Pegvisomant for the treatment of gsp-mediated growth hormone excess in patients with McCune-Albright syndrome.
BACKGROUND
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)alpha (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.


METHODS
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.


METHODS
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.
Akintoye
Sunday O
SO
Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, The Robert Schattner Center Room 209, 240 South 40th Street, Philadelphia, PA 19104, USA. akintoye@dental.upenn.edu
Kelly
Marilyn H
MH
Brillante
Beth
B
Cherman
Natasha
N
Turner
Sarah
S
Butman
John A
JA
Robey
Pamela G
PG
Collins
Michael T
MT
D001842:Bone and Bones / Q000378:metabolism; D002864:Chromogranins; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005221:Fatigue; D005357:Fibrous Dysplasia of Bone / Q000188:drug therapy / Q000235:genetics; D005359:Fibrous Dysplasia, Polyostotic / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D019382:Human Growth Hormone / Q000031:analogs & derivatives* / Q000502:physiology* / Q000627:therapeutic use; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008279:Magnetic Resonance Imaging; D009154:Mutation; D010146:Pain; D010902:Pituitary Gland / Q000473:pathology; D010919:Placebos; D011986:Receptors, Somatotropin / Q000037:antagonists & inhibitors*; D013546:Sweating; D016896:Treatment Outcome
D002864:Chromogranins; D018972:Insulin-Like Growth Factor Binding Protein 3; D010919:Placebos; D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; C406545:pegvisomant