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

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 responsive...

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Published in:Clinical endocrinology (Oxford) 2010-06, Vol.72 (6), p.807-813
Main Authors: Moyes, V. J., Walker, D. M., Owusu-Antwi, S., Maher, K. T., Metherell, L., Akker, S. A., Monson, J. P., Clark, A. J. L., Drake, W. M.
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Biological and medical sciences
Biomarkers, Pharmacological - analysis
Endocrinopathies
Exons - genetics
Female
Fundamental and applied biological sciences. Psychology
Gene Deletion
Genetic Heterogeneity
Genotype
Hormone Replacement Therapy
Human Growth Hormone - deficiency
Human Growth Hormone - therapeutic use
Humans
Hypopituitarism - drug therapy
Hypopituitarism - genetics
Hypothalamus. Hypophysis. Epiphysis (diseases)
Individuality
Male
Medical sciences
Middle Aged
Non tumoral diseases. Target tissue resistance. Benign neoplasms
Protein Isoforms - genetics
Receptors, Somatotropin - genetics
Treatment Outcome
Vertebrates: endocrinology
Young Adult
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Summary: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.
ISSN:0300-0664
1365-2265
DOI:10.1111/j.1365-2265.2009.03768.x