The influence of a GH receptor antagonist (GHRA) on the relationship between GH and IGF-I in adults with severe growth hormone deficiency (AGHD)
A Pokrajac1, CA Berg1, M Bidlingmaier2, CJ Strasburger2, SM Shalet1 & PJ Trainer1
Approximately 50% of patients with severe AGHD (defined by the international consensus criteria, peak GH <3 ng/ml) have a normal age- and gender-related IGF-I. It remains unclear whether in these individuals IGF-I is GH-dependent.
We performed a double-blind, randomised, placebo-controlled, cross-over study on the effect of pegvisomant (20 mg daily for 14 days) on the relationship between GH and IGF-I in 3 age-, gender- and BMI-matched cohorts (Norms: 5 GHD patients with normal IGF-I, Los: 5 GHD patients with low IGF-I and Cons: 6 healthy volunteers. IGF-I was measured prior to and after each limb, and 24 h GH sampling (20 minute interval) was performed at the end of each limb.
GH was measured by a pegvisomant-insensitive immunoradiometric assay (intra- and inter-assay CV <7%, lower limit of detection 0.1 ng/ml). IGF-I was measured by immunoradiometric assay (sensitivity 4.45.2%, with specificity of 5.77.4%, lower limit of detection 6 mcg/l). Statistical analysis was performed by GraphPad Prism software.
Pegvisomant decreased IGF-I in Cons and Norms (median 158.5 ng/ml (range 101206 ng/ml) v 103(77125) ng/ml, P<0.01; 124(81136) ng/ml v 95(51113) ng/ml, P<0.01), but not in Los (31(<3132) ng/ml v 34.5(<3138) ng/ml).
At the conclusion of the placebo limb, mean 24 h GH was higher in controls than in GHD patients (Cons: 0.49(0.120.89) ng/ml v Norms 0.1(<0.10.13) ng/ml, P<0.01). Pegvisomant increased mean 24 h GH in Cons (0.49(0.120.89) ng/ml v 1.38(0.222.45) ng/ml, P=0.03) and Norms (0.1(<0.10.13) ng/ml v 0.17(0.110.42) ng/ml, P=0.03), but not in Los, where GH remained predominately undetectable.
Our results indicate that GHD patients with normal IGF-I still have the potential to increase GH secretion in response to a fall in IGF-I, while those with low IGF-I levels are unable to increase GH secretion. Therefore, IGF-I appears to be GH-independent in GHD with low IGF-I, while being partially GH-dependant in GHD with normal IGF-I.