How Aggressively Should We Treat Short Stature

diated through the STAT5b-IGF-I pathway [5] ; (2) the response to systemically administered IGF-I might be enhanced by GH-induced local IGF-I production at key target tissues; (3) in addition to stimulating production of IGF-I, GH treatment increases serum concentrations of IGF binding protein-3 and acid-labile subunit, carrier proteins for the IGFs that also serve to increase the halflife of IGFs in serum; (4) the ‘diabetogenic’ actions of GH and the insulin-like actions of IGF-I could balance each other, thereby mitigating both glucose intolerance and hypoglycemia; (5) studies of the growth and IGF responses of idiopathic short stature children treated with GH have suggested some degree of both GH and IGF resistance in many such patients [6] , and (6) animal studies have indicated an additive growth response in rodents treated with combination GH plus IGF-I [7] . The paper by Backeljauw et al. [8] describes the first study to test the efficacy and safety of combination GH plus IGF-I in children with short stature and, as such, provides important insights into the potential utility and limitations of such an approach. The study group was, essentially, an idiopathic short stature population characterized by serum IGF-I concentrations below –1 SD. When compared with the group receiving GH alone, only subjects in group D (GH plus the highest dosage of IGF-I) showed a significant increase in growth velocity, but this was modest and only seen in year 1. Over the 3-year trial period, the cumulative change in height SD score was 1.9 in group D, compared to 1.3 in the GH-alone group. As expected, subjects receivGrowth hormone (GH) has been used for the treatment of GH deficiency (GHD) for over 50 years. With the development of recombinant DNA-derived GH in the early 1980s, the essentially unlimited supply of GH facilitated expansion of pediatric indications to many other forms of short stature, including idiopathic short stature, Turner syndrome, small for gestational age infants, Noonan syndrome and Prader-Willi syndrome, to name a few. In general, these other conditions, while typically displaying accelerated growth when treated with exogenous GH, did not show as robust a response to GH therapy as that observed in children with GHD. For GH to act, it must bind to a transmembrane dimeric receptor and initiate a signaling cascade(s) culminating in the production of insulin-like growth factor-I (IGF-I), primarily from liver, but also from a variety of other tissues [1] . Children with molecular defects of genes for the growth hormone receptor or for signal transducer and activator of transcription 5b (STAT5b), a critical part of the GH-signaling cascade, have auxologic characteristics essentially identical to congenital GHD, but are unresponsive to GH therapy [2] . In such cases, the molecular defect can be ‘bypassed’ through the use of IGF-I therapy, although the growth response in such cases is typically less than that observed with GH treatment of GHD [3, 4] . A rationale for the combination GH plus IGF-I therapy has several lines of support: (1) GH activates several postreceptor-signaling cascades, and it has been suggested that not all of GH’s growth-promoting actions are mePublished online: March 6, 2015 HORMONE RESEARCH IN PAEDIATRICS