Changes in serum IGF-I and IGFBP-3 concentrations during the IGF-I generation test performed prospectively in children with short stature.

Abstract

Genotype and phenotype heterogeneity in patients with GH insensitivity syndrome suggests that partial defects exist in the GH receptor. Children with partial GH resistance would be expected to have short stature, elevated GH levels and relatively low levels of IGF-I and IGFBP-3. Provocation tests of the GH-IGF-I axis may help to identify such children. The IGF-I generation test in particular may demonstrate impaired secretion of IGF-I and IGFBP-3. This prospective study assesses the usefulness of the IGF-I generation test in the identification of short children with possible GH insensitivity. Prepubertal children referred for assessment of short stature underwent a standard GH provocation test followed by an IGF-I generation test. Thirty-seven prepubertal children (14 girls, 23 boys) with short stature (height < 2nd centile UK standards 1990) aged 4.5-12.6 years were investigated prospectively. Assessment included history, physical examination, auxological observations (height, weight, bone age). GH provocation tests (glucagon 15 micrograms/kg i.m. or insulin 0.15 U/kg/i.v.) was followed by an IGF-I generation test (hGH 0.1 iu/kg/s.c. daily for 4 days). GH was assayed during the provocation test. IGF-I and IGFBP-3 were measured at 0900 h on day 0 and 4 of the IGF-I generation test. GH and IGF-I were measured by radioimmunoassay, IGFBP-3 by IRMA and basal GHBP by HPLC. Height SDS was calculated according to the UK Height Standards 1990. The absolute and percentage changes of IGF-I and IGFBP-3 during the IGF-I generation test were calculated. The 37 children were divided into three groups according to the peak GH level (mean +/- SEM) during the provocation test: Group 1 (peak GH < 20 mU/l) n = 11, five girls, six boys age 7.1 +/- 0.7 years, height SDS -2.5 +/- 0.1, peak GH 14.5 +/- 1.6 mU/l, IGF-I 92.0 +/- 10.4 micrograms/l, IGFBP-3 2.6 +/- 0.4 mg/l. Group 2 (peak GH 20-40 mU/l) n = 12, six girls, six boys age 8.6 +/- 0.7 years, height SDS -2.6 +/- 0.1, peak GH 28.4 +/- 1.6 mU/l, IGF-I 121-5 +/- 13.4 micrograms/l, IGFBP-3 2.9 +/- 0.2 mg/l. Group 3 (peak GH > 40 mU/l) n = 14, three girls, 11 boys, aged 8.5 +/- 0.6 years, height SDS -2.3 +/- 0.1, peak GH 60.7 +/- 4.1 mU/l, IGF-I 112.4 +/- 10.9 micrograms/l, IGFBP-3 3.1 +/- 0.3 mg/l. There were no significant differences in the absolute increases of IGF-I or IGFBP-3 (mean +/- SEM) during the IGF-I generation test, IGF-I; Group 1, 48.8 +/- 9.5 micrograms/l, Group 2, 42.7 +/- 4.8 micrograms/l. Group 3, 45.5 +/- 5.1 micrograms/l, IGFBP-3; Group 1, 1.1 +/- 1.2 mg/l. Group 2, 1.2 +/- 0.2 mg/l, Group 3, 0.85 +/- 0.1 mg/l. There were no significant differences in the percentage increases (mean +/- SEM) of IGF-I; Group 1, 55 +/- 9%, Group 2, 35 +/- 5%, Group 3, 42 +/- 8%, or IGFBP-3; Group 1, 64 +/- 17%, Group 2, 44 +/- 8%, Group 3.32 +/- 6%. GHBP values were normal in all three groups. In Group 3 (peak GH > 40 mU/l) four individual patients had either low basal IGF-I levels (n = 2) (< 5th centile of normal range for age) or low basal IGFBP-3 levels (n = 1) (< 5th centile of normal range for age) or low IGF-I responses in the IGF-I generation test (2 x CV of IGF-I assay) (n = 1). No single subject had all the characteristics of GH insensitivity syndrome. The responses during an IGF-I generation test did not identify a clear group of children with GH insensitivity. Individual patients had low basal IGF-I or IGFBP-3 values and a poor response in the generation test, features which, in the presence of high GH levels on provocation, are consistent with partial GH insensitivity.