Our population-based study of the relationship of major phytoestrogens, including detailed analyses of lignan consumption, with endometrial cancer risk, suggested an inverse association with quercetin intake and with consumption of isoflavones in lean women. There was little evidence of an association with any of the lignans considered or with total lignan intake. Further exploration of the association with the major food sources of isoflavones in this population suggested an inverse association with tofu intake. However, the relationship disappeared after covariates such as physical activity, smoking, and fat and fiber intakes were taken into account.
To our knowledge, the role of phytoestrogen consumption on endometrial cancer risk has been evaluated in only two additional case-control studies. Horn-Ross et al. [9
] evaluated the association between several phytoestrogens and endometrial cancer risk in a population-based case-control study (500 cases and 470 controls) among non-Asian women in the San Francisco Bay Area. As in our study, there was little evidence of an association between phytoestrogen intake and endometrial cancer risk. The other case-control study evaluating the association was a population-based study in China with 832 cases and 842 controls [10
]. This study focused more on the evaluation of soy foods, but reported on isoflavone consumption and endometrial cancer risk, with similar results to our study. Adjusted ORs for the highest quartile of intake compared to lowest was 0.77 (95% CI: 0.56–1.05; p for trend 0.05) in the study in China and 0.80 (95% CI: 0.50–1.27; p for trend: 0.29) in our study.
Other epidemiologic studies have focused on the role of foods high in phytoestrogens. Goodman et al. [12
] reported inverse associations for tofu, soy products, whole grains, vegetables, fruits, beer, and seaweed in a population-based case-control study in Hawaii. Conceivably, the benefits of consuming these foods may be unrelated to their phytoestrogen content. Furthermore, although the interest in phytoestrogens as anticarcinogenic agents is based primarily on their potential hormonal effects, there is increasing evidence that other non-hormonal mechanisms may be involved, particularly for soy foods. These isoflavonoid compounds may not only influence estrogen metabolism, but may also have antioxidant and antiangiogenesis effects, and may influence signal transduction and inhibit the action of DNA topoisomerases [8
]. The study by Xu et al. [10
] mentioned above, suggested an inverse association for soy food fiber and soy protein, but little evidence of an association for major sources of phytoestrogen such as soy milk and tofu. A meta-analysis [18
] of four case-control studies reporting on tofu and endometrial cancer [10
] estimated a summary risk estimate of 0.73 (95% CI: 0.57–0.94) for the highest vs. the lowest category of intake reported. This meta-analysis also estimated an OR of 0.88 (95% CI: 0.78–1.00) per 25 g./day of tofu intake based on the results of three case-control studies [10
]. Our continuous analysis offered little support for an association with tofu intake at this low level of intake, with an OR of 0.96 per 25 g/day of tofu (95% CI: 0.36–2.54) using a similar model as the studies included in the meta-analysis.
We found the inverse association with isoflavone intake limited to lean women (p for interaction= 0.047), while other studies found a stronger inverse association for the highest category of BMI with isoflavone consumption [9
], soy protein consumption [10
], or soy product consumption [12
]. The interaction in these other studies was not statistically significant and, therefore, additional evidence is needed before conclusions can be drawn regarding possible effect modification by BMI.
A possible alternative explanation to consider in the interpretation of the findings is confounding by other factors that have been shown to affect endometrial cancer risk. For example, it is possible that consumption of phytoestrogens and soy foods is more common among more health conscious women, who may avoid smoking, high fat foods, and consume high-fiber foods, and exercise more. Smoking [21
], fiber intake [18
], and physical activity [18
] have been shown to decrease endometrial cancer risk, whereas fat intake may increase risk [24
]. An inverse association between alcohol consumption and endometrial cancer has also been reported [25
]. To rule out these confounding effects, we further adjusted our risk estimates for phytoestrogens for these variables. Further adjustment for these variables seemed to have an impact in our risk estimate associated with tofu intake, but not for isoflavones or quercetin intakes.
The response rate in our study was low. Response rates in epidemiologic studies have been declining over the past 30 years and low response rates are now common in epidemiologic studies [26
]. Participation rates around 50% in population-based studies are not unusual in recent studies, particularly among controls [27
]. It is also well known that participants tend to be more educated and healthier than non-participants [26
]. In our study, for cases, we were able to compare those who participated to all women diagnosed with endometrial cancer in these counties in this time period. The cases included were younger and more likely to have localized disease. The mean age of those included was 61.7 yrs., compared to 63.6 yrs. in all women. About 81% of the women included in our study had SEER summary stage classified as localized, compared to 70% in all eligible cases. For controls, we unfortunately do not have any information on those who could not be reached or who refused to participate. We are reassured by the distribution of characteristics that are established risk factors for the disease (e.g., BMI) among cases and controls, with odds ratios for these factors (shown in ) being similar to those reported in the literature, with the exception of estrogen replacement therapy. However, only 8% of cases and controls used ERT, and when we repeated our analyses with phytoestrogens excluding unopposed estrogen users, our results did not change. Furthermore, non-response bias would only affect study validity if willingness to participate is related to the factors under evaluation [26
]. This is unlikely because the possible role of dietary factors in the etiology of endometrial cancer is not well known, and even less so that of phytoestrogens and soy foods. Also, the fact that our results are in agreement with the current literature provides further reassurance.
Given the popular use of alternative therapies to relieve menopausal symptoms, and the potential effects of phytoestrogens on the endometrium, we asked women questions about the use of phytoestrogen or soy supplements (pills and powders). However, the use of these supplements was rare in this population, and the few women who used them, did so very infrequently. Therefore, we were unable to assess whether the use of phytoestrogen supplements has any impact on endometrial cancer risk. Randomized controlled clinical trials have offered inconsistent results on the effect of isoflavones on menopausal symptoms, and little evidence of an impact on endometrial thickness (reviewed by Murray et al.[28
]). However, these studies were generally based on small numbers and short-term interventions. Therefore, the impact, either detrimental or beneficial, of isoflavone supplementation on the endometrium and endometrial cancer risk remains uncertain.
Studies of phytoestrogens confront not only the usual difficulties in accurately measuring dietary intake, but also the high inter- and intra-individual differences in phytoestrogen metabolism due to a variety of factors ranging from the use of antibiotics, intestinal transit time, gut microflora, and genetic polymorphisms [3
]. Furthermore, food sources of phytoestrogens may vary in different populations, making international comparisons difficult. As expected, isoflavone intake levels were very low in our population. On the other hand, lignan consumption levels were higher than in the only other study evaluating lignans and endometrial cancer risk [9
]. Although our study provided little evidence of a major role of phytoestrogens on endometrial cancer risk, further studies are needed, particularly prospective studies, in populations with a wider range of isoflavone intake, as may be typical in Asian populations.
Another issue to consider in evaluating results is the fact that, while phytoestrogens are capable of binding to two types of estrogen receptors (ER), ER alpha and ER beta, they have been shown to preferentially bind to ER beta, whereas the endometrium contains mostly ER alpha [29
]. This may explain the limited evidence found showing an effect for phytoestrogen supplementation on endometrial thickness [28
], endometrial hyperplasia [28
], or endometrial cancer [9
To our knowledge our study is the first epidemiologic study to evaluate the role of quercetin on endometrial cancer risk. The flavonoid quercetin is found in many foods, including vegetables, fruits, tea, wine, but is particularly high in onions, apples, and green tea [31
]. Although included in the phytoestrogen group [7
], quercetin is well-known for its strong antioxidant and anti-inflammatory activities [31
]. There is some epidemiologic evidence showing beneficial effects of quercetin intake on cancers of the lung [32
], colon and rectum [34
], stomach [35
], and prostate [36
]. However, other studies failed to find an association with breast [37
], ovarian [38
], and colorectal cancers [39
]. Although our findings will have to be confirmed by other studies, our results contribute to the epidemiologic literature of quercetin intake and cancer risk, by supporting beneficial effects for endometrial cancer.
In summary, our study provided little evidence that phytoestrogen consumption, at the levels consumed in non-Asian populations, had an impact on endometrial cancer risk. However, it does not rule out a possible effect at higher levels of consumption. The possible effect modification by body size and adiposity needs further evaluation. Our results suggest that diets high in quercetin may favor a reduction in endometrial cancer risk. Overall, the currently available evidence is too limited to draw any conclusions on the role of phytoestrogens and soy foods on endometrial cancer risk.