Hormonal and metabolic effects and pharmacokinetics of recombinant insulin-like growth factor-I in growth hormone receptor deficiency/Laron syndrome

Profound growth failure despite elevated GH levels in GH receptor defiency (GHRD) results from reduced insulin-like growth factor-I (IGF-I) synthesis. Recent reports of improved growth velocity in children with GHRD during IGF-I therapy indicate growth-promoting potential in humans. We evaluated the pharmacokinetics and metabolic/hormonal effects of recombinant human IGF-I (40 Mg/kg every 12 h) given sc for 7 days to six adults with GHRD. Hypoglycemia (<2.5 mmol/L) did not occur, and mean 2 h postprandial insulin levels were reduced. Urinary calcium increased 2-fold (P < 0.01), and serum calcium was unchanged. The mean integrated 24-h GH level was supressed (6.5 ± 2.1 to 1 ± 0.2 μg/L), as were the number of peaks, area under the curve, and clonidine-stimulated GH release (all P < 0.05). The mean pretreatment IGF-I level (36 ± 2 μg/L) was 19% of the Ecuadorian control value (190 ± 15 μg/L), it achieved a peak (253 ± 11 μg/L) between 2-6 h after IGF-I injection, and at 12 h it was 137 ± 8 μg/L. There were no significant changes in the half-life (8.2 ± 1.5 to 9.7 ± 1.9 h) or metabolic clearance (0.35 ± 0.1 to 0.24 ± 0.05 mL/kg·min) between days 1 and 7; however, distribution volume increased (183 ± 10 to 266 ± 36 mL/kg; P < 0.03). Baseline IGF-II levels were 47% of the control value and decreased during IGF-I therapy (273 ± 10 to 178 ± 9 μg/L; P < 0.01), correlating inversely with IGF-I levels (r = -0.3; P < 0.001). Although IGF-binding protein-3 (IGFBP-3) levels were not significantly influenced, baseline IGFBP-2 levels (153% of the control) increased 45% (P < 0.01). We conclude that IGF-I (40 μg/kg every 12 h) given sc to adults with GHRD is safe; achieves normal levels of IGF-I; reduces insulin, IGF-II, and GH levels; and increases IGFBP-2 concentrations and urinary excretion of calcium.