Increases in bioactive IGF do not parallel increases in total IGF-I during growth hormone treatment of children born SGA.

BACKGROUND: Some children born small for gestational age (SGA) experience supra-physiological insulin-like growth factor-I (IGF-I) concentrations during GH treatment. However, measurements of total IGF-I concentrations may not reflect the bioactive fraction of IGF-I which reaches the IGF-I receptor at target organs. We examined endogenous IGF-bioactivity using an IGF-I kinase receptor activation (KIRA) assay that measures the ability of IGF-I to activate the IGF-IR in vitro. AIM: To compare responses of bioactive IGF and total IGF-I concentrations in short GH treated SGA children in the North European Small for Gestational Age Study (NESGAS). RESULTS: Bioactive IGF increased with age in healthy pre-pubertal children (n=94). SGA children had low-normal bioactive IGF levels at baseline (-0.12 (1.8 SD), increasing significantly after one year of high-dose GH treatment to 1.1 (1.4) SD, p2SD (mean IGF-I 2.8 SDS), whereas only 15% (n=15) had levels of bioactive IGF slightly above normal reference values. At baseline, bioactive IGF (SDS) was significantly correlated to height (SDS) (r=0.29, p=0.005), in contrast to IGF-I (SDS) (r=0.17, p=0.10). IGF-I (SDS) was inversely correlated to delta height (SDS) after one year of high-dose GH treatment (r=-0.22, p=0.02). CONCLUSION: In contrast to total IGF-I concentrations, bioactive IGF stayed within the normal reference ranges for most SGA children during the first year of GH treatment

The exon3-deleted growth hormone receptor gene polymorphism (d3-GHR) is associated with insulin and spontaneous growth in short SGA children (NESGAS)

Objective The effect of a common polymorphism in the Growth Hormone (GH) receptor (d3-GHR) gene on growth, metabolism and body composition was examined in short children born small for gestational age (SGA) on GH treatment. Design In 96 prepubertal, short SGA children treated with high-dose GH (67 μg/kg/day) in the NESGAS study, insulin sensitivity (IS), insulin secretion and disposition index (DI) were determined during the first year of treatment. Body composition was analysed by DXA. The d3-GHR locus was determined by simple multiplex PCR. Results At baseline, children in the d3-GHR group (d3/fl (n = 37), d3/d3 (n = 7)) had significantly lower IS (median (25–75 percentile)) (223.3% (154.4–304.8)) vs. (269.7% (185.1–356.7)) (p = 0.03) and higher concentrations of glucose (mean (SD)) (4.4 mmol/L (0.6) vs. 4.2 mmol/L (0.7)) (p = 0.03), C-peptide (232.1 pmol/L (168.8–304.1) vs. 185.1 pmol/L (137.7–253.9)) (p = 0.04) and insulin (19.2 pmol/L (11.8–32.2)) vs. (13.7 pmol/L (9.3–20.8)) (p = 0.04) compared to children homozygous for the full length allele (fl/fl-GHR (n = 52)). There were no differences in DI or insulin secretion. Postnatal, spontaneous growth was significantly greater in the d3-GHR group compared to the fl/fl-GHR group (p = 0.02). There were no significant differences in growth response, body composition or metabolism after one year of GH therapy. Conclusion Short SGA children carrying the d3-GHR polymorphism had increased spontaneous growth, lower IS and a compensatory increase in glucose, C-peptide and insulin before GH therapy compared to children homozygous for the full-length allele

Increases in bioactive IGF do not parallel increases in total IGF-I during growth hormone treatment of children born SGA

Background: Some children born small for gestational age (SGA) experience supra-physiological insulin-like growth factor-I (IGF-I) concentrations during GH treatment. However, measurements of total IGF-I concentrations may not reflect the bioactive fraction of IGF-I which reaches the IGF-I receptor at target organs. We examined endogenous IGF-bioactivity using an IGF-I kinase receptor activation (KIRA) assay that measures the ability of IGF-I to activate the IGF-IR in vitro. Aim: To compare responses of bioactive IGF and total IGF-I concentrations in short GH treated SGA children in the North European Small for Gestational Age Study (NESGAS). Material and method: In NESGAS, short SGA children (n = 101, 61 males) received GH at 67 µg/ kg/day for 1 year. IGF-I concentrations were measured by Immulite immunoassay and bioactive IGF by in-house KIRA assay. Results: Bioactive IGF increased with age in healthy pre-pubertal children (n = 94). SGA children had low-normal bioactive IGF levels at baseline (-0.12 (1.8 SD), increasing significantly after one year of high-dose GH treatment to 1.1 (1.4) SD, P 2SD (mean IGF-I 2.8 SDS), whereas only 15% (n = 15) had levels of bioactive IGF slightly above normal reference values. At baseline, bioactive IGF (SDS) was significantly correlated to height (SDS) (r = 0.29, P = 0.005), in contrast to IGF-I (SDS) (r = 0.17, P = 0.10). IGF-I (SDS) was inversely correlated to delta height (SDS) after one year of high-dose GH treatment (r = -0.22, P = 0.02). Conclusion: In contrast to total IGF-I concentrations, bioactive IGF stayed within the normal reference ranges for most SGA children during the first year of GH treatment