In this large prospective cohort of women, long-term coffee consumption with 4 or more cups per day was associated with 25% lower risk of endometrial cancer compared to less than 1 cup of coffee, although fewer than 4 cups of coffee per day were not associated with endometrial cancer risk. Tea consumption was not associated with endometrial cancer risk.
There is some biologic evidence that coffee might reduce the development of endometrial cancer. Coffee is a primary dietary source of caffeine, and also contains many other biologically active components. Chlorogenic acid has relatively strong antioxidant properties that can prevent oxidative DNA damage and improves insulin resistance by increasing insulin sensitivity or inhibiting glucose absorption in the intestine (31
). Caffeine has been shown to up-regulate hepatic expression of CYP1A2, which can catalyze oxidation of estradiol to 2-hydroxyestradiol, which subsequently yields 2-methoxyestradiol, a metabolite with possible anti-tumorigenic properties (32
). We previously found lower C-peptide concentrations with high caffeinated (≥ 4 cups/d) and decaffeinated (≥ 1 cup/d) coffee intake, but not tea, especially among overweight-obese women (11
), and higher SHBG levels with high caffeinated coffee (≥ 4 cups/d) or caffeine (> 371 mg/d) intake among postmenopausal women, which was somewhat stronger among overweight-obese women (13
). Therefore, coffee may have contributed to a decreased risk of endometrial carcinogenesis due to the potential ability to lower concentrations of insulin and free estradiol in addition to the antioxidant ability of phenolic compounds in coffee.
The inverse association between coffee consumption and endometrial cancer risk in the present study agrees with two recent prospective cohort studies in Japan and Sweden (15
), and four case-control studies (17
). A small prospective study including 117 cases of endometrial cancer in Japan found a RR of 0.38 for 3 or more cups of coffee per day vs. 2 cups or less per week (15
). A large Swedish cohort study found a RR of 0.75 for 4 or more cups of coffee per day vs. 1 cup or less per day, using baseline intake (16
). Four case-control studies (18
) and two cohort studies in Norway (39
) and Sweden (40
) reported a non-significant inverse association, while two case-control studies in Europe (41
) reported a non-significant positive association.
Only two case-control studies assessed the relationship between decaffeinated coffee and risk of endometrial cancer, and found no association (18
). We found a non-significant inverse association with decaffeinated coffee intake of ≥ 2 cups/d. Due to a narrower range of intake and shorter term use of decaffeinated coffee compared to caffeinated coffee in our cohort, we may have been underpowered to detect a significant association with decaffeinated coffee intake. Only less than 2 % of the population in our cohort consumed decaffeinated coffee of ≥ 4 cups/d. The recent case-control study from Japan where coffee is not the major source of caffeine showed a significant inverse association with ≥ 3 cups/d of coffee, but not with total caffeine intake, for endometrial cancer, suggesting potential benefits of other coffee components (17
). This inference was consistent with the null association with tea intake in the present study, which is another source of caffeine, although we cannot rule out the possibilities that some of tea components negate the potential benefits of caffeine in tea or that the amount of caffeine in tea is too small to observe an effect.
In subgroup analyses, we found a stronger inverse association with high coffee intake among obese women, which was consistent with findings in the Swedish cohort study (16
). Since obese women tend to have insulin resistance, oxidative stress, and relatively low levels of SHBG (2
), the potential abilities of coffee to improve those conditions may have contributed to a decreased risk of endometrial cancer among obese women (11
). We also found a stronger inverse association with high coffee intake among ever smokers. Cigarette smoke has been shown to stimulate the synthesis of CYP1A2 as caffeine in coffee does (43
). It is possible that caffeine intake in the presence of cigarette smoking substantially enhances CYP1A2 activity, thereby increasing clearance of estradiol (44
). No previous studies examined the possibility of caffeine as an interacting factor by smoking status, so the results should be interpreted with caution. The inverse association with higher coffee intake among postmenopausal women, but not premenopausal women, was similar for ovarian and breast cancer (46
). The hormonal modulation of coffee on endometrium appears to be notable for women who have naturally low estrogen levels (i.e., postmenopausal women) or those who are not using postmenopausal hormone currently.
To our knowledge, this is the largest prospective cohort study that has evaluated coffee and tea consumption using repeated dietary questionnaires, and the first cohort study to examine the long-term intake of decaffeinated coffee on risk of endometrial cancer. Using the cumulative average intake can more precisely estimate the long-term intake and reduce within-person variation. Although the use of repeated measures of coffee and tea consumption can minimize exposure misclassification, some measurement error in the dietary assessment may still have occurred due to self-reported intake and between-person variation in cup size and strength of the coffee brew. However, coffee and tea consumption assessed by questionnaires has been shown to be valid and reproducible, and any remaining misclassification would have likely biased the results toward the null (25
). We carefully controlled for potential confounders in the analysis, but we cannot rule out the possibility of residual confounding. Unmeasured factors associated with coffee drinking habit may also have influenced our results. However, the factors are likely to be related to unhealthy lifestyles rather than healthy lifestyles, which make the observed association more inverse after adjusting for the factors. For example, we did not have information on substances added to coffee. Adding substantial amounts of sugar and cream to the coffee, which could contribute to insulin resistance or weight gain, may negate the potential beneficial role of coffee in relation to endometrial cancer risk. Due to the relatively small number of cases among premenopausal women in our cohort, we may have been underpowered to examine the effect modifying potential of menopausal status, for the risk of endometrial cancer. A narrow range of decaffeinated coffee compared to caffeinated coffee in our cohort limited the possibility to observe an association with higher decaffeinated coffee intake. All of the findings were limited by the fact that most coffee consumption was of the caffeinated variety and most caffeine came from coffee in our cohort. However, the findings of a nonsignificant modest inverse association with 2 or more cups of decaffeinated coffee intake and lack of association with caffeine-containing tea consumption may suggest the importance of coffee components against endometrial cancer.
In conclusion, our findings provide prospective evidence with the potential beneficial role of 4 or more cups of coffee per day against endometrial cancer risk. However, recommendations about high coffee consumption should be made with caution. Since our population is relatively health conscious, and thus may tend not to add substantial sugar and cream, the results of risk reduction with 4 cups of coffee per day may not be generalizable to coffee drinkers who typically add sugar or cream to coffee.