Reduced Thyroid Hormone Sensitivity Linked to Higher Thyroid Cancer Risk in Euthyroid Patients: Study Finds

The research team, led by Huaijin Xu, retrospectively analyzed data from 9,515 euthyroid adults who underwent thyroidectomy for nodular thyroid disease. All participants had normal thyroid hormone levels before surgery, and their nodules were confirmed as either benign or DTC postoperatively. 

To better understand the hormonal dynamics, the researchers examined several composite indicators of thyroid hormone sensitivity, including the thyroid-stimulating hormone index (TSHI), thyrotroph thyroxine resistance index (TT4RI), the ratio of free triiodothyronine to free thyroxine (FT3/FT4), and the thyroid’s secretory capacity (SPINA-GT). These indices reflect how the body responds to and regulates thyroid hormones.

The study led to the following findings:

• Individuals with higher TSHI and TT4RI, reflecting reduced central thyroid hormone sensitivity, had significantly increased odds of being diagnosed with differentiated thyroid cancer (DTC).
• Each unit increase in TSHI and TT4RI was linked to a 34% and 35% higher risk of DTC, respectively.
• Lower FT3/FT4 ratios and SPINA-GT values, indicating reduced peripheral sensitivity and secretory capacity, were also associated with greater cancer risk.
• These associations remained consistent across subgroups defined by age, sex, metabolic status, thyroid autoimmunity, and nodule size.
• The relationship between thyroid hormone sensitivity and DTC risk was non-linear, pointing to a more intricate physiological mechanism.
• TSHI and TT4RI showed stronger associations with thyroid malignancy than traditional markers like TSH.
• No single thyroid parameter demonstrated both high sensitivity and specificity in differentiating malignant from benign nodules.
• The findings highlight the potential value of using combined thyroid hormone sensitivity indices in more comprehensive diagnostic models.

The researchers emphasize that their findings shed new light on the pathophysiology of thyroid cancer in patients with euthyroid profiles. They propose that thyroid hormone sensitivity indices could serve as supplementary tools in preoperative evaluation and guide clinical decisions regarding the likelihood of malignancy in thyroid nodules.

“Recognizing the role of thyroid hormone sensitivity may enhance our understanding of thyroid cancer development and aid in building more accurate predictive models,” the authors noted.

"The study opens the door for future research to explore how modulating hormone sensitivity could influence thyroid cancer outcomes and whether these indices can be incorporated into clinical guidelines for managing thyroid nodules," they concluded.

Reference:

Xu, H., Liu, H., Hu, X., Jia, X., Xue, Z., Wang, A., Kang, S., & Lyu, Z. (2025). Reduced sensitivity to thyroid hormones is associated with differentiated thyroid cancer in the euthyroid thyroidectomy population. Frontiers in Endocrinology, 16, 1595002. https://doi.org/10.3389/fendo.2025.1595002