Sex Hormone and Colorectal Cancer: The Knowns and Unknowns.

Sex hormones have been suggested as a contributor to gender disparity in incidence and mortality of colorectal cancer, but previous observational studies on endogenous sex hormones and colorectal cancer risk have led to contradictory results. Leveraging the large-scale UK biobank resource, Dimou and colleagues performed both observational and Mendelian randomization (MR) analyses to investigate the association of serum testosterone and sex hormone binding globulin concentrations with the risk of colorectal cancer. Although the findings provide little evidence for independent roles of the hormones in colorectal cancer, further interrogation of possible mediating effects of sex hormones on the causal pathways of colorectal cancer could deepen our understanding of colorectal cancer etiology and improve tailored prevention. While MR analysis is useful for inferring causality in observational studies, the current null results should be interpreted with caution because of insufficient statistical power and predefined assumptions of linearity. Moreover, given the widespread use of testosterone supplementation in older men to restore age-related decline of endogenous concentrations, large and long-term randomized controlled trials are required to clarify the effect of testosterone on colorectal cancer risk, which would provide critical evidence for health decision making.