Mendelian Randomisation Analysis Suggests that Hypothyroidism Reduces Endometrial Cancer Risk

Background Thyroid dysfunction, hypothyroidism in particular, has been associated with endometrial cancer, but it remains unclear whether hypothyroidism itself or other aspects of thyroid dysfunction have a causal effect on endometrial cancer risk. Methods To clarify the effects of thyroid dysfunction phenotypes on endometrial cancer risk, we performed Mendelian randomisation analyses data from the largest available genome-wide association studies (GWAS). The robustness of associations was assessed through sensitivity analyses. To disentangle the potential influence of obesity on causal associations, we carried out multivariable Mendelian randomisation analysis. Results Mendelian randomisation analysis demonstrated a significant causal association between hypothyroidism and decreased risk of endometrial cancer (OR = 0.93; 95% CI 0.89- 0.97; p = 3.96 × 10-4). Hashimoto’s thyroiditis, a common cause of hypothyroidism, showed a similar, albeit nominal, association with endometrial cancer risk (OR = 0.92; 95% CI 0.86- 0.99; p = 0.03). Hypothyroidism was also significantly associated with decreased risk of endometrioid endometrial cancer (OR = 0.93; 95% CI 0.88-0.98; p = 4.02 × 10-3), the most common histological subtype. Sensitivity analyses confirmed the robustness of the significant associations. Multivariable Mendelian randomisation analysis revealed that BMI and hypothyroidism had independent effects on endometrial cancer risk. Interpretation This study provides evidence for a causal relationship between hypothyroidism and decreased risk of endometrial cancer. The protective effect of hypothyroidism is independent of BMI and may be related to the autoimmune effects of Hashimoto’s disease. Funding National Health and Research Council of Australia (APP1173170). Worldwide Cancer Research and Cancer Australia (22-0253). Evidence before this study We searched PubMed for epidemiological and Mendelian randomisation studies containing the terms ‘endometrial cancer’ or ‘uterine cancer’ or ‘obesity’, and ‘thyroid dysfunction’ or ‘hypothyroidism’ or ‘Hashimoto’s thyroiditis’ or ‘thyroid stimulating hormone’ or ‘triiodothyronine’ or ‘thyroxine’ or ‘thyroid peroxidase’ or ‘Graves’ disease’ or ‘hyperthyroidism’ without date restrictions. These searches revealed that thyroid dysfunction has been a subject of interest in relation to endometrial cancer. Indeed, observational studies have previously suggested an association between hypothyroidism and increased risk of endometrial cancer although the nature of these studies have limited their ability to establish causal relationships. Additionally, the potential confounding effect of obesity, a shared risk factor for both endometrial cancer and hypothyroidism, further complicates these relationships. Added value of this study By employing Mendelian randomization analysis, a powerful approach that reduces confounding, we identified a robust causal association between hypothyroidism and a decreased risk of endometrial cancer. This finding challenges the previously suggested association between hypothyroidism and increased endometrial cancer risk. Notably, our study did not find evidence that thyroid hormone levels influence endometrial cancer risk. However, we observed a suggestive association between Hashimoto’s thyroiditis, a common cause of hypothyroidism. Furthermore, we demonstrated the independent effects of body mass index (a surrogate measure for obesity) and hypothyroidism on endometrial cancer risk, with hypothyroidism potentially attenuating the impact of body mass index. Implications of the available evidence The identification of hypothyroidism as a protective factor for endometrial cancer raises intriguing questions about the disease’s pathogenesis. The available evidence suggests involvement of autoimmune effects, highlighting the need for further studies investigating the role of immune responses in endometrial cancer development. By elucidating the specific pathways and molecular mechanisms underlying the relationship of endometrial cancer with hypothyroidism, we may uncover potential targets for preventive or therapeutic interventions. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was funded by an Investigator grant from the National Health and Research Council of Australia, grant number APP1173170, and a project grant co-funded by Worldwide Cancer Research and Cancer Australia, grant number 22-0253. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All data analysed in this study are publicly available and their sources have been referenced throughout the manuscript and supplementary materials. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. 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