In this study, in a large multiethnic cohort of women from the MEC Study who were followed for a median period of 13.6 years, we found a lower risk of endometrial cancer among postmenopausal women with the highest intakes of total isoflavones, daidzein, and genistein. Associations remained after controlling for established endometrial cancer risk factors and for dietary factors related with total soy and isoflavone consumption. Although point estimates for total soy and tofu were in the direction of a decreased risk for the highest consumers of these foods, no statistically significant associations were detected for any particular soy-based food item or for the individual food items that had the greatest contributions to total isoflavone intake. Associations between endometrial cancer risk and soy and isoflavone intake were attenuated when examined as absolute intakes; however, this attenuation was considered a reflection of the confounding effects of energy intake when not accounting for isoflavone exposure relative to total calories. The non-statistically significant association of isoflavones with endometrial cancer risk in racial or ethnic stratified models likely resulted from the loss of statistical power, as no racial or ethnic heterogeneity was detected for the associations between diet and endometrial cancer in the total study sample. To the best of our knowledge, these findings represent the first published prospective analysis to examine the role of soy and isoflavone consumption on the risk of endometrial cancer.
Several case–control studies have examined the association of legumes and soy products with the risk of endometrial cancer. In an earlier population-based case–control study conducted in Hawaii (13
), we found a decreased risk of endometrial cancer among participants in the top quartile of soy products (odds ratio [OR] = 0.46, 95% CI = 0.26 to 0.83), tofu (OR = 0.53, 95% CI = 0.30 to 0.94), and legume intake (OR = 0.51, 95% CI = 0.31to 0.86) compared with participants in the bottom quartile. Similarly, a population-based case–control study conducted among women residing in Shanghai (14
) showed a reduction in risk in the top quartile of total soy protein intake compared with the bottom quartile (OR = 0.67, 95% CI = 0.48 to 0.92); however, no association was observed for tofu, soy milk, or processed soy products alone. Legumes were later reported to be associated with a decreased risk of this cancer in this same Shanghai population (15
). Despite the previous supportive evidence from case–control studies in Asian or largely Asian populations, the only previous prospective dietary study on this topic was conducted in a population of mostly white women followed for approximately 10 years (18
), which failed to detect an association between legume intake and endometrial cancer risk.
For isoflavones thought to mediate the potential protection from soy foods, our findings suggesting an inverse association with the risk of endometrial cancer are in contrast to three previous null reports. In population-based case–control studies conducted in the San Francisco Bay area (16
), New Jersey (17
), and Shanghai (14
), no associations were detected for total isoflavones or the specific isoflavones, daidzein, and genistein. Reasons for the inconsistencies between our findings and previous reports could be because of several factors. First, the consumption of soy foods and isoflavones in previous US-based samples may have been insufficient to observe an effect. We found an association for total isoflavones from foods only at intakes 7.82 mg per 1000 kcal/d or higher, approximately 11 times higher than the estimated US average of 0.7 mg per 1000 kcal/d (27
). Second, isoflavone measurements from food sources show considerable variation (28
), potentially leading to differences in food composition databases and varying degrees of measurement and misclassification error across studies. Third, total soy in our study was measured using only items on miso, tofu, and vegetarian meats allowing for some misclassification and the potential to attenuate associations for these exposures. Fourth, potential recall biases in case–control studies may have influenced previous estimates.
One potential mechanism by which isoflavones may lower the risk of endometrial cancer is through their binding affinity for the α and β estrogen receptors (10
), thereby limiting the proliferative effects of circulating estrogens. In vivo, daidzein and genistein have been shown to possess a high binding affinity for estrogen receptors α and β (29
), which may explain the associations observed for these isoflavones but not glycitein, in this study. As isoflavones in general are weak phytoestrogens, it is of substantial scientific interest whether their association with endometrial cancer risk in the MEC varied according to differences in an individual's lifetime estrogen exposure. Future analyses allowing for a longer follow-up period and accrual of additional endometrial cancers will provide the opportunity to more explicitly examine these relations. In addition, the inverse association of isoflavone consumption with endometrial cancer risk may be limited to critical exposure periods, as isoflavones have been found to act as estrogen antagonists in vitro at normal premenopausal estradiol concentrations, but possess additive agonistic effects at levels commonly observed in postmenopausal women (10
). Studies assessing soy and isoflavone intake in the entire lifespan are required to specifically address this issue.
We estimated that approximately 27% of the incident endometrial cancers in this multiethnic cohort of nonhysterectomized postmenopausal women may have been prevented if all women had consumed 7.82 mg per 1000 kcal/d or higher levels of total isoflavones. Although this counterfactual exposure scenario represents a rather large relative increase in intake from the current US average (27
), a single cup (243 g) of soy milk provides approximately 23 mg of total isoflavones. As such, a single daily serving of soy milk would be more than sufficient to achieve this level of intake for a reference 2000 kcal diet. Should further research support the advisability of increasing isoflavone intake to this level among all US women, based on these estimates, the implementation of such a recommendation could have an appreciable impact on the 43
470 cancers of the uterine corpus diagnosed annually (2
We found a lower risk of endometrial cancer among postmenopausal women with greater exposure of total isoflavones, daidzein, and genistein but not for greater exposure of soy foods or increased consumption of individual food items contributing to total isoflavone levels. One possible explanation for this finding is that a large proportion of isoflavones in the diets of older non-Asian women in the United States has been shown to come from food sources, such as soy proteins added to commercial baked goods, and through the consumption of foods with low to moderate isoflavone concentrations, such as coffee and orange juice, which are frequently consumed, rather than from traditional soy-based foods (31
). Similar findings were obtained for women in this study, with the majority of total isoflavones consumed through nontraditional soy-based foods among African American, Latina, and white women; however, greater than 82% of total isoflavones among Japanese American women were reported to have been consumed in the form of tofu or miso soup. Thus, even for Japanese Americans, the isoflavone contribution from any single food item, as measured by the QFFQ, appeared insufficient to demonstrate an independent association with endometrial cancer risk at levels detectable in our sample.
Our study has several strengths. These include the prospective design and prediagnostic assessment of diet, wide range of soy and isoflavone intake, detailed nutritional database used to obtain dietary estimates, and ability to statistically control for potential confounding by endometrial cancer risk factors or by correlated dietary and lifestyle behaviors.
There are also potential limitations in this study. First, total isoflavone intake was calculated using only daidzein, genistein, and glycitein and did not include values for isoflavones with smaller contributions to total isoflavone intake including biochanin A and formononetin. Second, only baseline data on hysterectomy status was available. Hysterectomies among controls during the follow-up period would reduce the number of person-years at risk, but this possibility is remote. Third, the large variation in soy and isoflavone intake across racial or ethnic groups may have led to insufficient overlap across levels of exposure and potential residual confounding in some models. In addition, a slightly higher proportion of Latinas and African American women were excluded from this analysis largely because of the higher prevalence of hysterectomies in this population. As the distributions of endometrial cancer risk factors were similar among women retained and excluded from the analysis, and no statistically significant racial or ethnic heterogeneity in the associations of dietary exposures with the risk of endometrial cancer were observed, these exclusions were unlikely to have had an appreciable impact on the study results. Fourth, these findings are based solely on baseline data and therefore cannot provide information regarding changes in dietary intake over time. Fifth, in spite of the inherent measurement error in the QFFQ, we had reasonable statistical power to detect the inverse associations found between isoflavone intake and endometrial cancer risk in the MEC. However, we were less optimally powered to detect endometrial cancer risks associated with episodically eaten soy-based foods. The minimum detectable relative risk in our study for the fifth quintile was 0.62 for soy products compared with the observed relative risk of 0.76, and the relative risk was 0.70 for tofu compared with the observed relative risk of 0.79 (); the corresponding minimum detectable relative risks accounting for potential measurement error in the QFFQ were 0.51 and 0.60 for soy and tofu, respectively.
In conclusion, results of this study suggest that higher intakes of total isoflavones, daidzein, and genistein may be associated with a reduced risk of endometrial cancer in postmenopausal women; however, risk estimates were not examined for dietary intakes obtained from isolated soy or isoflavone products, and the potential for detrimental effects arising from excessive intakes obtained through nonfood sources cannot be ruled out on the basis of this study. Additional prospective investigations in cohorts of women consuming a diverse range of these dietary exposures are needed to confirm the findings obtained in the MEC. As our estimates of dietary intake may partially reflect habitual exposure to isoflavones and soy-based foods consumed at moderate levels throughout life, additional studies examining changes in dietary patterns in adulthood are needed to determine whether dietary interventions among life-long low soy consumers may have an influence on subsequent disease risk. Collectively, these results provide support for a role of dietary isoflavones in the etiology of endometrial cancer and underscore the importance of exposure diversity in future confirmatory analyses.