IGF-1 levels, complex formation, and IGF bioactivity in growth hormone-treated children with Prader-Willi syndrome

Abstract

Context: Children with Prader-Willi syndrome (PWS) attain high-serum immunoreactive IGF-1 levels during a standard-dose GH treatment, which leads to concern, but lowering the dose deteriorates their body composition. Objective: The objective of the study was to evaluate serum IGF-1, IGF binding protein (IGFBP)-3, and acid-labile subunit (ALS) levels, complex formation, and IGF bioactivity in GH-treated PWS children. Design: This was a cross-sectional study. Setting: The setting of the study was a Dutch PWS cohort. Participants: Forty GH-treated PWS children compared with 41 age- and sex-matched healthy controls participated in the study. Interventions: Interventions included GH treatment (1.0 mg/m²·d = ∼0.035 mg/kg·d). Main Outcome Measures: Serum IGF-1, IGFBP-3, and ALS levels, complex formation, and IGF bioactivity by IGF-1 receptor kinase activation assay were measured. Results: Serum IGF-1, IGFBP-3, and ALS levels and IGF-1 to IGFBP-3 ratio were significantly higher in GH-treated PWS children than in healthy controls. The 150-kDa ternary complex formation was, however, also significantly higher than in controls, indicating that most of serum IGF-1 is sequestered in the ternary 150-kDa complex with ALS and IGFBP-3. Young GH-treated PWS children [median (interquartile range) aged 5.2 (4.3-7.2) y] exhibited higher serum IGF bioactivity than controls, but no difference was observed in IGF bioactivity between older GH-treated PWS children, aged 14.9 (13.8-16.2) years, and controls. The proportion of IGF bioactivity of total serum IGF-1 was, however, lower in GH-treated PWS children than in controls. Serum immunoreactive IGF-1 levels did not correlate with IGF bioactivity in GH-treated children with PWS, in contrast to a strong positive correlation in healthy controls. Conclusions: In GH-treated PWS children, most serum IGF-1 is sequestered in the 150-kDa complex. Higher IGF bioactivity was found only in young GH-treated PWS children and not in the older ones. IGF bioactivity during GH showed a wide variation, and there was a disrupted correlation with immunoreactive IGF-1 levels, which makes immunoreactive IGF-1 levels an inappropriate indicator for GH dosing in PWS children.