The investigation was prompted by longstanding observational studies that suggested a connection between thyroid abnormalities and cancers of the female reproductive system (endometrial, breast, ovarian, and cervical cancers). However, these earlier studies could not determine whether thyroid dysfunction caused these cancers or was merely associated with them.
To address this uncertainty, this research drew on large-scale genome-wide association study (GWAS) data. This powerful statistical approach used genetic variants as instrumental variables, enabling scientists to infer causality rather than simple correlation.
The study examined thyroid function markers including free thyroxine (FT4) and thyroid-stimulating hormone (TSH) along with clinical thyroid disorders such as hyperthyroidism and hypothyroidism. By analyzing genetic data from thousands of individuals, the team aimed to determine whether changes in thyroid activity could causally influence cancer risk.
The MR analysis revealed that genetically predicted hypothyroidism significantly reduced the risk of both endometrial and breast cancers. The women with genetic indicators of hypothyroidism had a 67% lower risk of endometrial cancer (odds ratio [OR]: 0.33, P = 0.002) and a 52% lower risk of breast cancer (OR: 0.48, P < 0.001).
This study found no causal evidence linking hyperthyroidism or variations in free thyroxine and thyroid-stimulating hormone levels to an increased or decreased risk of ovarian or cervical cancers. These results highlight the selective nature of thyroid–cancer associations and suggest that the protective effects of hypothyroidism are cancer-type specific.
To look deeper into how hypothyroidism might reduce cancer risk, this study conducted mediation MR analyses focusing on 2 key sex hormones: total testosterone and estradiol. The analyses demonstrated that lower testosterone levels partially mediated the relationship between hypothyroidism and reduced risks of endometrial and breast cancer, suggesting that hormonal regulation could be a critical pathway in this association.
Overall, these findings not only confirm a causal link between thyroid dysfunction and cancer risk but also open new avenues for preventive and therapeutic strategies targeting hormonal pathways. The bioinformatics analyses, which identified potentially relevant genes, further support the biological plausibility of these findings.
Source:
Gao, B., Zhang, C., Wang, D., Luo, D., Shan, Z., Teng, W., Tao, T., & Li, J. (2025). Causal link between thyroid function and female-specific cancers: A bidirectional two-sample and mediation Mendelian randomization study. International Journal of Women’s Health, 17, 3913–3927. https://doi.org/10.2147/ijwh.s552719
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