Use of a GH receptor antagonist (GHRA) to explore the relationship between GH and IGF-I in adults with severe GH deficiency (GHD).

OBJECTIVE: At diagnosis, approximately 50% of adults with severe GH deficiency (GHD) have an IGF-I within the reference range. It is unclear whether in such patients serum IGF-I levels are regulated by factors other than GH. DESIGN AND PATIENTS: We performed a double-blind, randomized, placebo-controlled, cross-over study to investigate the effect of the GH receptor antagonist - pegvisomant (20 mg daily for 14 days) on GH and IGF-I levels in three cohorts: patients with GHD and a normal IGF-I (NORMS); patients with GHD and a low IGF-I (LOWS) and healthy volunteers (CONS). RESULTS: Pegvisomant decreased IGF-I in CONS and NORMS [158.5 (101-206) vs. 103 (77-125) microg/l, P < 0.01; 124 (81-136) vs. 95 (51-113) microg/l, P < 0.01 respectively], but not in LOWS [31 (< 31-32) vs. 34.5 (< 31-38) microg/l], and this was associated with an increase in mean 24 h GH in CONS [0.49 (0.12-0.89) to 1.38 (0.22-2.45) microg/l (P = 0.03)] and in NORMS [69 (0-320)% from 0.1 (< 0.1-0.13) to 0.17 (0.11-0.42) microg/l (P = 0.03)], but not in the LOWS. The peak GH response to arginine was increased by pegvisomant in CONS and NORMS [6.1 (0.8-9) vs. 20.4 (13.1-28.8) microg/l, P = 0.03; 0.4 (0.1-0.5) vs. 0.5 (0.3-0.6) microg/l, respectively], but not in LOWS. CONCLUSIONS: These data indicate that patients with severe GHD with a normal IGF-I are able to increase GH secretion in response to a pegvisomant-induced fall in IGF-I, whereas those with low IGF-I levels are unable to increase GH secretion. Therefore circulating IGF-I appears to be GH-independent in GHD patients with a low IGF-I, but remains partially GH-dependent in GHD patients with a normal IGF-I.