Long-Acting Forms of Growth Hormone-Releasing Hormone and Growth Hormone: Effects in Normal Volunteers and Adults with Growth Hormone Deficiency

Abstract

Background: Growth hormone (GH) replacement therapy in adults and children has found broad acceptance by endocrinologists and patients, but the need for daily injections remains a significant barrier to more widespread use. Long-acting Formulations: Several approaches have been taken to develop long-acting forms of GH and to extend the half-life of GH-releasing factor. Each of these preparations has been tested in experimental animal models and found to extend the half-life of GH and GH-releasing hormone (GHRH) and to increase mean daily GH levels. Frequent sampling following administration of long-acting GHRH showed that the greatest increases occurred in trough GH levels, which increased 7.8-fold. The extended GH half-life and increased trough levels resulted in increases in insulin-like growth factor I (IGF-I) levels, which increased 1.4- to 4.1-fold and extended the duration of the IGF-I increase from 7 to 14 days. These increases in GH and IGF-I levels allow these compounds to be administered much less frequently, and several studies have shown that IGF-I levels can be maintained in a therapeutically effective range with much less frequent GH administration. Safety: Complications other than those generally associated with GH therapy include nodule formation and lipoatrophy at the injection sites. One long-term study of a long-acting formulation demonstrated that growth could be effectively stimulated in GH-deficient children, but that the peak growth velocity was only about 80% of that seen following daily subcutaneous GH injections. Subcutaneous nodule formation in some patients may have contributed to noncompliance and thus to the difference in growth velocity. Conclusions: Different types of GH and GHRH formulations have been developed with extended half-lives. In general, these preparations are pharmacokinetically and pharmacodynamically effective, extend GH half-lives with longer sustained elevation of IGF-I and permit much less frequent GH administration. Thus, it may be possible to develop a therapeutically effective form of GH for use in long-term treatment. The precise efficacy and safety assessments to use in monitoring long-term GH administration have not been definitively established.