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This version published online on October 29, 2009
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2009-1630
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Submitted on July 29, 2009
Accepted on September 30, 2009

The Exon 3-Deleted Growth Hormone Receptor Is Associated with Better Response to Pegvisomant Therapy in Acromegaly

Ignacio Bernabeu*, Cristina Alvarez-Escolá, Celsa Quinteiro, Tomás Lucas, Manel Puig-Domingo, Manuel Luque-Ramírez, Paz de Miguel-Novoa, Eva Fernandez-Rodriguez, Irene Halperin, Lourdes Loidi, Felipe F. Casanueva, and Mónica Marazuela

Endocrinology Division (I.B., E.F.-R., F.F.C.), Complejo Hospitalario Universitario de Santiago de Compostela, Universidad de Santiago de Compostela, 15706 Santiago de Compostela, Spain; Endocrinology Division (C.A.-E.), Hospital Universitario La Paz, Universidad Autónoma de Madrid, 28046 Madrid, Spain; Fundación Publica Galega de Medicina Xenómica (Unidad de Medicina Molecular) (C.Q., L.L.), Complejo Hospitalario de Santiago de Compostela, 15706 Santiago de Compostela, Spain; Endocrinology Division (T.L.), Hospital Puerta de Hierro-Majadahonda, Universidad Autónoma de Madrid, 28222 Majadahonda, Spain; Endocrinology Division (M.P.-D., I.H.), Hospital Clinic de Barcelona, Universidad de Barcelona, 8036 Barcelona, Spain; Endocrinology Division (M.L.-R., M.M.), Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, 28006 Madrid, Spain; Endocrinology Division (P.d.M.-N.), Hospital Clinico de San Carlos, Universidad Complutense de Madrid, 28040 Madrid, Spain; and Centro de Investigación Biomédica en Red de Fisiopatología Obesidad y Nutrición (F.F.C.), Instituto Salud Carlos III, 15706 Santiago de Compostela, Spain

* To whom correspondence should be addressed. E-mail: ignacio.bernabeu.moron{at}sergas.es; bernabeumoron@gmail.com.

Context: 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.

Design and Setting: A cross-sectional study was conducted in six Spanish university hospitals.

Patients: 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 (R2 = 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 (R2 = 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.






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