Reproductive Factors, Sex Hormone Levels, and Differentiated Thyroid Cancer Risk: A Mendelian Randomization Study

Background: Differentiated thyroid carcinoma (DTC) is occurring three times more frequently in females than in males. However, the underlying biological mechanisms driving this discrepancy remain poorly understood. To investigate the causal role of sex hormones and reproductive factors in the risk of DTC, we implemented a two-sample Mendelian randomization (MR) analysis. Methods: We utilized genome-wide association studies (GWAS) summary statistics to explore these associations. GWAS data on DTC were derived from a meta-analysis of six studies including 7705 cases and 963,612 controls of European ancestry. GWAS summary statistics on sex hormones, reproductive factors, and gynecological conditions were retrieved from publicly available sources. We used the inverse-variance weighted (IVW) method to estimate odds ratio (OR), with additional sensitivity analyses and conducted multivariable MR (MVMR) to account for potential confounding by body mass index (BMI) and thyrotropin (TSH). Results: We identified a positive association between sex hormone binding globulin (SHBG) and DTC (OR_ivw = 1.13, p = 0.046). After controlling for TSH and BMI in a MVMR analysis, the strength of this association remained similar but lost statistical significance. Bioavailable testosterone also showed a positive but marginally significant association with DTC after adjustment for BMI in the MVMR (OR_ivw = 1.13, p = 0.07). Putative causal association was observed with uterine fibroids in females under 50 years old (OR_ivw = 1.52, p = 0.017). Endometrial cancer was associated with DTC (OR_ivw = 1.15, p = 9.0 × 10^-3); however, a genetic correlation of r² = 13% suggested potential pleiotropy. No significant associations were observed for other investigated factors. Conclusions: Our study does not provide strong evidence for a causal role of reproductive and hormonal factors in DTC risk, despite the observed sex disparity in incidence rates. The associations observed with SHBG, bioavailable testosterone, uterine fibroids, and endometrial cancer indicate potential risk factors, but further investigation is required.