Sex hormones, adiposity, and metabolic traits in men and women: a Mendelian randomisation study

OBJECTIVE: Epidemiological and clinical studies have highlighted important roles for sex hormones in the regulation of fat distribution and systemic metabolism. We investigated the bidirectional associations between bioavailable serum testosterone (BioT) in both sexes and oestradiol (E2) in men and adiposity and metabolic traits using Mendelian randomisation (MR). DESIGN AND METHODS: As genetic instruments for sex hormones, we selected all the genome-wide significant, independent signals from a genome-wide association studies (GWAS) in up to 425 097 European ancestry UK Biobank participants. European population-specific, summary-level data for adiposity, metabolic, and blood pressure traits were obtained from the largest publicly available GWAS. Sex-specific, two-sample MR analyses were used to estimate the associations of sex hormones with these traits and vice versa. RESULTS: In women, higher BioT was associated with obesity, upper-body fat distribution, and low HDL-cholesterol although, based on analyses modelling the sex hormone-binding globulin-independent effects of BioT, the last two associations might be indirect. Conversely, obesity and android fat distribution were associated with elevated serum BioT. In men, higher BioT was associated with lower hip circumference and lower fasting glucose. Reciprocally, obesity was associated with lower BioT and higher E2, while upper-body fat distribution and raised triglycerides were associated with lower E2. CONCLUSIONS: Adipose tissue and metabolic dysfunction are associated with deranged sex hormone levels in both sexes. In women, elevated BioT might be a cause of obesity. Conversely, in men, higher BioT appears to have beneficial effects on adiposity and glucose metabolism.