ESPE Abstracts

Background: Age at onset of puberty exhibits a remarkable variation mirroring nutritional, environmental, socioeconomic and genetic factors. While large genome-wide association studies identified more than hundred genetic loci associated with age at menarche in girls, knowledge on loci associated with age at pubertal onset in boys is sparse. FSHB/FSHR genetic variants have been shown to affect pubertal timing in girls and reproductive parameters in men.

Objective and hypotheses: To investigate the effect of FSHB c.-211G>T, FSHR c.-29G>A, FSHR c.2039G>A and BMI on pubertal timing in two independent cohorts of healthy peripubertal boys.

Method: 1130 healthy Danish (longitudinal and cross-sectional data) and 424 Chilean (longitudinal data) boys underwent blood sampling and clinical examinations including orchidometry. Testicular volume ≥4 ml was considered as marker of puberty. Cohorts were standardized on WHO BMI z-scores.

Results: Age at pubertal onset, BMI and genotype frequencies differed significantly between cohorts. Age at pubertal onset was: Denmark 11.67 (11.59–11.76) years; Chile 11.00 (10.83–11.16) years [mean (95% CI)] (P<0.001). BMI z-score was 0.16 (±0.97) and 1.12 (±1.20) [mean (±SD)] (P<0.001), respectively. All genotype frequencies differed significantly between cohorts (P<0.001, chi-squared test). Age at pubertal onset was associated with 1) BMI z-score in both cohorts (beta=−0.35 years in both cohorts, P<0.001) 2) FSHB c.-211G>T (Denmark: beta=0.16, P=0.03; Chile: beta=0.39, P=0.04; corrected for BMI z-score). In a combined genetic model, FSHR c.-29G>A further modified this effect (Denmark: beta=0.11, P=0.01; Chile: beta=0.22, P=0.02; corrected for BMI z-score): boys with a genetic constellation resulting in weak FSH signalling (FSHB c.-211GT/TT + FSHR c.-29AA) entered puberty 8 (Denmark) and 11 months (Chile) later than boys with the most active FSH signalling (FSHB c.-211GG+FSHR c.-29GG/GA), respectively.

Conclusion: Genetic variation of FSHB, FSHR and BMI affects age at male pubertal onset. The association was observed in two independent cohorts of varying genotype distribution and BMI.