Circulating sex steroids do not influence risk of thyroid malignancy: insights from a bidirectional Mendelian...

Thyroid malignancies pose a significant global health burden, especially in women. Sex hormones are crucial for thyroid function, but their relationship with thyroid malignancy remains unclear. This study investigates the causal association between sex steroid levels and thyroid malignancy using a two-sample Mendelian randomization (MR) approach.

Genetic variants were used as instrumental variables to assess the effect of sex steroid levels on thyroid malignancy risk. Data were obtained from genome-wide association studies on thyroid malignancy, testosterone, sex hormone-binding globulin (SHBG), and estradiol levels. MR analysis was performed using the inverse variance-weighted (IVW) method, MR-Egger regression, and weighted median method, with sensitivity analyses to account for pleiotropy and heterogeneity. Multivariable MR (MVMR) was applied to account for testosterone, estradiol, and thyroid-stimulating hormone (TSH).

Analysis of data from UK Biobank (425,097 participants) and FinnGen (218,792 participants) showed no significant causal association between genetically predicted levels of total testosterone, SHBG, estradiol, or related estrogen pathway proteins and the risk of thyroid malignancy. No significant horizontal pleiotropy was detected for these associations. However, reverse MR analysis suggested a weak positive association, indicating that a genetic predisposition to thyroid malignancy may slightly increase SHBG levels [odds ratio (95% confidence interval): 1 (1-1.01), IVW P=0.01, MR-PRESSO P=0.03]. In MVMR, this association remained significant after TSH adjustment but became non-significant after adjusting for testosterone, estradiol, or all three hormones together.

This study provides genetic evidence that circulating sex steroids are not causally related to thyroid malignancy risk. The weak association between thyroid malignancy and SHBG levels appears largely mediated by the combined influence of testosterone, estradiol, and TSH, reflecting shared hormonal regulation. These findings suggest that natural variation in sex hormone levels has little impact on thyroid cancer susceptibility, and the minor SHBG elevation associated with thyroid malignancy requires further clarification.