Higher thyroid hormone levels were associated with increased cancer risk, according to a prospective cohort study conducted in The Netherlands.

Each unit increase of free thyroxine (FT4) was associated with a 42% increase in risk for any solid cancer (hazard ratio 1.42; 95% CI 1.12-1.79; P<0.05). Higher FT4 was also linked to increased risk for lung cancer (HR 2.33; 95% CI 1.39-3.2) and breast cancer (HR 1.77; 95% CI 1.10-2.84; P<0.05 for both), reported Layal Chaker, MD, of Erasmus University in Rotterdam, and colleagues.

Compared with individuals in the lowest FT4 level tertile, those in the highest had a 1.3-fold increased risk for any solid cancer (95% CI 0.99-1.28; P=0.004), a 1.79-fold increased risk for lung cancer (95% CI 1.23-2.59; P=0.002), and a 1.14-fold increased risk for breast cancer (95% CI 0.82-1.58; P=0.019), Chaker and colleagues reported in the Journal of Clinical Endocrinology and Metabolism.

The investigators adjusted for age, sex, socioeconomic status, alcohol consumption, smoking, body-mass index, hypertension, diabetes, and serum cholesterol. The study found no association between levels of thyroid stimulating hormone (TSH) and any type of cancer.

"To our knowledge, this is the first prospective cohort study to assess the relation between the full range of thyroid function and cancer incidence," Chaker and colleagues wrote. "Higher FT4 levels are significantly associated with an increased risk of any solid, lung, and breast cancer."



The prospective, population-based cohort study included 10,318 participants from the Rotterdam Study for whom baseline FT4 and TSH measurements were available. Their median age was 61, and 57% were female. Participants were followed from the date of their laboratory measurements until any cancer diagnosis, death, or Jan. 1, 2012. Median follow up was 10.4 years.

The levels of FT4 in the study ranged from 0.12 ng/dL to 4.73 ng/dL. The mean level was 1.23 ng/dL. The normal range was considered to be 0.85 to 1.94 mg/dL. The investigators did not conduct a separate analysis of participants with abnormal FT4 levels but treated thyroid hormone levels as a continuous variable.

When the investigators excluded participants taking thyroid medications, an indicator of abnormal thyroid function, the risk estimates were similar, except that the association lost statistical significance for breast cancer, likely because of the small sample size, Chaker and colleagues said.

An explanation for the lack of association with TSH, which has been reported in previous studies, "might be that, given the mean age of 63 years in our study, our results are due to an altered set point of the hypothalamus-pituitary-thyroid axis. It has been described that serum TSH levels increase with age while FT4 levels remain unchanged. This might explain the lack of an association with TSH in this elderly population," the investigators wrote.

Several molecular pathways might explain the link between thyroid hormones and cancer, Chaker and colleagues noted:
• The binding of thyroid hormones to their receptors can activate the oncogenic phosphatidylinositol-3-kinase (PI3K) pathway, independent of DNA binding. Thyroid hormones can also bind the protein integrin αvβ3, which leads to activation of the PI3K pathway.
• Thyroid hormones have been found to stimulate expression of the programmed death-ligand 1 (PD-L1) gene. This gene plays a key role in protecting cancer cells from T-cell mediated destruction.
• Thyroid hormones decrease expression of tumor necrosis factor (TNF)-α and the FAS ligand; both are cell surface factors that activate apoptosis of cancerous cells.
• Finally, thyroid hormones can alter the expression level of cyclin D1, a protein that regulates the cell cycle, and of cyclin dependent kinases, leading to various tumor types, such as breast cancer and neural cancers.

Limitations of the study include that thyroid hormone levels were measured only at baseline, so the study was not able to assess any link between changes in hormone levels and cancer risk. In addition, the study population was largely Caucasian and older, so results might not be generalizable to other populations, the investigators said.
"Future studies are needed to further elucidate the possible role of thyroid function in the pathogenesis of cancer, mainly lung cancer," Chaker and colleagues concluded.