Modulation of IGF-I receptors by exogenous hGH treatment in constitutionally short children

Objective: To study the in-vivo regulation of IGF-I binding sites on erythrocytes (RBC) following administration of growth hormone (hGH) to constitutionally short children. Recently, owing to biosynthetic techniques, treatment with hGH has been administered not only to children with GH deficiency but also to children with constitutional growth delay and with familial short stature. Patients and design: Growth hormone (rhGH-Norditropin, Novo/Nordisk) was administered at a dose of 0.1 U/kg/day s.c. to 11 children with constitutional short stature. Before and at 1-2 months after initiation of treatment IGF-I binding sites and serum IGF-I were determined. Erythrocytes were separated from whole blood by centrifugation over Ficoll Hypaque and used to assess IGF-I binding sites. Results: Serum IGF-I levels increased from 14.93 ± 1.50 nmol/l (mean ± SEM) to 30.29 ± 2.32 nmol/l, with a mean difference of 15.36 ± 2.21 (P = 0.00001). Concomitantly, the number of binding sites per cell decreased from 5.77 ± 0.81 sites per cell (m ± SEM) to 2.10 ± 0.36, with a mean difference of -3.67 ± 0.76 (P = 0.0003). The dissociation constant (K(d)) also decreased from 0.47 ± 0.16 nM (m ± SEM) to 0.10 ± 0.02 with a mean difference of -0.37 ± 0.16 (P = 0.02), indicating an increase in the affinity of the receptors. Conclusion: Treatment of children with constitutional short stature with hGH raises the circulating IGF-I levels and down-regulates the IGF-I receptors. This study shows that IGF-I is capable of regulating its homologous receptor concentrations in vivo and it is suggested that the measurement of IGF-I binding sites on RBC may be used for the diagnosis of subtle states of resistance to IGF-I.