Growth hormone therapy does not alter the insulin-like growth factor-I/insulin-like growth factor binding protein-3 molar ratio in growth hormone-deficient children

Background: Recent studies have linked raised levels of IGF-I and/or reduced levels of its main binding protein, IGF binding protein (IGFBP)-3, with the risk of developing cancer. A GH dose-dependent increase in IGF-I/IGFBP-3 molar ratio has been reported in subjects treated with GH, raising concern about the long-term safety. Objective: The aim of this study was to evaluate changes in serum IGF-I, IGFBP-3, and IGF-I/IGFBP-3 molar ratio over the first 12 months of replacement GH therapy in GH deficient (GHD) children. Methods: The study included 20 GHD children who had not previously received GH treatment, and 40 untreated non-GHD short children closely matched for age, gender, pubertal stage, and body mass index (BMI), as controls. Serum IGF-I, IGFBP-3 levels were measured before and after 12 months of GH treatment. Based on the molecular weight of IGF-I (7500) and IGF-BP-3 (40,000, mean of glycosylated variants), we calculated the molar ratio of IGF-I/IGFBP-3. Results: IGF-I/IGFBP-3 molar ratio significantly increased during GH therapy (p=0.01). No significant difference in IGF-I/IGFBP-3 ratio was found between GHD children and controls at the different time points. In the multiple regression analysis, BMI (beta=0.33) and age (beta=0.33) proved to be the major predictors of the IGF-I/IGFBP-3 molar ratio (adjusted r(2)=0.53, p < 0.0001). Conclusions: Our results suggest that at a conventional replacement dose GH does not alter the IGF-I/IGFBP-3 molar ratio. Potential fears related to long-term cancer risk are likely to be greatest in patients exposed to high-dose GH therapy and with genetic predisposition to high IGF-I and/or low IGFBP-3 concentrations.