Our findings show that MV PA, two to five years before diagnosis, is significantly associated with a lower risk of endometrial cancer even after adjustment for BMI and other endometrial cancer risk factors. Although there was a stronger association among postmenopausal women, there were too few women in the premenopausal group to make conclusions about stratified associations. Risk reduction when comparing women who perform MV PA to sedentary women persisted across both normal weight and overweight women, suggesting that benefit from MV PA is not limited to a single weight group. Even though there was attenuation of the odds ratio with inclusion of BMI (), the association between physical activity and endometrial cancer persisted in various models, both without and with adjustment for other predictors and confounders. This persistent association suggests that the benefit of PA on risk of endometrial cancer is not completely mediated through effects on BMI.
These findings are consistent with previous publications and meta-analyses linking physical activity to endometrial cancer risk reductions between 20 and 50%. The published null results may be explained in part by low case numbers (n
< 50) [9
]. Another null study was based in a highly active Chinese population where few participants were sedentary until late in life (30). An interaction between MV PA and BMI was not observed, and only limited studies have previously examined the combined association of MV PA and BMI on risk or odds of endometrial cancer [15
]. This study also confirms previous findings showing an association between sit time and endometrial cancer [17
Mechanisms thought to explain the relationship between endometrial cancer risk and physical activity largely relate to sex hormone and insulin pathways. Physical activity reduces serum levels of estradiol and increases levels of its binding protein, sex hormone–binding globulin (SHBG) [5
]. Increased physical activity levels are related to lower insulin levels [32
] and improved insulin sensitivity [33
], which lowers exposure to hormones and growth factors available in the blood. Increased physical activity has also been shown to improve free radical defenses by upregulating free scavenger enzymes and antioxidant levels [34
]. Exercise is also linked with an increase in antitumor immune defenses and improvements in antioxidant defense systems, increasing the number and activity of macrophages, lymphokine-activated killer cells and regulating cytokines [35
]. A 2002 paper on etiological evidence and biological mechanisms relating physical activity to cancer outcomes suggested a decrease in percent body fat as the major biological factor [36
One recently published study found a significant association between daily sitting time and increased risk for cardiovascular disease and overall mortality [37
]. Other studies have linked television viewing to higher risks of obesity [38
], metabolic syndrome [39
], and type II diabetes (38), independent of physical activity levels. A previous study looking at occupational sit time in relation to risk of endometrial cancer showed null results overall and an odds ratio of 0.64 (95% CI 0.42–0.99) comparing quartiles of postmenopausal women who sit more to those who sit less [15
]. However, job codes were used to estimate sit time in the null study and may not have been accurate for this purpose. Another recently published study found a 42% increase in endometrial cancer risk (95% CI (1.06–1.90), p
trend = 0.009) among those with the highest levels of lifetime occupational sit time [24
Limitations of this study include the possibility that the interviewer-administered questionnaires were subject to differential recall by case or control status. This could increase the magnitude of the observed difference in risk between groups. Weight data were collected by self-report and may be subject to underreporting. Subjects also might over-report physical activity levels due to social desirability bias. Also, the MAQ was validated for activity within the past year and not two to five years prior and thus may be slightly less valid. However, only MV PA was included in the analysis, and this may be easier to recall then low-intensity activities such as household work. Furthermore, the magnitudes of association for MV PA were similar to those observed in other case–control and cohort studies, strengthening the body of evidence surrounding the relationship between physical activity and endometrial cancer. Response rates were low as only 54.9% of cases and 64.5% of controls approached were enrolled in the study. Exclusion of very ill women could result in selection bias. Only 1.1% of the women refusing to participate did so because they were too ill, although it is possible that physicians may not have given consent to contact for patients in poor health. These biases may overestimate the association between physical activity and risk of endometrial cancer.
Strengths of our study include the use of validated and detailed physical activity measurements. Our questionnaire measured 29 different types of physical activities and was used to isolate those activities that were moderate to vigorous intensity. Moderate to vigorous intensity activity is supported in the literature as it is believed to reduce risk of some types of cancer [41
]. Also, timing of physical activity was explored, and measurements from two to five years in the past were used in attempt to lessen the possibility of overt disease or preclinical symptoms among cases that could affect activity levels. Physical activity levels in the years preceding diagnosis would affect unopposed estrogen levels and could be an etiologically relevant time period for onset of endometrial cancer, although the timing of exposure to protective factors for endometrial cancer is still under debate. Our data showing a null relationship between activities at ages 30–39 may be due to poor recall of activity levels or could imply that earlier exercise is not associated with endometrial cancer risk. Household and occupational activity has also been linked to lower endometrial cancer risk, but measurement estimates of expenditure are imprecise [15
]. Our study was population based, making results more generalizable than hospital or other population-specific groups.
Endometrial cancer is currently the fourth most common cancer among women [43
], and as obesity rates in the United States and worldwide continue to rise, endometrial cancer incidence will likely increase. A study based in the American Cancer Society Cancer Prevention cohort of over 900,000 individuals showed that among endometrial cancer patients, those with a BMI of above 25 had an increased risk of mortality compared with those who were normal weight [44
]. Women with a BMI of 40 had a 6.25-fold increase in mortality rate (95% CI 3.75–10.42). Data from the 2007–2008 NHANES report show that 68% the US population is overweight or obese [45
]. In 2007, the Centers for Disease Control and Prevention found that 24.1% of the US population reported no leisure-time physical activity, and 48.8% were not meeting recommended levels of physical activity [46
]. Given the current combination of high BMI and low activity among the population, endometrial cancer risk is an appreciable concern. Future studies need to consider how to increase physical activity in women at risk of developing endometrial cancer. Public health programs should be designed to promote exercise programs as an important intervention to minimize burden of both this disease and other weight-related health complications such as heart disease, diabetes, and hypertension. A randomized controlled trial on surrogate markers of risk or survival could be performed to further examine the relationship between endometrial cancer and physical activity, since to date all published studies on this relationship have been observational.