relatively small, and the definition of other appropriate indications for GH augmentation remains largely for the future. Careful clinical investigation using both GHRH, its antagonists, and GHRP's will assist in defining the interaction among these converging systems in the physiologic regulation of GH in humans.

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