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 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. HR = hazard ratio; CI = confidence interval; HPG = hypothalamic- pituitary-gonadal; HPA = hypothalamic-pituitary-adrenal; BMI = body mass index. INTRODUCTION E ndometrial cancer is the fourth most common cancer in Europe and North America (1). Some of the best known risk factors for endometrial cancer are endogenous concentra- tions of estrogens and exposure to unopposed exogenous estrogens (2). Psychological stress may play a role in endo- metrial 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 interme- diates 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 bioavail- able 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 reg- istry 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 sug- gested 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 differ- ent 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 ques- tion. 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 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 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@niph.dk 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 383 Psychosomatic Medicine 69:383–389 (2007) 0033-3174/07/6904-0383 Copyright © 2007 by the American Psychosomatic Society