The exon 3-deleted growth hormone receptor is associated with better response to pegvisomant therapy in acromegaly.
BACKGROUND
The deletion of exon 3 in the GH receptor (GHR) has been associated with a different biochemical picture and response to therapy in acromegaly.


OBJECTIVE
The aim of the study was to determine whether or not the GHR genotype influences the efficacy of pegvisomant treatment.


METHODS
A cross-sectional study was conducted in six Spanish university hospitals.


METHODS
Forty-four acromegalic patients with active disease and resistance to somatostatin analogs participated in the study.


RESULTS
The prevalence of the full-length GHR and the exon 3-deleted GHR homozygous and heterozygous genotypes was 41, 2, and 57%, respectively. There were no differences in IGF-I or GH pre-pegvisomant levels related to GHR genotype. The exon 3-deleted patients required approximately 20% lower doses of pegvisomant per kilogram of weight (28 +/- 11 compared to 22 +/- 7 mg per kg of weight; P = 0.033) to normalize IGF-I. A stepwise multivariate linear regression analysis (R(2) = 0.27; P = 0.003) identified male gender (beta = -0.79; P = 0.03) and d3-GHR genotype (beta = -0.64; P = 0.007) as the only significant predictors of the dose of pegvisomant per kilogram of weight. In addition, d3-GHR carriers required fewer months for IGF-I normalization (P < 0.01). A stepwise multivariate linear regression analysis (R(2) = 0.40; P = 0.001) revealed that the only significant predictor of the time to IGF-I normalization was the dose of pegvisomant per kilogram of weight (beta = 0.451; P = 0.001).


CONCLUSIONS
The exon 3 deletion in the GHR predicts an improved response to pegvisomant therapy in acromegaly.
Endocrinology Division, Hospital Clínico Universitario de Santiago de Compostela, Travesía da Choupana s/n, Santiago de Compostela, 15706 La Coruña, Spain. ignacio.bernabeu.moron@sergas.es
Ignacio
I
Bernabeu
Cristina
C
Alvarez-Escolá
Celsa
C
Quinteiro
Tomás
T
Lucas
Manel
M
Puig-Domingo
Manuel
M
Luque-Ramírez
Paz
P
de Miguel-Novoa
Eva
E
Fernandez-Rodriguez
Irene
I
Halperin
Lourdes
L
Loidi
Felipe F
FF
Casanueva
Mónica
M
Marazuela
D000172:Acromegaly / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D000328:Adult; D000368:Aged; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics*; D005091:Exons; D005260:Female; D005838:Genotype; D006727:Hormone Antagonists / Q000627:therapeutic use; D019382:Human Growth Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000502:physiology; D011379:Prognosis; D011986:Receptors, Somatotropin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D012189:Retrospective Studies; D017384:Sequence Deletion / Q000502:physiology; D016896:Treatment Outcome
D006727:Hormone Antagonists; D050505:Mutant Proteins; D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; C406545:pegvisomant