In the present large, prospective study in postmenopausal women, we observed that women with higher insomnia scores had a significantly higher risk of thyroid cancer that was confined to nonobese women. There was no significant association between sleep duration and the risk of thyroid cancer.
It is not clear why we did not observe an association between self-reported sleep duration and thyroid cancer. It could be because self-reported sleep duration is poorly correlated with objectively measured sleep duration. It is estimated that the correlation between self-reported sleep and objectively measured sleep (via actigraphy) is about 0.47 among middle-aged men and women (29
). However, we do not have objective measures of sleep duration in the WHI. It is also possible that sleep quantity is less important than poor sleep quality as a risk factor for thyroid cancer. Because this is the first study on sleep disturbance and thyroid cancer, more studies are needed to confirm, refine, or refute these findings.
In addition, the lack of association between insomnia score and thyroid cancer risk among obese women is somewhat surprising and unexplained. Obesity itself has been identified as an emerging risk factor for thyroid cancer. Obese postmenopausal women are more likely to have vasomotor symptoms that interfere with sleep (30
). On the other hand, inadequate sleep also could lead to obesity via alterations in appetite regulation (16
). It is possible that these complex relations make it more difficult to detect the independent effect of sleep disturbance on thyroid cancer. In addition, power might be an issue among obese women, because we had only 15 cases in the WHIIRS ≥11 category. Also, it could be due to competing risks in the obese women who had WHIIRS ≥11 (e.g., cardiovascular disease mortality related with insomnia and obesity).
Previous epidemiologic studies have shown that poor sleep quality and inadequate sleep duration are associated with numerous adverse health outcomes, such as total mortality, cardiovascular disease, and type 2 diabetes mellitus (8
). Epidemiologic studies also have reported that night shift workers are at a significantly increased risk of developing breast (32
), colon (36
), prostate (37
), and endometrial cancer (39
) compared with workers who did not report any rotating night shift work. Only a few studies have examined sleep duration and breast cancer risk in humans, but findings are conflicting. Two prospective cohort studies (40
) provide some support for a decreased risk of breast cancer in long sleepers (≥9 hours), whereas 2 other studies reported contradictory results (1
). To our knowledge, the present study is the first study to examine the association between sleep disturbance and thyroid cancer.
The biologic mechanism by which sleep disturbance might be associated with an increased risk of thyroid cancer is unknown. One plausible biologic mechanism is via elevated thyroid-stimulating hormone level due to sleep disturbance (11
), which could lead to an increased risk of thyroid cancer (12
). Several plausible biologic models that explain how sleep disturbance can influence the development of cancer in general have been proposed (43
). One possible mechanism is impaired immune function (44
). Both laboratory studies of acute sleep deprivation and observational studies of poor sleepers have reported that sleep disturbances can lead to a suppression of immune function and a shift in the balance of cytokine production from a predominance of type 1 cytokines, including anticancer cytokines such as interleukin-2 and interferon-γ, to type 2 cancer-stimulatory cytokines such as interleukin-10 (45
). It has been suggested that sleep disturbance could impair immune response by disrupting circadian rhythms at the level of immune cells as a result of disrupted endocrine and physiologic circadian rhythms (45
). Another possible mechanism is reduced production of melatonin caused by exposure to light at night (43
). Melatonin has been demonstrated to suppress the initiation phase of tumorigenesis and inhibit the proliferation of human cancer cell lines in experimental studies (10
). However, the null association between sleep duration and thyroid cancer risk noted in our study, along with inconsistent findings on sleep duration from other studies of other cancers, suggests that impaired immune system function and inflammation might play a more important role than melatonin deficiency for thyroid cancer. Like other cancer types, thyroid cancer also is influenced by inflammation. For example, studies have shown that thyroid cancer frequently occurs in one of the most common autoimmune thyroid diseases, Hashimoto's thyroiditis (47
Another proposed model is that sleep might influence cancer risk via alterations in levels of appetite-regulating hormones, such as leptin and ghrelin (16
), that lead to increased appetite and subsequently obesity, which is a risk factor for several cancers (48
). In addition, there could be changes in waking behavior; increased daytime fatigue due to poor sleep quality could lead to decreased physical activity, lethargy, or changes in eating behavior. A recent pooled analysis of 5 prospective studies found that obesity was positively associated with thyroid cancer risk in both men and women (5
). However, our analyses stratified by obesity status indicated that the significant association between sleep disturbance and thyroid cancer was confined to nonobese women, which suggests that changes in hormones involved in appetite regulation might not be a major pathway for the observed association.
Strengths of our study include its prospective design, detailed information on potential confounders, and validated cancer diagnoses. However, it has some limitations as well. First, our sleep disturbance measures relied on self-reporting of sleep habits through questionnaires, rather than more objective means such as wrist-actigraphy or polysomnography. This exposure misclassification is most likely to be nondifferential; thus, it could bias our estimates of effect toward the null. Second, we lacked information on ionizing radiation exposure (an important risk factor for thyroid cancer), which might confound our results. Our results would be overestimated if ionizing radiation exposure were associated with an increased level of sleep disturbance. However, there is no literature reporting that ionizing radiation exposure is associated with sleep disturbance. Thus, our results are unlikely to be entirely confounded by ionizing radiation. Finally, the study was conducted in postmenopausal women, so our findings might not be generalizable to other populations.
In conclusion, postmenopausal women with greater sleep disturbance, especially nonobese women, had a significantly increased risk of thyroid cancer. More large prospective studies are needed to confirm this finding and to examine the possible biologic mechanisms for the association.