Pegvisomant for the Treatment of gsp-Mediated Growth Hormone Excess in Patients with McCune-Albright Syndrome

Context: GH excess affects approximately 20% of the patients with McCune-Albright syndrome (MAS). MAS is caused by sporadic, postzygotic, activating mutations in the GNAS gene, which codes for the cAMP-regulating protein, Gsα (gsp oncogene). These same mutations are found in approximately one third of the sporadic cases of acromegaly. Objective: We examined efficacy of the GH receptor antagonist, pegvisomant, in controlling gsp oncogene-mediated GH excess and skeletal disease (fibrous dysplasia of bone) associated with MAS. Setting and Patients: Five MAS patients with GH excess were treated with 20 mg/d sc injection of pegvisomant for 12 wk in a randomized, double-blind, placebo-controlled crossover study at the National Institutes of Health. Main Outcome Measures: The primary measure of efficacy was normalization of IGF-I. Secondary outcome measures were reduction in serum IGF binding protein-3 (IGFBP-3), improvement of fatigue and sweating, and reduction in markers of bone metabolism and bone pain. Results: Combined mean changes in serum IGF-I at 6 and 12 wk were −236.4 ng/ml (53%, P < 0.005) and −329.8 ng/ml (62%, P < 0.001), respectively. IGFBP-3 decreased by 0.8 mg/liter (24%, P < 0.01) and 2.9 mg/liter (37%, P < 0.005), respectively. There were no significant changes in signs and symptoms of acromegaly or markers of bone metabolism and bone pain, nor was there a significant change in pituitary size. Retrospective comparison of the degree of control achieved with pegvisomant vs. other medications (long-acting octreotide ± dopamine agonist) in the same group showed that the two regimens were similarly effective. Conclusions: Pegvisomant effectively reduced IGF-I and IGFBP-3 levels in gsp-mediated GH excess but had no effect on fibrous dysplasia.