Changes in circulating IGF1 receptor stimulating activity do not parallel changes in total IGF1 during GH treatment of GH-deficient adults

Abstract

Context: Previously we demonstrated that IGF1 receptor stimulating activity (IGF1RSA) offers advantages in diagnostic evaluation of adult GH deficiency (GHD). It is unknown whether IGF1RSA can be used to monitor GH therapy. Objective: To investigate the value of circulating IGF1RSA for monitoring GH therapy. Design/methods: 106 patients (54 m; 52 f) diagnosed with GHD were included; 22 were GH-naïve, 84 were already on GH treatment and discontinued therapy 4 weeks before baseline values were established. IGF1RSA was determined by the IGF1R kinase receptor activating assay, total IGF1 by immunoassay (Immulite). GH doses were titrated to achieve total IGF1 levels within the normal range. Results: After 12 months, total IGF1 and IGF1RSA increased significantly (total IGF1 from 8.1 (95% CI 7.3-8.9) to 14.9 (95% CI 13.5-16.4) nmol/l and IGF1RSA from 115 (95% CI 104-127) to 181 (95% CI 162-202) pmol/l). After 12 months, total IGF1 normalized in 81% of patients, IGF1RSA in 51% and remained below normal in more than 40% of patients in whom total IGF1 had normalized. Conclusions: During 12 months of GH treatment, changes in IGF1RSA did not parallel changes in total IGF1. Despite normalization of total IGF1, IGF1RSA remained subnormal in a considerable proportion of patients. At present our results have no short-term consequences for GH therapy of GHD patients. However, based on our findings we propose future studies to examine whether titrating GH dose against IGF1RSA results in a better clinical outcome than titrating against total IGF1.

The insulin-like growth factor-I receptor stimulating activity (IRSA) in health and disease

“…In addition, IRSA remained below normal in more than 40% of patients in whom total IGF-I had normalized [89]. Interestingly, the increase of the IGF-I/IGFBP3 ratio (which has been suggested to reflect an estimate of bioavailable IGF-I) after 12 months GH treatment was almost similar to the reported increase of IRSA [89].…”

“…After start of GH treatment both IRSA and total IGF-I significantly increased but changes in IRSA did not parallel changes in total IGF-I [89]. After 12 months of GH treatment total IGF-I normalized in 81% of patients, whereas in only 50% of patients the IRSA was in the normal reference range [89]. In addition, IRSA remained below normal in more than 40% of patients in whom total IGF-I had normalized [89].…”

“…Before start of GH treatment IRSA (measured by the IGF-IR KIRA assay) in adult patients with proven GHD was more frequently below the normal range (<-2 SD) than immunoreactive total IGF-I concentrations (81.9 vs. 61.7%, respectively) and this was especially observed in patients older than 40 years of age [88]. After start of GH treatment both IRSA and total IGF-I significantly increased but changes in IRSA did not parallel changes in total IGF-I [89]. After 12 months of GH treatment total IGF-I normalized in 81% of patients, whereas in only 50% of patients the IRSA was in the normal reference range [89].…”

“…After 12 months of GH treatment total IGF-I normalized in 81% of patients, whereas in only 50% of patients the IRSA was in the normal reference range [89]. In addition, IRSA remained below normal in more than 40% of patients in whom total IGF-I had normalized [89]. Interestingly, the increase of the IGF-I/IGFBP3 ratio (which has been suggested to reflect an estimate of bioavailable IGF-I) after 12 months GH treatment was almost similar to the reported increase of IRSA [89].…”

Increases in Bioactive IGF do not Parallel Increases in Total IGF-I During Growth Hormone Treatment of Children Born SGA

“…We believe this gives a biologically relevant estimate of the ability of serum IGF-I to activate the IGF-IR, and hence IGF-bioactivity. Indeed, a discrepancy between bioactive and total levels of IGF-I has been reported in both adults (14) and children (15) and it was reported that in adults, bioactive IGF concentrations correlated better with the diagnosis of GH deficiency (GHD) than total IGF-I levels (16).…”