This meta-analysis suggested an increased endometrial cancer risk associated with total fat, saturated fat, and animal fat intakes. However, these findings were based on a limited numbers of case-control studies and were not observed in the one or two cohort studies evaluating these associations. Case-control data suggested a 24 percent increased risk per 10 percent kcal from total fat, and a 29 percent increased risk per 10 g/1,000 kcal of intake for saturated fat. Similarly, results from case-control studies suggested a strong association for animal fat, whereas two cohort studies suggested an inverse association. Our meta-analysis of six case-control studies reporting on cholesterol also suggested a positive association, but the confidence interval included the null value.
In general, it is assumed in nutritional epidemiology that cohort studies provide better estimates of the association of dietary factors with risk of cancer and other chronic diseases. This is mainly because temporality of the association and potential differential recall bias are not in dispute. On the other hand, in the case of endometrial cancer, there is an important caveat that must be considered when weighing results from cohort vs. case-control studies. Specifically, women who have had a hysterectomy are at virtually no risk of developing endometrial cancer. Properly, two of the three cohort studies [26
] evaluating dietary lipids and endometrial cancer excluded women with a hysterectomy at baseline. Notably, the third [27
] did not, an additional reason for exclusion of that study from consideration in meta-analysis. However, none of the three studies [26
] updated hysterectomy status of their population during follow-up; ideally, women would be censored at the time of hysterectomy. If indications for hysterectomy are associated with fat intake, and fat intake is also associated with endometrial cancer risk (as suggested by the case-control studies), then failure to account for updated hysterectomy status would bias results toward the null, or may even result in an inverse association.
For breast cancer, a cancer site with a risk factor profile similar to that for endometrial cancer, it has also been noted that generally case-control studies have observed elevated risks with increasing dietary fat intake [41
], whereas results from cohort studies have been null [42
]. However, a meta-analysis published in 2003 [43
] and including 31 case-control studies and 14 cohort studies found similar weak positive associations for dietary fat intake and breast cancer for case-control (summary estimate: 1.14; 95% CI: 0.99-1.32) and cohort studies (summary estimate: 1.11; 95% CI: 0.99-1.25).
Because of the limited number of studies evaluating these associations, we estimated confidence intervals when they were not reported so that we could include as many studies in the analyses as possible. In addition to the assumptions related to distribution of cases and controls, these calculations also assume that confounding factors have minimal impact on the variance. That is, the variance estimate derived from the distribution of cases and controls is based on “crude” distributions, and do not take intake account the influence of confounding variables. In the case of dietary fat intake (measured as g/day or kcal/day) as the exposure of interest and total energy intake (kcal/day) as a confounding variable, this may not be a reasonable assumption (e.g., see Willett et al
] for descriptions of differences in confidence limits according to energy adjustment method). For nutrient density measures, however, this is probably a reasonable assumption.
To our knowledge this is the first systematic literature review and meta-analysis of the role of fat intake on endometrial cancer risk. In the 1997 WCRF/AICR Report [6
], based on a narrative (and not comprehensive) review of this association, saturated and animal fat intakes were deemed to “possibly
” increase risk, while there was “insufficient
” evidence for total fat and cholesterol. These conclusions were based on four case-control studies [23
], all included in our review, plus two hospital-based case-control studies [16
] which evaluated “added fats”. We excluded these two papers as our review was based on dietary lipids as nutrients. Furthermore, odds ratios in these latter two papers did not adjust for total energy intake.
The association of total fat intake and cancer risk is controversial and the role of different types of fat is not well understood [46
]. Although the association with endometrial cancer has received relatively little attention, several lines of evidence support a possible association. A meta-analysis of dietary intervention studies to lower fat intake found effects on decreased serum estradiol levels [5
]. Although this may not be due specifically to the fat content of the diet, these studies suggest that dietary patterns low in fat may favorably influence long-term exposure to high levels of endogenous estrogens. These results are congruent with earlier observations of lower plasma estradiol levels and increased fecal excretion of estrogens in vegetarians than non-vegetarians [49
]. Diets high in fat may enhance reabsorption of estrogens in the gut [50
]. Although controversial, several lines of evidence suggest that increased dietary fat is also associated with increased risk of obesity [3
]. Higher dietary fat intake tends to be associated with lower dietary fiber and fruit and vegetable intake, with resultant lower exposure to nutritive antioxidants and a large variety of other potentially anticarcinogenic phytochemicals [51
There is also growing evidence that the metabolic consequences are different for different fatty acids [3
]. Saturated fat intake tends to be highly correlated with total and animal fat intake and the potential mechanisms by which total fat intake may influence endometrial carcinogenesis generally apply to the effects of saturated and animal fat intake as well. Epidemiologic and intervention studies have shown that saturated fat intake has a negative impact in insulin resistance, while monounsaturated and polyunsaturated fat improves it [53
]. Insulin resistance is believed to play a major role in the development of endometrial cancer [54
]. There is growing interest in the effects of dietary fats on immune function and inflammatory responses [55
]. Saturated and animal fat intake also travel with animal foods in the diet, particularly with red meat, which has been suggested to increase endometrial cancer risk (Bandera et al
., Consumption of animal foods and endometrial cancer risk: a systematic literature review and meta-analysis, submitted).
In summary, the current epidemiologic evidence suggests a possible role for total fat, saturated fat, and animal fat on endometrial cancer risk. However, because the limited available cohort data did not confirm these findings, conclusions cannot be drawn until more data are published, particularly from cohort studies.