Insulin-like growth factor-I (rhIGF-I) therapy of short stature.

The United States Food and Drug Administration (FDA) approved the use of subcutaneously injected rhIGF-I in late 2005 for treatment of children with severe short stature from growth hormone (GH) insensitivity due to genetic defects in the GH receptor or postreceptor mechanisms or from the development of GH inactivating antibodies. The approval was based on 15 years experience treating these rare conditions with rhIGF-I. Because of the very small numbers of children with these conditions, there has been an effort to justify and promote broader use for rhIGF-I. Attempts to identify GH unresponsiveness in children with idiopathic short stature (ISS) have yielded only a handful of patients with rare genetic disorders. IGF-I treatment for unequivocal GH insensitivity improves but does not correct growth failure, in contrast to the typical experience with GH replacement of GH deficiency. This emphasizes the importance of direct effects of GH at the growth plate, including the stimulation of maturation of cartilage precursor cells and local production of IGF-I, effects that cannot be duplicated by exogenous administration of rhIGF-I. Adverse effects testify to the more than adequate delivery of administered rhIGF-I to other tissues; these include lymphoid hyperplasia, coarsening of the facies, and increased percentage body fat. The absence of convincing evidence of GH insensitivity in a substantial number of children with ISS, the limited ability of endocrine IGF-I to restore normal growth in those with unequivocal GH unresponsiveness, the suppression of endogenous GH (and thereby, local GH effects on growth) that occurs with IGF-I administration, the risk profile, and the absence of data on efficacy in other than proven severe GH insensitivity, led the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society to conclude that rhIGF-I use is only justified in conditions approved by the FDA and that other growth promotional use should only be investigational. Nonetheless, substantial numbers of children are being treated with rhIGF-I off-label, exuberant estimates of potentially eligible patients are projected, and several uncontrolled clinical trials have been undertaken which are not based on sound preliminary data or established growth principles, and a single four-arm study begun comparing monotherapy with rhGH to combination rhGH with three dosages of rhIGF-I as a single daily injection, a means of administration of rhIGF-I that has not been tested.