title: d3-GHR genotype does not explain heterogeneity in GH responsiveness in hypopituitary adults.
abstract: 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 DeltaIGF-I at 6 months were comparable between groups. DeltaIGF-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 DeltaIGF-I at 12 months and DeltaIGF-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Endocrinology, St. Bartholomew's Hospital, London, UK.
authors.forename: V J
authors.initials: VJ
authors.lastname: Moyes
authors.forename: D M
authors.initials: DM
authors.lastname: Walker
authors.forename: S
authors.initials: S
authors.lastname: Owusu-Antwi
authors.forename: K T
authors.initials: KT
authors.lastname: Maher
authors.forename: L
authors.initials: L
authors.lastname: Metherell
authors.forename: S A
authors.initials: SA
authors.lastname: Akker
authors.forename: J P
authors.initials: JP
authors.lastname: Monson
authors.forename: A J L
authors.initials: AJ
authors.lastname: Clark
authors.forename: W M
authors.initials: WM
authors.lastname: Drake
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D054316:Biomarkers, Pharmacological / Q000032:analysis; D005091:Exons / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D018740:Genetic Heterogeneity; D005838:Genotype; D020249:Hormone Replacement Therapy; D019382:Human Growth Hormone / Q000172:deficiency / Q000627:therapeutic use*; D006801:Humans; D007018:Hypopituitarism / Q000188:drug therapy* / Q000235:genetics*; D007206:Individuality; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms / Q000235:genetics; D011986:Receptors, Somatotropin / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D054316:Biomarkers, Pharmacological; D020033:Protein Isoforms; D011986:Receptors, Somatotropin; D019382:Human Growth Hormone