TSH Levels Linked to Papillary Thyroid Cancer, With Sex Differences

Nancy A Melville

September 28, 2017

Thyroid-stimulating hormone (TSH) levels show a significant association with the risk of papillary thyroid cancer (PTC) that appears gender-based, with lower-than-normal serum TSH levels years before a cancer diagnosis linked to an increased risk of PTC in women, while in contrast a higher-than-normal prediagnostic level is linked to a greater risk in men.

Furthermore, increased TSH levels falling even within the normal TSH range show a trend of being associated with a decreased risk of PTC in both genders.

"The findings by gender are novel," first author Yawei Zhang, MD, PhD, of the Yale School of Public Health and the Yale Cancer Center, in New Haven, Connecticut, told Medscape Medical News.

"Our study is the largest study so far that includes a relatively large number of male cases," he said, noting, "It is important to study TSH and papillary thyroid cancer by gender because women are much more likely to develop thyroid cancer than men."

In addition to being female, other well-established risk factors for thyroid cancer include older age, exposure to ionizing radiation, and a history of benign thyroid disease. Hyperthyroidism and hypothyroidism, respectively, are known to be linked to thyroid-cancer risk, but little is known about the effect of treatment on the risk, Dr Zhang said.

And "Whether treatment of these diseases is associated with reduced risk of thyroid cancer is currently unclear," he noted.

These latest findings warrant a rethinking of current TSH reference limits, which are controversial, Dr Zhang said, adding, "Clinicians who are managing patients with abnormal thyroid function and those with thyroidectomy should consider thinking about optimal TSH levels in their patients."

Gender Differences Larger in Classical PTC, Stronger in Case of Larger Tumors

In terms of TSH, previous studies have linked thyroid hormones and TSH levels to tumor-promotion in various cancers, and TSH suppression is in fact recommended in the management of differentiated thyroid cancer (DTC); however, studies linking TSH and thyroid hormones specifically to PTC have not been consistent.

For the current study, published in the August issue of Cancer Epidemiology, Biomarkers & Prevention, Dr Zhang and colleagues identified 741 patients with PTC, including 341 women and 400 men, from databases including the Department of Defense Automated Central Tumor Registry (ACTUR) and the Defense Medical Surveillance System (DMSS), and compared their prediagnostic serum samples with those of an equal number of matched controls.

For the PTC patients, the median time between the blood draw for the serum samples and the PTC diagnosis was approximately 4 years (1454 days).

Overall, serum TSH levels falling below the normal range were linked to a significant increase in the risk of PTC compared with the middle tertile of the normal range (odds ratio [OR], 2.65), and TSH levels above the normal range were also associated with an increased risk, however to a lesser degree, with borderline significance (OR, 1.58).

Meanwhile, women with prediagnostic serum TSH levels below the normal range showed a substantially greater risk of PTC compared with those with serum levels in the middle of the normal range (OR 3.74).

Conversely, while there was no increased risk among men with low TSH levels, men with levels above the normal range had a significantly greater risk of PTC compared with men with normal levels (OR, 1.96).

Although not as significant an association as seen with TSH levels outside of normal ranges, a notable trend was also observed of increased TSH levels within the normal range and a decreased risk of PTC in women (P for trend = .0005) and men (P for trend = .041).

The gender differences regarding TSH levels and PTC risk were primarily seen with classical PTC cases, and the association was stronger in cases involving larger tumor sizes.

Not Clear How Tx for Hyper- or Hypothyroidism Affects Thyroid Cancer Risk

In the overall population, serum concentrations of the thyroid hormones T3, T4, and free T4 above or below the normal range were not associated with an elevated risk of PTC; however, there was a suggestion of an inverse association between T3 levels above the normal range and PTC risk only among men (OR 0.59).

The risk of PTC, meanwhile, increased with increasing serum concentrations of T3 only among women (overall P for trend = .019).

A patient history of thyroid diseases associated with low and high TSH levels — hyperthyroidism and hypothyroidism, respectively — is known to be linked to thyroid-cancer risk; however, less is known about the effect of treatment on the risk, Dr Zhang said.

"Whether treatment of these diseases is associated with reduced risk of thyroid cancer is currently unclear," he said.

Dr Zhang added that an important limitation of the study was the lack of data on participants' medical history. "Therefore, our study was not able to investigate the issue," he said.

Most previous studies showing an association between elevated TSH levels and risk of thyroid cancer have been either cross-sectional or case-control, leaving open the possibility of a reverse causation or treatment effect, the authors note.

Of only three previous cohort studies on the issue, one showed a significantly reduced risk of thyroid cancer associated with elevated TSH levels, and the other two linked lower, but not significant, TSH levels with thyroid cancer.

A notable previous meta-analysis including 22 studies showed that higher TSH levels were associated with an increased thyroid cancer risk (J Clin Endocrinol Metab. 2012;97:2682–2692); however, all of those studies were cross-sectional and involved measurement of TSH levels after treatment of thyroid cancer had already started.

While the new findings would need replication in different populations before any conclusions could be made regarding clinical implications, they add importantly to the ongoing debate over the TSH upper reference limit, discussed in a review (Nature. 2011;7;232-238).

"Given the findings of an inverse association between TSH and papillary thyroid cancer within the normal range and the controversial reference limits of TSH levels, a need for reevaluation of TSH reference limits is warranted," Dr Zhang said.

The study received funding from the National Institutes of and American Cancer Society. Dr Zhang had no relevant financial relationships. Disclosures for the coauthors are listed in the paper.

Cancer Epidemiol Biomarkers Prev. 2017;26:1209-1218 Abstract

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