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d3-GHR genotype does not explain heterogeneity in GH responsiveness in hypopituitary adults

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Summary Objective 

Heterogeneity in growth hormone (GH) responsiveness in adult hypopituitary patients receiving recombinant human GH (rhGH) is poorly understood; doses vary up to fourfold between individuals. Deletion of exon 3 in the GH receptor (d3-GHR) has been linked to enhanced rhGH responsiveness in children. We investigated the role of the d3-GHR polymorphism in determining adult rhGH responsiveness. Methods 

One hundred and ninety-four patients treated with an identical rhGH dosing protocol in a single centre were genotyped for the d3-GHR, and the results correlated with changes in serum IGF-I and clinical parameters of GH responsiveness after 6 and 12 months of GH replacement therapy. Results 

Allele frequencies for homozygous full length (fl/fl), heterozygous d3 (fl/d3) and homozygous d3 (d3/d3) were 52%, 38·7% and 9·3%, respectively, and were in Hardy–Weinberg equilibrium. Baseline IGF-I and ΔIGF-I at 6 months were comparable between groups. ΔIGF-I at 12 months was significantly greater in the d3/d3 group (P = 0·028). No difference was detected between fl/d3 and fl/fl groups. Regression analyses of ΔIGF-I at 12 months and ΔIGF-I/rhGH dose confirmed a significant relationship of d3/d3 genotype on rhGH response. There was no difference between groups in maintenance rhGH dose between genotypes. Conclusion 

Homozygosity for d3-GHR confers a marginal increase in GH responsiveness at 12 months but without a detectable change in maintenance rhGH dose required. Both d3 alleles are required to achieve this response; given that only 10% of the population are d3 homozygotes, the d3GHR does not explain the marked heterogeneity of GH responsiveness in hypopituitary adults.
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Document Type: Research Article

Affiliations: 1: Department of Endocrinology, St. Bartholomew’s Hospital 2: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, London, UK

Publication date: June 1, 2010

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