Causal Link Between Thyroid Function and Female-Specific Cancers: A Bidirectional Two-Sample and Mediation Mendelian Randomization Study.

Background: Observational studies have reported associations between thyroid function, encompassing free thyroxine, thyroid-stimulating hormone, hyperthyroidism, and hypothyroidism, and female-specific cancers such as endometrial, breast, ovarian, and cervical cancers. However, the causal relationship remains unclear. Objective: The researchers aimed to explore the causal relationship between thyroid function and female-specific cancers, while also investigating the role of sex hormones (total testosterone and estradiol) as potential mediators in this association. Methods: Initially, the researchers preformed bidirectional two-sample (T-S) Mendelian randomization (MR) analysis using summary-level Genome-wide association studies to investigate the causal relationship between thyroid function and female-specific cancers. Subsequently, the researchers employed mediation MR analysis to assess the potential role of sex hormones as intermediaries in this relationship. The robustness of the findings of this study was further validated through a series of sensitivity analyses. Lastly, the researchers conducted bioinformatics analyses to explore underlying mechanisms, leveraging potentially relevant genes. Results: Bidirectional T-S MR analyses indicated that hypothyroidism reduces the risk of endometrial cancer (OR: 0.33, Conclusion: The researchers established the causal relationship between thyroid function and female-specific cancers, offering novel perspectives for the early prevention and intervention of endometrial and breast cancer. Furthermore, the researchers investigated the mediating role of sex hormones in the association between hypothyroidism and these cancers, providing valuable insights for future mechanistic research.