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

Bingrui Gao1, Chenxi Zhang1, Deping Wang1,2

  • 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.

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Hypothyroidism may causally reduce the risk of endometrial and breast cancers, potentially by lowering total testosterone levels. This study clarifies thyroid function

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Area of Science:

  • Endocrinology
  • Gynecologic Oncology
  • Genetic Epidemiology

Background:

  • Observational studies suggest links between thyroid function (thyroid-stimulating hormone, thyroxine, hyperthyroidism, hypothyroidism) and female cancers (endometrial, breast, ovarian, cervical).
  • The causal nature of these associations and potential mediating factors remain unclear.

Purpose of the Study:

  • To investigate the causal relationship between thyroid function and female-specific cancers using Mendelian randomization.
  • To explore the mediating role of sex hormones, specifically total testosterone and estradiol, in these associations.

Main Methods:

  • Bidirectional two-sample (T-S) Mendelian randomization (MR) analysis utilizing summary-level Genome-wide association studies data.
  • Mediation MR analysis to assess the role of sex hormones.
  • Sensitivity analyses and bioinformatics analyses to validate findings and explore mechanisms.

Main Results:

  • Hypothyroidism was causally associated with a reduced risk of endometrial cancer (OR: 0.33, P=0.002) and breast cancer (OR: 0.48, P<0.001).
  • Mediation analysis indicated that hypothyroidism may lower the risk of these cancers by decreasing total testosterone levels.

Conclusions:

  • This study establishes a causal link between hypothyroidism and reduced risk of endometrial and breast cancers.
  • Sex hormones, particularly total testosterone, may mediate the protective effect of hypothyroidism against these cancers, offering insights for prevention and intervention.