Effect Modification by Levels of Sex Hormones in the Association between Adiposity and Cancer Incidence in the UK...

The role of sex hormones in the sex difference between adiposity and cancer risk remains unclear. We examined body mass index (BMI) and visceral adipose tissue (VAT) estimated using a validated equation in relation to cancer incidence according to serum sex hormone-binding globulin (SHBG), testosterone, and estradiol among 451,500 UK Biobank participants. For cancers showing a sex-specific adiposity association, we used Cox regression to calculate multivariable HRs per increase between the 10th and 90th percentiles of adiposity according to low versus high sex hormone levels. We documented 42,949 cancers over a median follow-up of 13.1 years. BMI and VAT were more strongly associated with a higher risk of esophageal, liver, and colorectal cancers in males than in females. In males, BMI showed a stronger association with esophageal (HR for high vs. low SHBG = 2.38 vs. 1.62; Pinteraction = 0.04) and liver cancers (HR = 3.24 vs. 1.96; Pinteraction = 0.03) among those with high versus low SHBG, whereas an opposite pattern was observed for colorectal cancer (HR = 1.12 vs. 1.47; Pinteraction = 0.03). Among females, BMI was associated with a higher esophageal cancer risk in those with low (HR = 1.68) but not high SHBG (HR = 0.64; Pinteraction = 0.025); for liver cancer, results were similar but statistically nonsignificant. No interaction by estradiol or testosterone was detected. Similar results were observed for VAT. SHBG may be an important factor underlying the sex difference in adiposity-associated risk for colorectal, esophageal, and liver cancers.

Understanding the interactions between sex hormones and adiposity can help explain sex differences in cancer risk associated with body fat. Our findings suggest that SHBG may be a promising target for future research on strategies to reduce the risk of colorectal, esophageal, and liver cancers in individuals with excess adiposity.