In this large prospective cohort study, we found no associations between total fruit and vegetable intake or intake of specific botanical groups and risk of endometrial cancer. Total fruit intake and intake of bananas and cruciferous vegetables showed modest positive associations with disease; however, there was no clear trend over quintiles or deciles. Additionally, analyses stratified by age, body mass index, hormone therapy, smoking status, and physical activity did not reveal any clear associations or trends of total fruit and vegetable intake, total fruit intake, or total vegetable intake with risk of endometrial cancer.
Previous studies that have examined fruit and vegetable intake in relation to endometrial cancer risk have been largely case-control studies (23
). These studies have varied in sample size, the population studied, the extent of dietary information collected, the type of analysis conducted, the presentation of results, and in their findings. Furthermore, they have presented their results in terms of total intake of fruits and vegetables, intake of specific groups of fruits and vegetables (e.g. cruciferous vegetables; legumes; dark-green, leafy vegetables, etc.), specific fruit and vegetable items, intake of micronutrients (e.g., β-carotene, vitamin C, lycopene, etc.), and food patterns (plant-based pattern; phytoestrogen-rich diet). Nine (23–25, 27, 30/31*
, 32–34, 37) of 16 case-control studies provided some evidence of an inverse association with either fruit or vegetable intake. However, within the nine positive studies, there were inconsistencies in the findings: four (23, 25, 30/31, 34) found significant inverse associations between both fruit and vegetable intake and risk, whereas the remaining five studies (24
) reported an inverse association with total vegetable intake but not with total fruit intake.
Two systematic reviews of the evidence (both limited to the case-control studies) found evidence for modest inverse associations with endometrial cancer risk of: 1) total vegetable intake, particularly cruciferous vegetables, and total fruit intake (4
) and 2) “non-starchy vegetables” and cruciferous vegetables (5
). Both reviews noted the tentativeness of the associations, given the lack of data from cohort studies and the modest magnitude of the inverse associations.
In contrast to findings from some case-control studies, the two published cohort studies (8
) have provided no evidence of an association of fruit and vegetable intake with endometrial cancer risk. The study by Terry et al. (8
) had a limited number of cases (N = 133) and only presented results for total fruit and vegetable intake combined. They reported finding no clear pattern of risk by levels of combined fruit and vegetable intake, but noted that “the data suggest an increased risk with very low fruit and vegetable intake.” However, there were only 2 cases with “little or no” fruit and vegetable intake, and the pattern of risk for the two intermediate of four consumption levels suggested decreased risk with decreased intake. The second cohort study (9
) involved 435 incident cases ascertained in a cohort of 41,000 postmenopausal women who completed a diet and lifestyle questionnaire in 1992–1993 and were followed until 2003. No association with endometrial cancer risk was seen for intake of total fruit, total vegetables, cruciferous vegetables, citrus fruit, high-β-carotene foods, high-lycopene foods, or legumes, whereas intake of high-lutein foods and high-vitamin C foods were modestly but positively associated with endometrial cancer risk.
Our results are consistent with those of the two previous cohort studies and particularly those of the study by McCullough et al. (9
). The lack of any suggestion of inverse associations in the prospective studies suggests that recall bias or selection bias may have played a role in the findings of slightly more than half of the case-control studies.
Fruits and vegetables contain a wide variety of biologically active compounds including carotenoids, vitamin C, tocopherols, indoles, isothiocyanates, sulfurofane, isoflavones, phytosterols, and flavonoids (6
). These compounds have the potential to affect the initiation and promotion of epithelial cancers through a range of mechanisms, including: quenching of reactive oxygen species by anti-oxidants such as β-carotene, vitamin C, tocopherol, and flavonoids (7
); modulation of endogenous antioxidant enzymes such as glutathione S-transferases (7
); modulation of drug-metabolizing enzymes including cytochrome P-450 and detoxifying enzymes (40
); inhibition of nitrosamine formation (7
); shifting of estrogen metabolism toward the 2-hydroxylation pathway, thought to inhibit cell proliferation (7
); binding of carcinogens to glucuronates and sulfates enabling their excretion (40
); enhancement of cell differentiation (40
); induction of apoptosis (40
); and stimulation of immune surveillance (7
). While animal and cell culture experiments provide support for some of these mechanisms, little is known about the effects of different phytochemicals at doses habitually consumed by humans on specific tissues of interest (7
). As suggested by reviews of the association of consumption of fruits and vegetables with cancers at different sites (5
), the effects of phytochemicals may differ by site. Furthermore, phytochemicals can activate multiple, overlapping pathways and may have synergistic, additive, or inhibitory effects (7
). For example, while isothiocyanates and indoles present in cruciferous vegetables induce conjugating enzymes and would therefore be expected to inhibit carcinogenesis (45
), they also may play a role in the activation of carcinogens (46
). Finally, fruits and vegetables contain complex mixtures of phytochemicals whose net effects may be the result of opposing influences on endometrial carcinogenesis.
Given the difficulty of extrapolating from experimental studies to humans, prospective epidemiologic studies which characterize habitual dietary intake are crucial for assessing the long-term effects of different types of diet on human health. Although there is a need for further cohort studies on diet and endometrial cancer risk, the lack of any suggestion of a protective effect of consuming a diet high in fruits and vegetables, or high in specific classes of vegetables, suggests that consumption of fruits and vegetables does not reduce the risk of this disease in older women. One important possibility not addressed by this study is that a relatively high intake of fruits and vegetables earlier in life, and particularly in adolescence, may inhibit endometrial carcinogenesis.
Strengths of the present study include its prospective nature, large sample size, classification of botanical groups which may operate through distinct mechanisms, the wide range of intake of fruits and vegetables in this study population, and information on potential confounding factors. A number of limitations should be kept in mind. Dietary assessment using food frequency questionnaires is subject to measurement error which could have affected our results (47
). In spite of the fact that intake of fruits and vegetables assessed by FFQ has shown reasonable correlations with consumption estimated by other methods, such as food records and multiple 24-hour recalls, it is still possible that our dietary assessment failed to detect a moderate inverse association with cancer risk. Additionally, dietary intake in this study was assessed only at baseline, and therefore does not reflect changes that may have occurred during the 8 years of follow-up. However, results from two cohort studies suggest that reporting of fruit and vegetable intake remains consistent over a number of years (49
). The small number of premenopausal women in the present cohort precluded separate analysis of this group. Finally, information on intake of certain vegetable items which may play a role in inhibiting the development of cancer, including allium (onions and garlic) and fungi, were not available in this study.
In conclusion, this large prospective cohort study found no evidence that intake of all fruits or vegetables, of specific botanical groupings, or of groupings based on appearance (dark green, leafy vegetables; orange vegetables, etc.) is associated with reduced risk of endometrial cancer