In this well-established large cohort of postmenopausal women in the United States, we found that self-reported extreme habitual sleep duration, either short (
h) or long (
h), was significantly associated with a moderate increase in risk of CRC independent of a number of confounding factors, compared with the normally recommended hours of sleep, 7–8
h per night. A U-shaped association was observed. The association between sleep duration and risk of CRC was modified by HRT. Frequent experience (
3 times per week) of trouble falling asleep or getting back to sleep was associated with slightly increased risk of CRC. The association may be partially mediated by sleep duration.
Two previous studies on night shift work and the risk of CRC generated inconsistent findings. A prospective cohort study has shown that longer years of rotating night shift work was associated with moderately increased risk of CRC among female nurses (Schernhammer et al, 2003
). However, the other study did not find an association between night shift work and colon or rectal cancer among women naval radio–telegraph operators (Tynes et al, 1996
Only seven studies have investigated the association between sleep duration and cancer risk. The study findings from four prospective studies and one population-based study on sleep duration and risk of breast cancer were mixed (Verkasalo et al, 2005
; McElroy et al, 2006
; Pinheiro et al, 2006
; Wu et al, 2008
; Kakizaki et al, 2008b
). One Japanese prospective study has associated long sleep duration with a decreased risk of prostate cancer (Kakizaki et al, 2008a
). No association was found for sleep duration and endometrial cancer in the WHI-OS (Sturgeon et al, 2012
). In a large prospective study in Europe,<6
h of sleep was associated with moderately increased overall cancer incidence compared with 7–8
h of sleep (von et al, 2012
). Owing to the paucity of the research, no conclusion can be drawn on sleep duration and cancer risk.
Until the present study, there has been no prospective study on sleep duration and risk of CRC. We observed a U-shaped association between sleep duration and incidence of CRC. A similar pattern has been reported for sleep duration and coronary heart disease (Ayas et al, 2003
), type 2 diabetes (Yaggi et al, 2006
), and all-cause mortality (Parish, 2009
). The association between short sleep duration and an increased risk of CRC was in line with the finding from a colonoscopy-based case–control study of 338 cases and 902 controls, which showed a 50% increase in risk of colorectal adenoma for <6
h compared with
h of sleep. However, this study did not report the association between long sleep duration and risk of colorectal adenoma (Thompson et al, 2011
). Our observation on the association between long sleep duration and increased risk of CRC was consistent with a retrospective hospital-based case–control study in Hong Kong among 822 cases with CRC and 926 controls, which found that cases slept for significantly longer hours than controls did (Ho et al, 2006
The mechanisms underlying the observed positive associations between extreme short and long sleep durations and risk of CRC are unknown and likely to be different. The harm of short sleep or sleep restriction has been well-recognised, including impaired glucose and appetite control (Grandner et al, 2010
) and compromised immune function. Sleep enhances adaptive immune responses, whereas sleep disturbances can lead to immune suppression and a shift to a predominance of cancer-stimulatory cytokines (Dimitrov et al, 2007
). There is no consensus on the probable mechanisms for the harm of long sleep. Our study finding on the positive association between long sleep duration and risk of CRC may not be explained by the melatonin hypothesis. A previous study has shown that a higher endogenous estradiol level is an independent risk factor for CRC in the WHI Study (Gunter et al, 2008
). If long sleep duration was thought to decrease oestrogen levels by augmenting the production of melatonin, we would expect to observe an inverse association between long sleep duration and risk of CRC. Nevertheless, the association between the number of hours of sleep and circulating levels of melatonin has not been well-established (Viswanathan and Schernhammer, 2009
), with only one cross-sectional study showing that the postmenopausal Singapore women who slept 9 or more hours a night had a 42% higher mean level of urinary melatonin than those who slept 6 or fewer hours (Wu et al, 2008
). Long sleep duration is also considered being a marker of frailty and ill health (Knutson and Turek, 2006
). Interestingly, we only observed the association between long sleep duration and increased risk of CRC among women who received HRT. It indicates that hormone-related mechanism may mediate such an association or vice versa. In a cross-sectional study of 614 individuals, each additional hour of sleep was significantly associated with an increase in levels of C-reactive protein and interleukin-6; and each hour reduction in sleep was associated with an increase in levels of tumour necrosis factor-α
(Patel et al, 2009
). Therefore, sleep duration may contribute to systemic inflammation and subsequently CRC.
We noticed a slight increase in risk of CRC associated with frequent experience of trouble getting back to sleep or falling asleep, snoring, and very restless sleep. Two studies have investigated sleep disturbance in association with cancer incidence or mortality. One prospective study observed a modestly increased overall cancer risk for those prescribed any hypnotic compared with non-users (Kripke et al, 2012
) and the other suggested that baseline sleep-disordered breathing was associated with increased overall cancer mortality in a community-based study (Nieto et al, 2012
). These two previous studies did not include sleep duration in the statistical models. It is conceivable that sleep duration partially mediated the association between trouble falling asleep or getting back to sleep, or very restless sleep and risk of CRC because sleep duration was tightly associated with these factors in our study. In light of a moderate prevalence of these sleep habits in the general population, even a slight increase in CRC risk would have a public health impact. Further research using refined ascertainment of sleep habits may identify new risk factors for CRC.
We found a statistically significant interaction between sleep duration and use of HRT. The finding suggested that HRT may not only improve sleep in postmenopausal women but also counteract potential carcinogenic effect associated with short sleep duration. The differential associations by long sleep duration were also interesting, although the underlying mechanism remains unknown. Nevertheless, our observations suggested that there is a common biological mechanism shared by HRT and regulation of sleep duration (e.g., circadian rhythm), as well as the distinct carcinogenic effect associated with short vs
long sleep duration in the context of HRT. The investigation on sleep duration by different types of HRT (such as oestrogen alone or oestrogen combined with progestin) in a large study may provide more insight into such an interactive effect. Short sleep duration has been associated with obesity in cross-sectional studies (Cappuccio et al, 2008
) and obesity is a risk factor for CRC. However, obesity, as well as physical activity, was not shown to be interacting with sleep duration in modifying risk of CRC in our study. Similarly, the study on colorectal adenoma also did not find BMI to be a confounding factor (Thompson et al, 2011
Strengths of this study include its prospective design and large number of cases. We evaluated a broad spectrum of potential confounding factors that may account for the underlying association. However, residual confounding effect by recognised factors, such as fatigue, or unmeasured factors, such as undiagnosed comorbid conditions, may not have been fully accounted for in this analysis owing to potential limitations in study questionnaires. Given the prospective design of this study, the possibility of reverse causality was unlikely to explain the findings. The major analyses lagged by 2 years and the sensitivity analysis lagged by 5 years, both strengthened our confidence in the validity of the study findings.
There are several limitations to our study. First, self-reported sleep duration at study baseline may not have captured actual habitual sleep duration, but rather perceived habitual sleep duration. Subjective report can either under- or over-report sleep duration compared with objective measures using polysomnography (Bliwise and Young, 2007
). This potential non-differential measurement error may dilute the association between extreme sleep duration and CRC risk. Nevertheless, one study has shown that self-reported sleep duration correlates well with actigraphic assessment of sleep (Lockley et al, 1999
). Second, we did not have information on change in sleep duration over time, occupational history, including night shift work history, or nocturnal exposure to light for our study cohort. In the WHI Study, the question on nocturnal sleep duration at baseline was not ascertained during the follow-up visit. Third, as our analyses are confined to older women, the results may not be generalisable to men or younger women owing to sleep and endocrine differences by age and sex (Manber and Armitage, 1999
). Finally, although short sleep duration has been associated with increased risk of colorectal adenoma (Thompson et al, 2011
), we could not accurately examine colorectal adenoma because only prior history of colorectal polyp removal was queried at baseline.
In summary, insufficient sleep is a common public health issue and there is increasing awareness of the impact of sleep problems on health (Ferrie et al, 2011
). It is plausible that dysregulation of a system that governs circadian endocrine, immune, and metabolic function may be linked to cancer incidence in humans (Sephton and Spiegel, 2003
). Our finding of a significantly increased risk of CRC in postmenopausal women with extreme sleep duration suggests the need for additional research to replicate this finding, and to further elucidate if it represents a causal association vs
an association secondary to some other unidentified factors. If confirmed, our study findings suggest that the health benefits of adequate amount of sleep, 7–8
h per night, include reduced risk of CRC.