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IGF-1 Levels, Complex Formation, and IGF Bioactivity in Growth Hormone-Treated Children With Prader-Willi Syndrome
N E Bakker1, J van Doorn1, J S Renes1
1Dutch Growth Research Foundation (N.E.B., A.C.S.H.-K.), 3016 AH Rotterdam, The Netherlands; Department of Pediatrics (N.E.B., J.S.R., A.C.S.H.-K.), Subdivision of Endocrinology, Erasmus Medical Center/Sophia Children's Hospital, 3000 DR Rotterdam, The Netherlands; and Department of Clinical Chemistry and Haematology (J.v.D., G.H.D.), Laboratory of Endocrinology and Department of Medical Genetics, Section of Metabolic Diseases, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.
Insights
In Prader-Willi syndrome (PWS) patients on growth hormone (GH) therapy, high IGF-1 levels are common but do not reflect bioactivity. IGF-1 levels are not a reliable indicator for GH dosing in PWS children.
Area of Science:
- Endocrinology
- Pediatrics
- Metabolic Disorders
Background:
- Children with Prader-Willi syndrome (PWS) often show high serum insulin-like growth factor 1 (IGF-1) levels during standard growth hormone (GH) treatment.
- Lowering GH dosage to manage high IGF-1 levels can negatively impact body composition in PWS children.
Purpose of the Study:
- To evaluate serum IGF-1, IGF binding protein 3 (IGFBP-3), and acid-labile subunit (ALS) levels in GH-treated PWS children.
- To assess IGF-1 complex formation and IGF bioactivity in this cohort.
- To determine the correlation between IGF-1 levels and IGF bioactivity in PWS.
Main Methods:
- Cross-sectional study of 40 GH-treated PWS children and 41 healthy controls from a Dutch PWS cohort.
- Measurement of serum IGF-1, IGFBP-3, and ALS levels.
- Assessment of IGF-1 complex formation and IGF bioactivity using IGF-1 receptor kinase activation assay.
Main Results:
- GH-treated PWS children had significantly higher serum IGF-1, IGFBP-3, and ALS levels compared to controls.
- Most serum IGF-1 in PWS children was sequestered in the 150-kDa ternary complex with IGFBP-3 and ALS.
- Higher IGF bioactivity was observed in younger GH-treated PWS children, but not in older ones. The proportion of IGF bioactivity was lower in PWS children than controls.
- Serum immunoreactive IGF-1 levels did not correlate with IGF bioactivity in GH-treated PWS children, unlike in healthy controls.
Conclusions:
- In GH-treated PWS children, serum IGF-1 is largely bound within the 150-kDa complex, limiting its bioactivity.
- IGF bioactivity varies significantly and is not consistently elevated in all GH-treated PWS children.
- Serum immunoreactive IGF-1 levels are an unreliable marker for guiding GH dosage in PWS due to a disrupted correlation with IGF bioactivity.
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/m(2) · 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.
