Introduction: Recombinant Growth Hormone (GH) has changed the lives of many patients with Prader-Willi Syndrome (PWS). GH treatment has beneficial effects on body composition, physical performance, cognition, psychomotor development, respiratory function and quality of life of patients with PWS. Due to the narrow therapeutic range, GH treatment is subject to strict limits. Clinicians measure serum immunoreactive Insulin-like Growth Factor 1 ('total IGF-I') levels to titrate the dose of GH. However, in patients with PWS, IGF-I levels are often much higher than expected based on GH dose. As a result, clinicians have to reduce the GH dose, with consequent loss of beneficial effects. Based on our previous data (Bakker et al, JCEM 2017) and the observation that patients with PWS seem to benefit from relatively high GH doses, we hypothesize that IGF might be less active, or less available, in PWS. Low IGF bioactivity or bio-availability would imply that high total IGF-I levels might not have negative side effects in patients with PWS. In that case, GH dose reduction might not be needed.
Methods: We measured total IGF-I, bioactive IGF and free 'bio-available' IGF in 22 PWS patients and 112 healthy controls. IGF-I bioavailability ('free IGF-I) was measured by commercially available ELISA (Ansh Labs, Webster, TX). IGF-bioactivity was measured by an in-house IGF-I receptor kinase activation assay (KIRA), a cell-based system where IGF bioactivity is reflected by phosphorylation of the IGF receptor. Both IGF-I bioavailability and IGF-bioactivity were compared with total (immunoreactive) IGF-I values.
Results: We found a striking difference in free IGF-I between PWS and control samples. Free IGF-I correlated poorly to total IGF-1 levels. Correlation between IGF-bioactivity and total IGF-1 was also very low. Most importantly, PWS patients with high immunoreactive IGF-I during GH treatment showed normal IGF-bioactivity.
Conclusion: Our results indicate that total IGF-I is a poor marker of IGF-bioactivity in PWS patients, as IGF-bioactivity in PWS patients with high total IGF-I concentrations was comparable to IGF-bioactivity in controls. It suggests that clinicians might not need to lower GH dose in patients with a high total IGF-I. Further studies are needed to confirm our data and find more reliable parameters for GH dose titration in PWS.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology