Mendelian Randomisation Analysis Suggests that Hypothyroidism Reduces Endometrial Cancer Risk

BackgroundThyroid 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. MethodsTo 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. ResultsMendelian 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 x 10-4). Hashimotos 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 x 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. InterpretationThis 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 Hashimotos disease. FundingNational Health and Research Council of Australia (APP1173170). Worldwide Cancer Research and Cancer Australia (22-0253). Research in context Evidence before this studyWe searched PubMed for epidemiological and Mendelian randomisation studies containing the terms endometrial cancer or uterine cancer or obesity, and thyroid dysfunction or hypothyroidism or Hashimotos 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 studyBy 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 Hashimotos 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 evidenceThe identification of hypothyroidism as a protective factor for endometrial cancer raises intriguing questions about the diseases 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.