The present population-based case-control study is one of only a few studies that assessed endometrial cancer risk in relation to lifetime physical activity from multiple sources. Greater total lifetime physical activity was associated with a 39% risk reduction, which is consistent with an average risk reduction of about 30% found in other studies that assessed total physical activity (1
). Our findings further suggest that overweight and obese women may derive the greatest benefit from physical activity, although differences between the subgroups did not reach statistical significance in the present study.
The consideration of all sources of physical activity throughout life likely reduced misclassification bias. For example, non-exercisers may have physical activity from other sources, and thus may not truly be sedentary. As in most other studies, we relied on recall of physical activity and did not measure sedentary activities, which may have introduced some measurement error, particularly since we assessed lifetime history of physical activity. Given that both cohort and case-control studies have reported inverse associations of similar magnitude (average of 23% and 29%, respectively, comparing the most active to the least active women (2
)), it is unlikely that the risk reduction observed in this study, as well as other case-control studies, is solely due to differential recall by cases and controls.
Since few studies assessed lifetime history of physical activity, data are sparse on the effects of physical activity in different life periods. Our findings suggest that physical activity throughout adult life is important, with risk reductions of similar magnitude for physical activity during the reproductive years, older adulthood, and the 10 year period prior to diagnosis. A recent review concluded that recent activity and lifetime activity may be more important than activity in the distant past (3
). We also found no evidence that physical activity at ages 10–19 years was associated with endometrial cancer risk, although we cannot exclude the possibility that physical activity in the distant past may be recalled with less accuracy than recent activity.
When we classified reported activities according to intensity, we found a highly significant inverse trend for moderate activities, with a risk reduction of 56% associated with the highest level of moderate activity. Similarly, other studies reported inverse associations for light to moderate activities such as household activities (23
), regular walking and light gardening (8
), and walking for transportation (11
). This finding is important as moderate activities, particularly at a later age, are easier to adopt and maintain than strenuous activities.
Given that obesity is a strong risk factor for endometrial cancer and correlated with physical inactivity, we adjusted the analyses for the effect of BMI, and through stratified analyses we explored whether BMI has a modifying effect on the inverse association with physical activity. Consistent with other studies (2
), we found that adjustment for BMI and other risk factors only slightly attenuated the inverse associations, and as some other studies have reported (10
), we found inverse associations with physical activity more pronounced in overweight and obese women. Among obese control women, those who were active (≥65.1 lifetime MET-hours/week) had a lower median BMI (33.8) than those who were inactive (34.7). This finding minimizes the possibility that the inverse association with physical activity observed in obese women was solely due to inaccurate reporting. Given the limited sample size in most studies, including ours, larger studies will be needed to assess the modifying effects of BMI with greater precision before firm conclusions can be drawn.
Endometrial cancer risk is strongly associated with an estrogen:progesterone ratio which is skewed towards elevated estrogen levels; this can result from either an absolute progesterone deficit or an estrogen excess (35
). Our findings are consistent with the hypothesis that physical activity may reduce endometrial cancer risk by lowering exposure to estrogen, either directly or through lowering excess adipose tissue (36
). Several cross-sectional studies in postmenopausal women reported lower estrogen levels in physically active women which was independent of body weight (37
), and a recent intervention study demonstrated that moderate exercise leading to loss in body fat reduced circulating estrogen levels (40
). It has also been suggested that even in the absence of weight loss, physical activity may improve insulin sensitivity and affect bioavailable estrogen (14
). Other biologic mechanisms may involve effects on inflammation and immune function (3
In conclusion, the present results add to the growing epidemiologic evidence that physical activity is an important modifiable lifestyle factor impacting the development of endometrial cancer. Given that few risk factors identified to date are potentially modifiable, the findings of this study are of direct public health relevance. Current US guidelines for adults recommend 2.5 hours per week of moderate-intensity physical activity, with additional health benefits conferred by 5 hours per week of moderate activity (41
). This level of activity roughly corresponds to the ≥6.9 hours per week of moderate activity that was associated with decreased endometrial cancer risk in the present study. Increases in physical activity are likely to decrease obesity, which has been estimated to account for half of all endometrial cancer cases (42
), thereby lowering the incidence of endometrial cancer.