Objective: Variability in growth hormone (GH) responsiveness is evident in adult hypopituitary patients receiving recombinant GH (rhGH). Doses vary up to 4-fold for unexplained reasons. Deletion of exon 3 in the GH receptor (d3-GHR) has been linked to an increased response to GH treatment in children, although data are conflicting. We investigated the role of the d3-GHR polymorphism in determining GH responsiveness in adult GH deficient patients.
Methods: With ethical approval, 200 patients treated with an identical rhGH dosing protocol in a single centre were studied. Analysis of GHR genotype was correlated with retrospective clinical and biochemical data. Simple multiplex PCR was performed with analysis of amplification products on agarose gels stained with ethidium bromide. Three genotype groups were identified; homozygous full length (fl/fl), heterozygous d3 (fl/d3) and homozygous d3 (d3/d3). Initial and long term GH response was measured; ΔIGFI from baseline to 6 months and to final IGFI achieved. ANOVA and multiple regression analyses were used to compare GH response and maintenance rhGH dose between the 3 genotype groups.
Results: Allele frequencies were fl/fl 52%, fl/d3 38%, d3/d3 10% and were in Hardy-Weinberg equilibrium. Baseline IGFI results were comparable between groups. There was no difference between groups in ΔIGFI at 6months. Final ΔIGFI was significantly greater in the d3/d3 group (P=0.017 ANOVA; P=0.006 by multiple regression analysis correcting for GH dose). There was no difference detected between fl/d3 and fl/fl groups. No other differences were detected and there was no difference in maintenance rhGH dose. GH responsiveness was not influenced by gender, oestrogen or external pituitary irradiation.
Conclusion: Homozygosity for d3-GHR appears to confer an increase in long term GH responsiveness but without a detectable change in maintenance rhGH dose required. No difference was detected for heterozygous patients suggesting that both d3 alleles are required to enhance GH responsiveness.