Our systematic literature review and meta-analyses suggest a modest reduction in endometrial cancer risk with higher consumption of beta-carotene, vitamin C, and vitamin E from food sources, based on data from case-control studies. We estimated a 12% reduction of endometrial cancer risk per 1,000 mcg/1,000 kcal for beta-carotene, a 15% decreased risk per 50 mg/1,000 kcal vitamin C, and a 9% reduction in risk in per 5 mg/1,000 kcal vitamin E. However, there was little indication of an association in the only prospective study evaluating these associations. There was also little indication of a benefit from using beta-carotene, vitamin C, or vitamin E supplements.
To our knowledge this is the first published systematic literature review and meta-analysis of the relationship between these dietary anti-oxidant vitamins and endometrial cancer. In the 1997 WCRF/AICR Report [5
], based on a narrative (and not comprehensive) review of the literature, while the evidence was suggestive of a decreased risk associated with carotenoids, the evidence was deemed “insufficient”, as only four case-control studies were identified [15
]. In the 2007 WCRF/AICR Report [3
], the evidence was deemed “limited - no conclusion
” for beta-carotene, based on our meta-analysis [4
] of one cohort study [17
] and seven case control studies [13
]. The classification of “limited- no conclusion
” was given to exposures for which available data were so limited or inconsistent that no firm conclusion could be made. Since publication of the 2007 report we identified and included in the meta-analysis one additional case-control study [21
], which strengthened the evidence of an inverse association from case-control study data. Beta-carotene has been considered for decades an anticarcinogenic agent based on its potent antioxidant [31
], antimutagenic [32
], and immuno-regulatory [33
] actions. However, the role of beta-carotene in carcinogenesis has been controversial following the results from the CARET [34
] and ATBC [35
] trials, in which it was shown that beta carotene supplementation unexpectedly increased lung cancer risk in smokers. Whether beta-carotene from food sources as opposed to supplements may still play an important role in cancer prevention is unclear. The doses of beta-carotene in these trials were substantially higher than that typically found in the diet. In addition, food sources of beta-carotene typically contain other compounds that may decrease risk of cancers, including other antioxidant carotenoids.
There was also mention in the 1997 WCRF/AICRF Report [5
] of inconsistent findings and insufficient evidence for vitamin C, based on four case-control studies [15
], and the 2007 WCRF/AICR Report [3
] found the evidence “limited-no conclusion
”, based on our meta-analysis [4
] of one cohort [17
] and eight case-control studies [13
] examining the association. Since publication of the 2007 Report, one more case-control study evaluating this association has been published [21
] and was included in the meta-analysis presented in this manuscript. This study reported a strong inverse association with vitamin C. Vitamin C is a water-soluble antioxidant essential to maintain the extracellular matrix through its role in hydroxylation of proline, an amino acid integral to the synthesis and structural integrity of collagen. The role of vitamin C on cancer chemoprevention has been attributed to its ability to stimulate immune function, inhibit nitrosamine formation, and block the metabolic activation of carcinogens, as well as its potential for preventing oxidative stress [36
]. It has been demonstrated in a number of studies that vitamin C helps to minimize DNA damage[37
].Vitamin C may also influence cellular differentiation, possibly through modulation of gene expression [37
]. While the evidence relating supplemental vitamin C to cancer prevention may be equivocal [38
], the meta-analysis conducted here relates to vitamin C from foods. As such, any observed estimated effect may not be attributable solely to vitamin C, but may reflect a combination of the multiple beneficial vitamins and other factors found in foods rich in vitamin C, or in dietary patterns that emphasize these foods.
Vitamin E was not mentioned in the 1997 WCRF/AICR Report and the 2007 Report also found the evidence to be “limited -no conclusion
”, based on our meta-analysis [4
] of one cohort study [17
] and five case-control studies [13
]. Since the publication of the report, we identified one more case-control study [21
] evaluating the association, which provided additional evidence for an inverse association. Vitamin E is a lipid-soluble antioxidant that is known to help prevent lipid peroxidation. As oxidative stress is thought to be one central mechanism in carcinogenesis, high vitamin E levels may generally help prevent carcinogenesis due to oxidative damage. For example, there is some suggestion that vitamin E may enhance DNA repair [39
]. Vitamin E may also play an important role in immune function [40
]. As the meta-analysis conducted here refers to vitamin E from food sources rather than supplemental vitamin E, a possible inverse association of vitamin E with endometrial cancer may be acting as a marker for other foods or dietary patterns associated with higher levels of vitamin E intake.
We found high heterogeneity among studies for vitamin C and beta-carotene. Because of the small number of studies evaluating these associations we were not able to conduct meta-regression or detailed sensitivity analyses to explore sources of heterogeneity. However, type of study (population-based vs. hospital-based) did not seem to explain heterogeneity. As shown in our tables and figures, most studies included in our meta-analyses adjusted for the most important confounding variables, BMI and total energy intake. In contrast, another important confounder, cigarette smoking, was not taken into account by all studies. However, this did not seem to be an important source of heterogeneity, as, for example, an inverse association between beta-carotene and endometrial cancer was suggested in studies adjusting [18
] and not adjusting [21
] for smoking. Other potential sources of heterogeneity are the different dietary assessment tools used (as shown in , the number of items in the questionnaires vary considerably among studies) and possible various degrees of residual confounding in the different studies.
In conclusion, our meta-analyses suggest a possible inverse association of dietary antioxidants vitamin C, vitamin E, and beta-carotene from food sources with endometrial cancer risk and point to the need to evaluate their potential protective effect in well-designed large cohort studies. As supplemental sources of these antioxidants are widely used in the US and some other countries, more studies reporting on the effects of supplemental intake would also be helpful to determine whether findings from food and supplemental sources are congruent. Furthermore, little is known regarding the interaction between antioxidants and other lifestyle factors. Based on the current literature, the 2007 WCRF/AICR grading of the evidence for the associations of vitamin C, vitamin E, and beta-carotene intakes with endometrial cancer risk of “limited-no conclusion” remains appropriate.