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Published online before print April 30, 2007, 10.1097/PSY.0b013e31804301d3
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Psychosomatic Medicine 69:383-389 (2007)
© 2007 American Psychosomatic Society

ORIGINAL ARTICLES

Self-Reported Stress and Risk of Endometrial Cancer: A Prospective Cohort Study

Naja Rod Nielsen, PhD, Katrine Strandberg-Larsen, MS, Morten Grønbæk, MD, PhD, DrMedSci, Tage S. Kristensen, MS, DrMedSci, Peter Schnohr, MD and Zuo-Feng Zhang, MD, PhD

From the National Institute of Public Health (N.R.N., K.S.-L., M.G.), Copenhagen, Denmark; Department of Epidemiology (N.R.N., Z.-F.Z.), UCLA School of Public Health, Los Angeles, California; National Institute of Occupational Health (T.S.K.), Copenhagen, Denmark; Copenhagen City Heart Study (P.S.), Epidemiological Research Unit, Bispebjerg University Hospital, Copenhagen, Denmark.

Address correspondence and reprint requests to Naja Rod Nielsen, National Institute of Public Health, Øster Farimagsgade 5A, 1399 Copenhagen K, Denmark. E-mail: nrn{at}niph.dk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objectives: To assess a possible relationship between perceived stress and first-time incidence of primary endometrial cancer. Psychological stress may affect the synthesis and metabolism of estrogens and thereby be related to risk of endometrial cancer.

Methods: The 6760 women participating in the Copenhagen City Heart Study were asked about their stress level at baseline from 1981 to 1983. These women were prospectively followed up in the Danish nationwide cancer registry until 2000 and <0.1% were lost to follow-up. Cox proportional hazard models were used to analyze data.

Results: During follow-up, 72 women were diagnosed with endometrial cancer. For each increase in stress level on a 7-point stress scale, there was a lower risk of primary endometrial cancer (hazard ratio (HR) = 0.88; 95% confidence interval (CI), 0.76–1.01). This inverse association was particularly strong in women who received hormone therapy (HR = 0.77; 95% CI, 0.61–0.96) and in normal-weight women (HR = 0.73; 95% CI, 0.58–0.91).

Conclusions: Stress may affect gonadal synthesis of estrogens and alter the sensitivity of the uterus toward estrogen stimulation. These mechanisms may explain the lower risk of endometrial cancer observed among stressed women in this study. Despite these results, stress may still be a risk factor for a range of other diseases and should therefore not be considered a healthy response.

Key Words: psychological stress • endometrial neoplasms • prospective studies • estrogens

Abbreviations: HR = hazard ratio; CI = confidence interval; HPG = hypothalamic-pituitary-gonadal; HPA = hypothalamic-pituitary-adrenal; BMI = body mass index


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Endometrialcancer is the fourth most common cancer in Europe and North America (1). Some of the best known risk factors for endometrial cancer are endogenous concentrations of estrogens and exposure to unopposed exogenous estrogens (2). Psychological stress may play a role in endometrial carcinogenesis by affecting synthesis and metabolism of estrogens as well as by decreasing the sensitivity of the uterus toward estrogen stimulation (3–5). Estradiol, which is the most active estrogen metabolite, can bind to the estrogen receptors, activate gene expression, and thereby increase cell proliferation. By this pathway, estrogens may promote the growth of already initiated cells. Some evidence also indicates that estrogens can be metabolized into more reactive intermediates that can, in turn, lead to structural changes in the DNA and thereby act as initiating agents (6). Chronic stress from caregiving has been associated with lower levels of bioavailable estradiol among female nurses (7). If high levels of stress hormones result in lower levels of endogenous estradiol, we would expect psychological stress to lower the incidence of endometrial cancer. A possible relationship between stress and endometrial cancer, however, remains to be studied.

Stress may affect the risk of endometrial and breast cancer through the same hormonal pathway, namely, impairment of estrogen synthesis. Thus, previous studies on the relationship between stress and risk of breast cancer may be relevant for the study of endometrial cancer (8–13). In several large registry linkage studies, major life events such as death of a spouse, divorce, or cancer in a child were not associated with risk of breast cancer (14–18). Some cohort studies have suggested that women exposed to chronic stress in everyday life may be less likely to develop breast cancer than women not exposed to such stress (7,19,20). This is in agreement with the hypothesis that prolonged exposure to stress may impair the estrogen synthesis. In contrast, a higher risk of breast cancer associated with measures of stress has also been reported in some prospective studies (21–24). However, these studies have been smaller than the ones reporting no association or a protective effect. In general, the combined evidence from studies of stress and breast cancer showed no increased or even a decreased risk of breast cancer associated with different measures of stress.

On the other hand, combined evidence from experimental and animal studies have suggested that stress may promote the initiation and progression of cancer by impairment of the elements involved in the immune surveillance of the cell (25). Stress could, by this pathway, potentially increase the risk of cancer. However, cancer is a heterogeneous group of diseases with multiple causes and the involvement of the immune system may therefore depend on the specific cancer in question. In general, endometrial cancer is considered to be an estrogen-dependent disease and we would therefore expect a possible effect of stress on the hormonal system to be more important than the effect of stress on the immune system in this particular study.

We aim to address the association between stress and endometrial cancer in a prospective cohort study including 6760 women prospectively followed up for 18 years. Our hypothesis is that perceived stress may suppress synthesis of and sensitivity toward estrogens and thereby be related to a lower risk of endometrial cancer.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Study Population
The Copenhagen City Heart Study is a longitudinal study initiated in 1976. An age-stratified sample of 19,698 men and women were randomly drawn from the Central Population Registry and invited to participate in the study. A physical examination was performed and participants were asked to complete a questionnaire regarding various risk factors. From 1981 to 1983, the study population was supplemented with 500 men and women, and additional study assessments were performed for both new and continuing study participants. The study participants were asked about their stress level only at the second examination; this information is used as baseline for the present study. The 12,698 women and men participating in the second examination constituted a 70% response proportion; the vast majority of the participants were Caucasians. Of the 12,698 participants in the second examination, 7018 were women. A detailed description of the Copenhagen City Heart Study has previously been published (26). Women with endometrial cancer before baseline (n = 38) or with lacking information on stress (n = 25) or other covariates (n = 195) were excluded, leaving 6760 women for the analyses.

Ethical Approval
The Danish Ethics Committee for the City of Copenhagen and Frederiksberg approved the study (# 01-144/01). All participants gave written informed consent.

Perceived Stress
The study participants were asked about their level of stress in terms of intensity and frequency at baseline from 1981 to 1983. This information was not updated during follow-up, which may in some instances have resulted in several years’ time lag between stress assessment and development of endometrial cancer. In the questionnaire, stress was exemplified as the sensation of tension, nervousness, impatience, anxiety, or sleeplessness and no time frame was specified. "Stress intensity" was reported as: (0) none, (1) light, (2) moderate, or (3) high. "Stress frequency" was reported as: (0) never/hardly ever, (1) monthly, (2) weekly, or (3) daily. To combine the two dimensions of stress intensity and stress frequency, the two questions were added and combined into a 7-point stress score ranging from 0 (indicating low stress) to 6 (indicating high daily stress). For example, if a woman reported moderate, daily stress, she would be given a stress score of 5 (2 points for moderate at the intensity dimension plus 3 points for daily at the frequency dimension).

Covariates
The confounder identification was based on a causal diagram, which included the most current prior knowledge about causal relationships between perceived stress, covariates, and endometrial cancer (Figure 1) (27). This served as a way to visualize and explicitly elaborate the assumptions about the web of causation for the relationship between stress and endometrial cancer and to identify variables that must be measured and controlled to obtain unconfounded estimates. According to the diagram, the analyses were adjusted for the following available covariates: a) age (continuous); b) education (<8 years, 8–11 years, or ≥12 years); c) physical activity in leisure time (none or very little activity; 2–4 hours of light activity per week; >4 hours of light activity or 2–4 hours of high-level activity; and competitional level or >4 hours of hard-level activity per week); d) body mass index (BMI) (continuous); e) tobacco smoking (never-smoker; ex-smoker; smokers of 1–14 g per day, 15–24 g per day, and >24 g per day); f) diabetes mellitus (yes/no); g) number of children (0, 1–2, ≥3); h) menopause (yes/no); and i) hormone therapy (yes/no).


Figure 115
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  		Figure 1. Causal diagram for the relationship between perceived stress and risk of endometrial cancer.

 

Follow-Up
The women were followed from date of the second examination until date of first diagnosis of primary endometrial cancer (n = 72), death (n = 2418), emigration out of Denmark (n = 28), or end of follow-up on December 31, 2000 (n = 4242). Thus, <0.1% were lost to follow-up due to emigration. Using the civil registry number, which is unique to every Danish citizen, primary endometrial cancer events were identified through linkage to the Danish National Cancer Registry, which contains data on all cancer diagnoses in Denmark since 1942. The following International Classification of Diseases 7 codes were used to identify primary invasive endometrial cancer cases: 172.0 to 172.2. The vital status of the women was followed in the Central Death Registry. Information on diagnosis of endometrial cancer has been updated until December 31, 2000, making it possible to follow the women for 17 to 19 years.

Statistical Methods
Data were analyzed by means of Cox proportional hazards models with age as the time variable. Stress intensity, stress frequency, and the combined stress score all met the assumption of proportional hazards. First, we estimated the age-adjusted hazard ratio (HR) of endometrial cancer associated with stress intensity, stress frequency, and the combined stress score in separate models. By including age as the time variable, the estimates were soundly adjusted for confounding by age. Second, a multivariate Cox proportional hazards model was fitted to adjust for potential confounding from baseline covariates. Trend tests were used to test for linear dose-response trends in the associations between stress and endometrial cancer. Third, statistical interactions between stress and all variables included in the multivariate model were addressed and subgroup analyses were conducted for interactions with a p < .20. Thus, subgroup analyses were done for hormone therapy (p for interaction = .08) and BMI (p for interaction = .09). No cases of endometrial cancer occurred among underweight women (BMI ≤18.5), so the analyses were only stratified into normal weight (BMI ≤25) and overweight (BMI >25). Finally, separate analyses for the first and last 9 years of follow-up were done to address the possible effect of prolonged follow-up.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
Baseline Characteristics
Mean age at baseline was 57 years (range 21–91). Ten percent of the women reported high levels of stress (Table 1). Women reporting medium stress were slightly younger and had lower BMI than women reporting both low and high levels of stress. A higher proportion of women who reported high stress used hormone therapy, were current smokers, were physically inactive in their leisure time, and had low education compared with women with lower levels of stress. A lower proportion of highly stressed women were premenopausal and were nulliparous. The percentage with diabetes mellitus was similar at the different stress levels.


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  		TABLE 1. Baseline Characteristics of Women Participating in the Second Examination of the Copenhagen City Heart Study in 1981–1983

 

Perceived Stress and Incidence of Endometrial Cancer
At the end of follow-up, 72 incident cases of primary endometrial cancer had occurred. The adjusted HRs for endometrial cancer were 0.52 (95% confidence interval (CI), 0.26–1.04) and 0.72 (95% CI, 0.28–1.89) for women reporting medium and high stress intensity, respectively, compared with women who did not perceive their life as stressful (Table 2). In terms of stress frequency, women reporting daily stress had an HR of 0.40 (95% CI, 0.14–1.15) compared with women who reported to never experience stress. There seemed to be an inverse dose-response association between stress frequency and risk of endometrial cancer (p for trend = .07). For the combined stress score, the HR for endometrial cancer for each unit increase on the 7-point stress scale was 0.88 (95% CI, 0.76–1.01). Adjustment for potential confounders made the associations slightly stronger.


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  		TABLE 2. First-Time Incidence of Primary Endometrial Cancer Associated With Perceived Stress

 

Stratified Analyses
Fifteen percent (n = 1041) of the women received hormone therapy at baseline and the association between stress and endometrial cancer was only apparent in these women (Table 3). Among the women receiving hormone therapy, stress intensity (p for trend = .06) and stress frequency (p for trend = .01) were both inversely associated with the risk of endometrial cancer, and the HR for primary endometrial cancer was 0.77 (95% CI, 0.61–0.96) for each unit increase in stress level on the 7-point stress scale among these women. No associations between perceived stress and risk of endometrial cancer were observed among women who did not receive hormone therapy.


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  		TABLE 3. First-Time Incidence of Primary Endometrial Cancer Associated With Perceived Stress by Hormone Status at Baseline

 

Among the 4004 women with a BMI of ≤25 kg/m2, there was a clear inverse association between both stress intensity (p for trend = .01) and stress frequency (p for trend = .005) and the risk of endometrial cancer (Table 4). The HR for primary endometrial cancer was 0.73 (95% CI, 0.58–0.91) for each unit increase in stress level on the 7-point stress scale among these women. No clear association between stress and the risk of endometrial cancer was noted among women with a BMI >25 kg/m2.


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  		TABLE 4. First-Time Incidence of Primary Endometrial Cancer Associated With Perceived Stress by Body Mass Index at Baseline

 

No notable effect modification occurred in subgroups of menopausal status, physical activity, smoking, education, and number of children (data not shown). Half the cases of endometrial cancer (n = 36) occurred in the first 9 years of follow-up, whereas the other 36 cases occurred in the last 9 years of follow-up. The association between stress score and endometrial cancer was stronger in the first 9 years (HR = 0.85; 95% CI, 0.70–1.04) compared with the last 9 years (HR = 0.91; 95% CI, 0.75–1.10) of follow-up.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
Among the 6760 women followed up for 18 years, perceived stress seemed to be associated with lower risk of primary endometrial cancer in an inverse dose-response manner. The association was confined to women who received hormone therapy and women of normal weight. No studies have, to our knowledge, previously addressed the relationship between stress and endometrial cancer. Both breast and endometrial cancers are estrogen-dependent cancers with a clear relationship to endogenous concentrations of estrogens (2,28). If stress in fact affects the risk of endometrial cancer through a hormonal pathway, then our results are in accordance with the lower risk of breast cancer previously observed among stressed women in the same cohort (19). Other studies that have addressed the effect of chronic stress, such as that arising from caregiving or from high-strain jobs, have also reported a lower risk of breast cancer among stressed women (7,20). In studies that have applied other measures of stress, such as stressful life events, the results have been more conflicting (8).

Strengths and Weaknesses
The prospective design of the Copenhagen City Heart Study ensured temporality between self-reported stress and incidence of endometrial cancer. Linkage of civil registry numbers to nationwide population-based registers enabled identification of virtually all cases of diagnosed endometrial cancer and allowed for nearly complete long-term follow-up.

How stress is defined and measured remains a point of debate. In this study, stress was defined as an individual state of high arousal and displeasure, sometimes referred to as distress (29). By using a measure of perceived stress, we accounted for the fact that each individual has different capacities and ways to cope with stressful situations (30). Perceived stress was assessed by combining two questions on stress intensity and stress frequency asked at baseline. Because the two questions used as an operational measure of perceived stress are not yet validated against a more extensive scale, such as the Perceived Stress Scale (31), we cannot fully determine the magnitude of the misclassification. A disparity between the ideal and the operational measure may have reduced our ability to address the relationship between perceived stress and endometrial cancer; by using only two measures of stress intensity and stress frequency instead of a more extensive scale, an even stronger relationship between perceived stress and risk of endometrial may have been blurred. However, in a recent study, two single-item measures on stress were found to be just as reliable and valid as three fully validated multi-item measures on perceived stress (32). This may provide some assurance that the single-item measurements used in the present study actually provided reasonable measurements of stress. Perceived stress was only assessed at baseline and may have changed over time in a manner that is most likely independent of subsequent development of endometrial cancer. In another Danish cohort study (33), which included a question on perceived stress, the majority (62%) of the participants reported the same level of stress in 1994 as in 2000 (Nielsen, unpublished data, 2006). Although this finding indicates that a measure of perceived stress may be relatively stable over time, a large minority changed stress levels. The association between stress and risk of endometrial cancer was strongest in the first 9 years compared with the last 9 years of follow-up. This may either be due to changes in stress levels over time and thus exposure misclassification, or it may be due to a differential effect of stress depending on whether it affects the multistage carcinogenesis early as an initiating agent or later as a promoting agent.

Women with breast cancer are often treated with tamoxifen, a nonsteroidal compound with partially estrogenic and anti-estrogenic effects depending on the target tissue. Such treatment seems to increase the risk of second primary endometrial cancer among women with breast cancer (2). Women who had breast cancer before baseline may also report higher levels of stress; thus, confounding from history of breast cancer could arise. However, although 126 of the women included in this study were diagnosed with breast cancer before baseline, none of them developed primary endometrial cancer during follow-up, and confounding from breast cancer history is therefore unlikely.

An inverse association between tobacco smoking and risk of endometrial cancer has previously been reported (34). More women with high levels of stress also engaged in tobacco smoking in this study, which may raise concern about residual confounding from smoking. We carefully adjusted our analyses for smoking in five categories and such adjustment only slightly changed the risk estimates.

We assumed that hypertension was a possible intermediate on the pathway between stress and endometrial cancer. We also assumed that use of oral contraceptives was unrelated to stress. Neither of these variables was therefore included in the statistical analyses. However, it could be argued that these factors may have been associated with stress because of unmeasured confounding and thus should have been included in the analyses. However, adjustment of hypertension and oral contraceptive use did not change the risk estimates (data not shown).

Possible Pathways Between Stress and Endometrial Cancer
A stress-induced distortion of estrogen synthesis may explain the lower incidence of endometrial cancer among women with high levels of stress. The hypothalamic-pituitary-gonadal (HPG) axis regulates the synthesis of estrogens in a normally functioning female reproductive system. Stress can affect the signals of this axis by activating the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Several experimental studies have found that the activation of the HPA axis can inhibit the function of the HPG axis and thereby decrease the synthesis of estrogen (3,5,35–37). Although human evidence is sparse, significantly lower levels of bioavailable estradiol was also found among female caregivers compared with noncaregivers in a recent epidemiologic study (7). These mechanisms may explain the lower risk of endometrial cancer observed among normal-weight women. In overweight women, peripheral conversion of androgens to estrogens in adipose tissue is another important source of estrogens (38). No evidence indicates that stress hormones have an effect on this extra-gonadal synthesis of estrogens. Also, overweight women seem to be in a proinflammatory state that facilitates carcinogenesis by creating an environment susceptible to tumor initiation and promotion as well as increased estrogen production (39). This may counteract the stress-induced suppression of estrogens and thus explain the less pronounced effect of stress on endometrial cancer among overweight women. Because of the long delay between the development and the detection of the disease and the fact that we were only able to follow the study participants in registries, we cannot determine if stress, through its effect on estrogen synthesis and metabolism, hinders initiating and/or interrupts promotion of already initiated cells.

Experimental evidence shows that stress may also produce a direct effect on the uterus by changing the response of its structures toward estrogen (40–42). It is well known that unopposed estrogens increase the proliferative activity of uterine tissues as well as lead to morphogenetic changes, which may increase the risk of developing tumors in these tissues. Chronic exposure to glucocorticoids, which is a major end point in a physiologic stress response, has been shown to produce a complex anti-estrogenic effect in the uterus of mice by turning the estrogen-dependent changes from the direction of precancerous, atypical hyperplasia formation to the more favorable development of simple and cystic hyperplasia (40). Acute stress and administration of glucocorticoids in doses normally experienced during a stress response have both been reported to decrease the uterus’s sensitivity toward estrogen stimulation and decrease estrogen receptor concentration in ovariectomized rats treated with estrogen (41,42). In these studies, the effects of stress on the uterine structures depended on the presence of estrogens. The majority of the women in the Copenhagen City Heart Study were postmenopausal at baseline and therefore had a relatively low ovarian synthesis of estrogens. If the effect of stress on the sensitivity of the uterine structures to estrogens depends on the presence of estrogen, then it may explain the stronger effect of stress observed among women receiving hormone therapy in the present study.

In conclusion, this is the first prospective cohort study to address an association between stress and endometrial cancer. Perceived stress seemed to be associated with a lower incidence of endometrial cancer in women receiving hormone therapy and in women of normal weight. These results are biologically plausible and are in agreement with the lower risk of breast cancer previously observed in the same cohort.

We thank the staff and the participants of the Copenhagen City Heart Study.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 
Received for publication January 30, 2006; revision received November 1, 2006.

This study was supported by the Health Insurance Foundation and the Lundbeck Foundation.

DOI:10.1097/PSY.0b013e31804301d3


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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N. R. Nielsen, T. S. Kristensen, P. Schnohr, and M. Gronbaek
Perceived Stress and Cause-specific Mortality among Men and Women: Results from a Prospective Cohort Study
Am. J. Epidemiol., September 1, 2008; 168(5): 481 - 491.
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