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

• Published in: The journal of clinical endocrinology and metabolism Vol. 95; no. 1; pp. 222 - 229
• Main Authors: Bernabeu, Ignacio, Alvarez-Escolá, Cristina, Quinteiro, Celsa, Lucas, Tomás, Puig-Domingo, Manel, Luque-Ramírez, Manuel, de Miguel-Novoa, Paz, Fernandez-Rodriguez, Eva, Halperin, Irene, Loidi, Lourdes, Casanueva, Felipe F, Marazuela, Mónica
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.01.2010; Copyright by The Endocrine Society
• Subjects: Acromegaly - diagnosis; Acromegaly - drug therapy; Acromegaly - genetics; Adult; Aged; Biological and medical sciences; Cross-Sectional Studies; Dose-Response Relationship, Drug; Drug Resistance - drug effects; Drug Resistance - genetics; Endocrinopathies; Exons; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Genotype; Hormone Antagonists - therapeutic use; Human Growth Hormone - administration & dosage; Human Growth Hormone - analogs & derivatives; Human Growth Hormone - therapeutic use; Humans; Hypothalamus. Hypophysis. Epiphysis (diseases); Male; Medical sciences; Middle Aged; Mutant Proteins - physiology; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Prognosis; Receptors, Somatotropin - antagonists & inhibitors; Receptors, Somatotropin - genetics; Receptors, Somatotropin - physiology; Retrospective Studies; Sequence Deletion - physiology; Treatment Outcome; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Endocrinopathy; Obesity; Nutrition; Pegvisomant; Diseases of the osteoarticular system; Nutrition disorder; Acromegaly; Metabolic diseases; Somatotropin; Association; Exon; Treatment; Adenohypophyseal hormone; Pituitary diseases; Deletion; Antagonist; Endocrinology; Nutritional status; Hormonal receptor
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2009-1630

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 (β = −0.79; P = 0.03) and d3-GHR genotype (β = −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 (β = 0.451; P = 0.001). Conclusions: The exon 3 deletion in the GHR predicts an improved response to pegvisomant therapy in acromegaly. Exon 3-deleted growth hormone receptor is associated with better response to pegvisomant therapy in acromegaly, with lower required doses and less time required to IGF-I normalization.