CONTEXT: Obesity in men is associated with low serum testosterone and both are associated with several diseases and increased mortality.

OBJECTIVES: Examine the direction and causality of the relationship between body mass index (BMI) and serum testosterone.

DESIGN: Bi-directional Mendelian randomization (MR) analysis on prospective cohorts.

SETTING: Five cohorts from Denmark, Germany and Sweden (Inter99, SHIP, SHIP Trend, GOOD and MrOS Sweden).

PARTICIPANTS: 7446 Caucasian men, genotyped for 97 BMI-associated SNPs and three testosterone-associated SNPs.

MAIN OUTCOME MEASURES: BMI and serum testosterone adjusted for age, smoking, time of blood sampling and site.

RESULTS: 1 SD genetically instrumented increase in BMI was associated with a 0.25 SD decrease in serum testosterone (IV ratio: -0.25, 95% CI: -0.42--0.09, p = 2.8*10-3). For a body weight reduction altering the BMI from 30 to 25 kg/m2, the effect would equal a 13% increase in serum testosterone. No association was seen for genetically instrumented testosterone with BMI, a finding that was confirmed using large-scale data from the GIANT consortium (n = 104349).

CONCLUSIONS: Our results suggest that there is a causal effect of BMI on serum testosterone in men. Population level interventions to reduce BMI are expected to increase serum testosterone in men.