The exon 3 deleted growth hormone receptor gene is associated with small birth size and early pubertal onset in healthy boys.
BACKGROUND
The GH/IGF-I axis influences gonadal development and function. Recently, a deletion of exon 3 in the GH receptor gene (GHRd3) has been linked to increased responsiveness to GH.


OBJECTIVE
Our objective was to evaluate the influence of the GHRd3 gene on birth size and pubertal onset.


METHODS
We conducted a cross-sectional study, part of The COPENHAGEN Puberty Study, at a tertiary center for pediatric endocrinology.


METHODS
Participants included 618 healthy boys aged 6.1-19.8 yr.


METHODS
We assessed pubertal onset by genital staging and testicular palpation and parental reported birth weight and length. GHR genotypes were determined by multiplex PCR.


RESULTS
Age at onset of genital development (G2+) was significantly earlier in the GHRd3 homozygotes (GHRd3/d3) [10.86 (10.35-11.37) yr, mean (95% confidence interval)] compared with the full-length homozygotes (GHRfl/fl) [11.76 (11.35-12.00) yr, P = 0.002]. The odds ratio of having detectable testosterone levels for a given age was significantly higher in GHRd3/d3 compared with GHRfl/fl group (odds ratio = 3.1; 95% confidence interval = 1.2-8.9; P = 0.036). The GHRd3/d3 group the higher prepubertal IGF-I levels compared with the GHRfl/fl group (9.2% (0.1-18.1%), P = 0.048) after adjustment for IGF-binding protein-3 levels. Lower gestational-age-adjusted birth weight and length were found in the GHRd3/d3 group compared with the GHRfl/fl group and the GHRfl/d3 group, respectively (all P < or = 0.018).


CONCLUSIONS
The GHRd3/d3 genotype was associated with smaller birth size and earlier age at pubertal onset compared with the GHRfl/fl genotype. Thus, this common polymorphism could play a role for prenatal growth and gonadal development in boys.
Sørensen
Kaspar
K
Department of Growth and Reproduction, GR-5064, Copenhagen University Hospital, Blegdamsvej 9, DK 2100 Copenhagen, Denmark. kaspar.Soerensen@rh.regionh.dk
Aksglaede
Lise
L
Petersen
Jørgen Holm
JH
Leffers
Henrik
H
Juul
Anders
A
D000293:Adolescent; D000375:Aging / Q000502:physiology; D001724:Birth Weight / Q000502:physiology*; D002648:Child; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004247:DNA / Q000235:genetics; D005091:Exons / Q000235:genetics*; D005640:Follicle Stimulating Hormone / Q000097:blood; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics; D011627:Puberty / Q000235:genetics*; D011986:Receptors, Somatotropin / Q000235:genetics*; D013739:Testosterone / Q000097:blood; D055815:Young Adult
D018972:Insulin-Like Growth Factor Binding Protein 3; D011986:Receptors, Somatotropin; D013739:Testosterone; D007334:Insulin-Like Growth Factor I; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D004247:DNA