Circulating Levels of Testosterone, Sex Hormone Binding Globulin and Colorectal Cancer Risk: Observational and Mendelian Randomization Analyses

Abstract

BackgroundEpidemiological studies evaluating associations between sex steroid hormones and colorectal cancer risk have yielded inconsistent results. To elucidate the role of circulating levels of testosterone, and sex hormone-binding globulin (SHBG) in colorectal cancer risk we conducted observational and Mendelian randomization (MR) analyses. MethodsThe observational analyses included 333,530 participants enrolled in the UK Biobank with testosterone and SHBG measured. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox proportional hazards models. For MR analyses, genetic variants robustly associated with hormone levels were identified and their association with colorectal cancer (42,866 cases/ 42,752 controls) was examined using two-sample MR. ResultsIn the observational analysis, there was little evidence that circulating levels of total testosterone were associated with colorectal cancer risk; the MR analyses showed a greater risk for women (odds ratio per 1-standard deviation (SD): 1.09, 95% CI: 1.01-1.17), although pleiotropy may have biased this result. Higher SHBG concentrations were associated with greater colorectal cancer risk for women (HR per 1-SD: 1.16, 95% CI: 1.05-1.29), but was unsupported by the MR analysis. There was little evidence of associations between free testosterone and colorectal cancer in observational and MR analyses. ConclusionsCirculating concentrations of sex hormones are unlikely to be causally associated with colorectal cancer. Additional experimental studies are required to better understand the possible role of androgens in colorectal cancer development. Impact:Our results from large-scale analyses provide little evidence for sex hormone pathways playing a causal role in colorectal cancer development.

Endogenous Circulating Sex Hormone Concentrations and Colon Cancer Risk in Postmenopausal Women: A Prospective Study and Meta-Analysis

“…Previously, in the WHI-CT, we found a more than 2-fold higher colorectal cancer risk when the highest and lowest quartiles of SHBG were compared ( 12 ). In contrast, results from our current analysis of postmenopausal European women found no association between SHBG concentrations and colon cancer risk, consistent with results from US, UK, and Japan-based studies ( 10 , 14 , 36 ) as well as a recent Mendelian randomization study ( 37 ). Overall, these results do not support a causal role for SHBG in colorectal cancer development and suggest that the previously reported associations were likely biased (eg, through confounding) or were the result of chance.…”

“…It should be noted, however, that this study used a less sensitive assay to measure sex hormone concentrations, and more than 60% of the participants had measured testosterone concentrations below the LLOQ ( 14 ). In the current analysis of postmenopausal European women, similar to studies of UK and US women ( 8 , 36 ) and a recent Mendelian randomization study ( 37 ), we found no association between circulating testosterone levels and colon cancer risk. We also found no association between circulating concentrations of androstenedione and DHEA with colon cancer risk.…”

Genetically predicted high IGF-1 levels showed protective effects on COVID-19 susceptibility and hospitalization: a Mendelian randomisation study with data from 60 studies across 25 countries

“…Estrogen has been shown not only to enhance immunological markers and response, but also to be linked to T-cell proliferation, which might be involved in the immune response to the infection of SARS-CoV-2 ( Taneja, 2018 ). Most hormone (about 60%) is tightly bound to sex hormone-binding globulin (SHBG), which is an important regulator of the bioactivities of estrogens and testosterone ( Raverot et al, 2010 ; Dimou et al, 2021 ). In addition, sex hormone signaling could also regulate the insulin-like growth factor (IGF-1) concentrations, which were also reported to be associated with acute respiratory distress syndrome ( Ahasic et al, 2012 ).…”

Genetically Predicted High IGF-1 Levels Showed Protective Effects on COVID-19 Susceptibility and Hospitalization: A Mendelian Randomisation Study with Data from 60 Studies Across 25 Countries

“…(7) Most hormone (about 60%) is tightly bound to sex hormone-binding globulin (SHBG), which is an important regulator of the bioactivities of estrogens and testosterone. (8,9) In addition, sex hormone signaling could also regulate the insulin-like growth factor (IGF-1) concentrations, which were also reported to be associated with acute respiratory distress syndrome. (10) It is therefore hypothesized that sex hormone and its related biomarkers might contribute to the sex difference of COVID-19 outcomes.…”