Putative causal inference for the relationship between obesity and sex hormones in males: a bidirectional Mendelian randomization study

Background: Obesity is a chronic disease with a high prevalence rate and is an established risk factor for human health. Body mass index (BMI) is a common and primary indicator used in assessing obesity. This work aims to investigate the putative causal relationship among BMI, sex hormone-binding globulin (SHBG), bioavailable testosterone (BioT), and estradiol levels.Materials and Methods: We conducted a bidirectional Mendelian randomization study, using single-nucleotide polymorphisms (SNPs) strongly associated with BMI, SHBG, BioT, and estradiol as instrumental variables. All SNPs were identified from the genome-wide association study (GWAS) summary data of large sample studies recruiting more than 150,000 European adult male individuals. The inversevariance-weighted (IVW) approach was used as a primary algorithm for putative causal estimation.Results: Genetically predicted elevated BMI was associated with decreased SHBG (IVW, (3 = -0.103, 95% confidence interval [CI] [-0.113 to -0.092], P = 1.50 x 10-77) and BioT levels (IVW, (3 = -0.139, 95% CI [-0.165 to -0.113], P = 9.54 x 10-26) and high estradiol levels (IVW, (3 = 0.014, 95% CI [0.009-0.019], P = 2.19 x 10-7). Increased SHBG levels were causally associated with low BMI (IVW, (3 = -0.051, 95% CI [-0.098 to -0.005], P = 0.030) and BioT (IVW, (3 = -0.126, 95% CI [-0.175 to -0.077], P = 5.97 x 10-7) and high estradiol levels (IVW, (3 = 0.046, 95% CI [0.035-0.056], P = 6.51 x 10-17). Conversely, no evidence of an effect of estradiol imbalance on SHBG levels (IVW, (3 = 1.035, 95% CI [-0.854 to 2.926], P = 0.283) and BMI (IVW, (3 = 0.091, 95% CI [-0.094 to 0.276], P = 0.336) was obtained. However, increased BioT levels were causally associated with lower SHBG levels (IVW, (3 = -0.044, 95% CI [-0.061 to -0.026], P = 8.76 x 10-7), not BMI (IVW, (3 = -0.006, 95% CI [-0.035 to 0.023], P = 0.679).Conclusions: The findings support a network putative causal relationship among BMI, SHBG, BioT, and estradiol. SHBG, BioT, and estradiol may partly mediate the effect of obesity on male health. Reasonably modulating BioT and estradiol, especially SHBG, facilitated the attenuation of the harmful effects of obesity on male health.