The NIH-AARP Diet and Health Study provided a unique opportunity to prospectively examine the association of alcohol with endometrial cancer risk in a large cohort of women. Endometrial cancer risk was unaffected by amounts or types of alcoholic beverages consumed.
Five prospective studies8–10, 13, 14
and 10 case-control studies15, 17, 19, 20, 22–24, 26, 27, 31
also observed overall null associations, while a few others reported a positive or negative association between alcohol and endometrial cancer risk.12, 16, 21, 25
We were particularly interested in examining the association with higher amounts of consumption (notably ≥ 24 grams/day), but found no evidence of increased risk even among these heaviest consumers. Similar to our null results, no association was observed in the Million Women Study 14
and in the National Breast Screening Study11
with highest alcohol consumers, ≥ 15 drinks/week (i.e. ≥ 21 grams/day) and ≥30 grams/day respectively. Our results contrast with those of Setiawan and colleagues who had a comparable number of cases in the highest category of alcohol intake (≥ 24 grams/day) similarly based on intake during the year preceding the baseline questionnaire, but found a statistically significant two-fold increased risk.12
Another smaller cohort study similarly found an increased risk (RR=1.78) only among the highest alcohol consumers (>30 grams/day), but this was not statistically significant.10
We found some suggestion of higher risks associated with alcohol consumption among lean women, MHT users, and those with older ages at menopause with significant interactions with each parameter. Given the positive association between alcohol intake and smoking (heavy drinkers are often heavy smokers), we examined relationships among never smokers only. While interactions with obesity and MHT use remained statistically significant, the interaction for age at menopause was no longer significant (P
interaction=0.120). The one cohort study that examined age at menopause reported observing no interaction with alcohol intake (P
interaction = 0.39).10
Similar to our data which suggest an increased endometrial cancer risk associated with alcohol intake among lean women, a previous study reported a stronger positive association in lean women (BMI<25 kg/m2
however others have found an inverse association16
or stronger positive association21
in heavier women. Earlier studies examining possible interactions between alcohol intake and MHT have not been consistent in their observations,28
but our results align with reports that alcohol consumption is more strongly related to increased estradiol levels among MHT users than non-users.36, 37
We also examined the joint association between BMI and MHT in its alcohol-endometrial cancer association, and our data suggest that moderate alcohol intake among lean women using MHT had the strongest increased risk. A limitation of the baseline questionnaire is that MHT formulation was not captured. While formulation was captured on the follow-up questionnaire, case numbers were too small to examine formula-specific interactions. Since estrogens alone are associated with much higher RRs than estrogen plus progestin formulations, future work needs to address the relationship between alcohol intake and MHT formulations.
The mechanisms by which alcohol, obesity, and estrogen influence endometrial cancer risk are not well understood. Adipose tissue is a significant site of endogenous estrogen production particularly among postmenopausal women,38
a mechanism hypothesized to underlie the high risks of endometrial cancer observed among obese women. Alcohol consumption has been related to elevated circulating estrogen levels,4–7
but an increased risk associated with alcohol may be undetectable among heavier women because of their generally higher estrogen levels. This notion was supported by a previous analysis that showed that most endometrial cancers among MHT users occurred in lean and moderately overweight women (BMI <30 kg/m2
) and most endometrial cancers among nonusers occurred in obese women (BMI≥30 kg/m2
We did not see this compensative effect of higher endogenous levels among MHT users. On the other hand, the modest levels of estrogen in MHT users may be more sensitive to the synergistic effect of increased estrogen associated with MHT and alcohol intake. However, we cannot rule out the possibility that we observed the effect modifications by BMI and MHT use by chance alone. Further studies are required to establish a relationship between alcohol intake and blood estradiol levels in women who are lean and type and use of MHT.
We also attempted to assess whether the alcohol-endometrial cancer association differed by endometrial cancer tumor characteristics and observed a slight increase in risk for lower grade tumors. Our finding, however, needs to be cautiously interpreted given that it was based on small numbers and no other published studies have reported this finding. We were not able to classify cases according to histologic type of tumor because of incomplete information among those selected for this alcohol analysis.
The major strengths of our study include the large, prospective evaluation of alcohol consumption on incident risk of endometrial cancer. In addition, the detailed NIH-AARP study questionnaire allowed for examination of the association between a wider range of total and beverage-specific alcohol intakes with endometrial cancer risk and provided information on potential confounders and effect modifiers, which allowed for a thorough assessment of the independence of alcohol from other related factors and the joint effects between alcohol and these lifestyle factors, and tumor characteristics. However, the questionnaire asked about average drinking intake in the year prior to questionnaire completion date and included both drinking and non-drinking days, which did not allow for investigation of patterns of drinking (regular/irregular, binge/not binge)39
, duration of drinking, or of changes in lifetime drinking pattern. In addition, we could not separately assess cancer risk for nondrinkers and former drinkers. If nondrinkers are former drinkers who stopped drinking due to their illness,40
our estimates might be biased towards the null.
In conclusion, our results do not support alcohol as a strong contributor to endometrial cancer risk, even with moderate or greater alcohol intake, except possibly an increased risk among women who are lean and are MHT users, or for low grade cancers. Future studies examining the association between alcohol and endometrial cancer should be conducted in large studies with lifetime alcohol consumption history to assess associations by beverage type, potential effect modifiers, and clinical characteristics of the tumors.