d3-GHR genotype does not explain heterogeneity in GH responsiveness in hypopituitary adults.
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.
Moyes
V J
VJ
Department of Endocrinology, St. Bartholomew's Hospital, London, UK.
Walker
D M
DM
Owusu-Antwi
S
S
Maher
K T
KT
Metherell
L
L
Akker
S A
SA
Monson
J P
JP
Clark
A J L
AJ
Drake
W M
WM
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
D054316:Biomarkers, Pharmacological; D020033:Protein Isoforms; D011986:Receptors, Somatotropin; D019382:Human Growth Hormone