Introduction: Prader-Willi Syndrome (PWS) is a complex syndrome including hyperphagia, pituitary hormone deficiencies, low muscle mass and cognitive impairment. Treatment with recombinant Growth Hormone (GH) has beneficial effects on body composition, physical performance, cognition, psychomotor development, respiratory function, and quality of life of patients with PWS. GH treatment has a narrow therapeutic range. 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 of GH. Preliminary data1 showed that IGF-bioactivity was low and not related with total IGF-I in children with PWS, suggesting that IGF might be less active, or less available, in PWS. Proof of low IGF bioactivity or bio-availability in PWS would have great clinical consequences, as this would imply that high levels of total IGF-I might not have negative side effects and can therefore be accepted in patients with PWS.
Methods: We measured total IGF-I, bioactive IGF and free (bio-available) IGF in 22 PWS (15 with and 7 without GH) patients and 112 healthy controls. In order to measure IGF-bioactivity, we have set up and optimized an in-house IGF-I receptor kinase activation assay (KIRA). KIRA is a cell based system where IGF bioactivity is reflected by phosphorylation of the IGF receptor. In order to measure IGF-I bioavailability (free IGF-I), we used a new commercially available ELISA (Ansh Labs, Webster, TX). 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 levels were extremely low in PWS. Both free IGF-I and IGF-bioactivity correlated poorly with total IGF-1 levels. IGF bioactivity in GH-treated PWS patients was comparable to (non-GH treated) healthy individuals. GH-treated patients with extremely high total IGF-I levels have normal IGF-bioactivity.
Conclusion: Total IGF-I is a poor marker of IGF-bioactivity and bio-availability in PWS patients. Our results suggest that a GH dose reduction may not be needed in PWS patients with a high total IGF-I. Further studies are needed to confirm our data and to investigate whether IGF-I bioactivity and IGF bio-availability are more reliable parameters for GH dose titration in PWS.
Reference: 1. Bakker N, et al. JCEM.
18 May 2019 - 21 May 2019