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

Bingrui Gao,1 Chenxi Zhang,1 Deping Wang,1,2 Dongdong Luo,1,3 Zhongyan Shan,1 Weiping Teng,1 Tao Tao,4 Jing Li1 1Department of Endocrinology and Metabolism, The Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, People’s Republic of China; 2Department of Endocrinology and Metabolism, Hongqi Hospital Affiliated to Mudanjiang Medical College, Mudanjiang, Heilongjiang, 157011, People’s Republic of China; 3Department of Endocrinology and Metabolism, The Second Hospital of Dalian Medical University, Dalian, Liaoning, 116027, People’s Republic of China; 4Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People’s Republic of ChinaCorrespondence: Jing Li, Department of Endocrinology and Metabolism, The Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, People’s Republic of China, Email [email protected]; [email protected]: 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, P = 0.002) and breast cancer (OR: 0.48, P < 0.001). Mediation MR analyses further suggested that hypothyroidism may lower the risk of both endometrial and breast cancers by decreasing levels of total testosterone.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. Keywords: thyroid function, cancer, female, testosterone, causality, mendelian randomization