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

Craniofacial and Skeletal Diseases Branch (S.O.A., M.H.K., B.B., N.C., P.G.R., M.T.C., S.T.) and Diagnostic Radiology Department (J.A.B.), Clinical Center, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Sunday O. Akintoye, B.D.S., D.D.S., M.S., University of Pennsylvania, School of Dental Medicine, Department of Oral Medicine, The Robert Schattner Center Room, 209, 240 South 40th Street, Philadelphia, Pennsylvania 19104. E-mail: akintoye{at}dental.upenn.edu.

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, G_s (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.

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