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 IGFBP- 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 (β=0.33) and age (β=0.33) proved to be the major predictors of the IGF-I/IGFBP-3 molar ratio (adjusted r2=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

Increased chromosome fragility in lymphocytes of short normal children treated with recombinant human growth hormone

A few years ago it was reported that some growth-hormone-deficient children had developed leukemia following therapy with human growth hormone. This raised concern that this therapy may stimulate tumor development. Since it is known that the tendency to develop cancer is closely related to chromosome breakage, we decided to investigate whether recombinant human growth hormone (rhGH) therapy can increase chromosome fragility. Ten short normal children were studied during their first year of treatment. Lymphocytes were collected at 0, 6 and 12 months of rhGH therapy, and we assessed the rate of spontaneous chromosome aberrations, the frequency of sister chromatid exchanges, the proliferative rate indices, the expression of common fragile sites induced by aphidicolin, and the sensitivity towards the radiomimetic action of bleomycin. At 6 months of therapy, there was a significant increase in bleomycin-induced chromosome aberrations, which remained unchanged after 1 year of treatment. An increase in spontaneous chromosome rearrangements at 6 and 12 months of therapy was also observed. These findings are further supported by data obtained from the analysis of 16 short normal children already on rhGH therapy