Standard and low-dose IGF-I generation tests and spontaneous growth hormone secretion in children with idiopathic short stature

OBJECTIVE Abnormalities in the GH-IGF-I axis, consistent with GH insensitivity (GHI), have been reported in some patients with idiopathic short stature (ISS). The standard IGF-I generation test (IGFGT) has not demonstrated mild GHI in subjects with ISS. The aim of this study was to investigate the GH-IGF-I axis in ISS by performing standard and novel low-dose IGFGTs together with determination of spontaneous GH secretion. PATIENTS AND METHODS Twenty-one (17 male) prepubertal children with ISS, mean age 8.3 years (4.5-12.2), mean height -3.48 SD (-5.40 to -1.79), mean peak GH to provocation with glucagon/clonidine 32.3 mU/l (14.1-66.0) were studied. Serum IGF-I and IGFBP-3 levels were measured during standard (GH 0.033 mg/kg/day x 4) and low (GH 0.011 mg/kg/day x 4) dose IGFGTs at 0, 12, 36 and 84 h. The low-dose IGFGT was performed in seven naive GH-deficient patients (4 male), mean age 8.5 years (range 4.1-11.1). Determination of spontaneous 24-h GH secretion was performed in the 21 ISS patients. RESULTS Basal IGF-I and IGFBP-3 standard deviation scores (SDS) in ISS patients were -1.39 (-2.4-1.16) and -0.45 (-1.13-0.38), respectively, IGF-I being lower than IGFBP-3 (P < 0.0001). IGF-I increased in the standard IGFGT at 12 h (P < 0.005), 36 h (P < 0.001) and 84 h (P < 0.001); maximal increment 1.54 (-0.32-3.48), and in the low-dose test at 12 h (P < 0.005), 36 h (P < 0.001) and 84 h (P < 0.005); maximal increment 0.53 (0.08 to -1.23). IGFBP-3 SDS increased in the standard IGFGT at 36 h (P < 0.01) and 84 h (P < 0.001); maximal increment 0.72 (-0.44-1.96), and in the low-dose test at 84 h (P < 0.005); maximal increment 0.33 (-0.08-0.87). Five/19 patients with an IGF-I response > 2 x coefficient of variation (CV) of assay in the standard test failed to respond in the low-dose test, suggestive of mild GHI. In GH-deficient patients, IGF-I increased at each time point (P < 0.05) and IGFBP-3 at 36 h (P < 0.05). Mean GH secretion, expressed in SDS, compared with 66 normal stature controls was: basal GH -0.48 (-0.84-0.93), height of GH peaks compared with zero -0.36 (-1.26-1.51) (both P < 0.05), total GH secretion -0.76 (-1.22-0.42), total GH secretion above baseline -0.67 (-1.21-0.94) (both P < 0.01). CONCLUSIONS In children with ISS, basal IGF-I and IGFBP-3 SDS values were below the mean, IGF-I showing a greater response in both IGFGTs. In the standard IGFGT, the IGF-I increase at 36 h was equal to that at 84 h. The low-dose IGFGT, in combination with the standard test, may identify patients with mild GHI.