Genetic Variation of Follicle-Stimulating Hormone Action Is Associated With Age at Testicular Growth in Boys.
Although genetic factors play a pivotal role in male pubertal timing, genome-wide association studies have identified only a few loci. Genetic variation of follicle-stimulating hormone (FSH) action affects adult reproductive parameters and female pubertal timing.



To investigate whether genetic variation affecting FSH action is associated with onset of puberty in boys.



Cross-sectional and longitudinal study of two cohorts of healthy boys.



This was a population-based study.



Danish (n = 1130) and Chilean (n = 424) boys were followed through puberty and genotyped for FSHB c.-211G>T, FSHR c.-29A>G, and FSHR c.2039G>A.



Clinical pubertal staging including orchidometry, anthropometry, and serum gonadotropin levels.



Although the cohorts differed markedly (e.g., body composition and genotype frequencies), genetic variation affecting FSH production (FSHB c.-211G>T) was associated with age at pubertal onset, as assessed by testicular enlargement, in both cohorts. The effect appeared further modified by coexistence of genetic variation affecting FSH sensitivity (FSHR c.-29G>A): After correcting for body mass index (BMI), boys with a ligand-receptor variant combination resulting in weak FSH action (i.e., FSHB c.-211GT/TT and FSHR c.-29AA) entered puberty 0.64 years [95% confidence interval (CI), 0.12 to 1.17 years; Denmark] and 0.94 years (95% CI, 0.00 to 1.88 years; Chile) later than boys with the most effective FSH action. Effects explained 1.7% (Denmark) and 1.5% (Chile) of the variance. In addition, BMI z score was negatively associated with pubertal timing (β = -0.35 years in both cohorts), explaining 17.2% (Denmark) and 7.2% (Chile) of the variance.



In two ethnically distinct populations, we independently identified an association of two genetic loci with male pubertal timing.
Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.|International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
Alexander S
AS
Busch
Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.|International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
Casper P
CP
Hagen
Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.|International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
Katharina M
KM
Main
Institute of Nutrition and Food Technology, University of Chile, Casilla 226-3, Santiago 8360160, Chile.
Anita
A
Pereira
Institute of Nutrition and Food Technology, University of Chile, Casilla 226-3, Santiago 8360160, Chile.
Camila
C
Corvalan
Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.|International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
Kristian
K
Almstrup
Institute of Maternal and Child Research, Faculty of Medicine, University of Chile, Casilla 226-3, Santiago 8360160, Chile.
Veronica
V
Mericq
Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.|International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
Anders
A
Juul
D000293:Adolescent; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D002677:Chile; D003430:Cross-Sectional Studies; D003718:Denmark; D005640:Follicle Stimulating Hormone / Q000235:genetics; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011627:Puberty / Q000235:genetics*; D011962:Receptors, FSH / Q000235:genetics*; D013737:Testis / Q000254:growth & development*; D055815:Young Adult
D037201:Follicle Stimulating Hormone, beta Subunit; D011962:Receptors, FSH; D005640:Follicle Stimulating Hormone