The impact of obesity and sexual behavior on prostate cancer risk is mediated by testosterone levels: a mendelian randomization study and mediation analysis

Background

The relationship between obesity, sexual behavior, and prostate cancer (PCa) has been widely debated, contributing to a lack of understanding of its potential mechanisms and hindering the development of effective prevention measures.

Purpose

The aim of this study was to examine the causal effect of body mass index (BMI), age at first sexual intercourse (AFS), and bioavailable testosterone levels on PCa while also quantifying the potential roles of mediators.

Method

We conducted a Mendelian randomization (MR) study using summary statistics from genome-wide associations of BMI (152,893 European males), AFS (182,791 European males), bioavailable testosterone (184,205 European males), and PCa (79,148 cases, 61,106 controls, European ancestry). Inverse-variance weighted method, weighted median method, MR-Egger regression, Least Absolute Shrinkage and Selection Operator (LASSO), and outlier test were used for MR analyses. Reverse MR and mediation analysis were performed. Data analyses were conducted from December 2022 to July 2023.

Results

The results showed that genetic liability to BMI was protective of PCa (OR, 0.82; 95% CI: 0.74-0.91; P = 3.29 × 10⁻⁴). Genetic liability to later AFS (OR, 1.28; 95% CI: 1.08-1.53; P = 5.64 × 10⁻³) and higher bioavailable testosterone levels (OR = 1.11, 95% CI: 1.01–1.24, P = 0.04) were associated with an increased risk of PCa. All of these potential causal effects could only be forwarded and were not affected by prostate specific antigen (PSA) screening. After controlling for bioavailable testosterone levels, the causal impact of BMI and AFS on PCa was no longer significant. The mediation analysis suggested that the causal influence of AFS/BMI on PCa relied on bioavailable testosterone levels.

Conclusion

In conclusion, the difference between the univariable and multivariable MR results suggested that the causal influence of BMI and AFS on PCa relied on bioavailable testosterone levels. Further work is needed to identify other risk factors and to elucidate the specific mechanisms that underlie this causal pathway.