We found a strong association between obesity and an increased risk of endometrial cancer, consistent with the conclusion of the recent review by WCRF/AICR that body fatness is a convincing cause of this disease. In that meta-analysis, obesity was shown to increase the risk of endometrial cancer by about 50% per 5 units of BMI (i.e., kg/m2) in both cohort and case-control studies, with a good deal of heterogeneity in the size of the effect(13
). On this scale, our results were a 66% increase in risk per 5 units of BMI, higher than reported in most other studies. Our results showed that some other conditions related to obesity also were associated with risk. As in other studies (summarized in Saltzman(14
), reviewed in Friberg (15
)), risk estimates for t2 DM were above unity, although non-significantly. The association of hypertension with risk is less consistent and, in our study and others, not independent of obesity(6
). In our study osteoporosis was related to a somewhat lower risk of endometrial cancer (fully adjusted OR=0.7, 95% CI= 0.4–1.2), similar to what others have observed(16
). A previous diagnosis of endometrial fibroid tumors was related to an increased risk of endometrial cancer. A recent paper(19
) found increased risk for endometrial cancer in women with fibroid tumors using record linkage methods, although in that study the risk was not significantly increased among women with follow-up of ≥5 years. Since women with hysterectomy were ineligible for our study, and fibroids are the major reason for hysterectomy(20
), women in our study were likely to have relatively small or less symptomatic fibroids. There is likely to be confounding by estrogen levels in our study, since both osteoporosis(21
) and fibroids(22
) are related to estrogen levels. BMI and other variables included in our models do not completely control for estrogen level(23
The other condition found to be significantly related to risk was anemia, with controls more likely to report this condition than cases. To our knowledge this has not been reported before. In this study we have not been able to rule out the possibility of anemia acting as a marker of irregular menstruation or menorrhagia that could be related to a modified risk of endometrial cancer mediated by alterations in estrogen exposure. Confirmation of this finding in further studies is needed before a relationship can be established.
In studying medications, we found an elevated risk of endometrial cancer for thiazide use after adjustment for age, BMI, risk factors, and other conditions and treatments related to obesity (i.e., in the fully adjusted model). To our knowledge, this association has not been previously reported. An analysis restricted to hypertensive subjects eliminated to a large extent the concern about confounding by indication for thiazides. Also, the fact that other medications used to treat hypertension (i.e., other diuretics, calcium channel blockers, etc) were not related to endometrial cancer –in the overall and the restricted analyses-suggests a causal relationship for thiazides. Risk increased with longer duration of use. Studies of the prototypic thiazide hydrochlorothiazide in rats showed no carcinogenic effects(24
). Some studies have suggested that thiazides could increase the risk of t2 DM by increasing insulin resistance (reviewed in Sowers (25
)), possibly explaining the elevated risk for endometrial cancer, although other, well designed studies, have not confirmed this association(26
). Several studies have found chronic use of thiazides to be related to a decreased risk of hip fractures(28
) and to a reduced risk of radial bone loss (i.e., osteoporosis)(29
). Hip fractures are related to osteoporosis, a hormone-dependent condition caused by a reduction in estrogen levels. In postmenopausal women, administration of estrogens prevents osteoporosis and fractures (30
). An elevated risk of endometrial cancer could be explained if thiazides had an estrogen-like activity. Further research is needed to confirm this hypothesis. Thiazides are usually selected as the initial treatment for hypertension, especially among subjects without other risk factors, such as diabetes or previous cardiovascular events(31
). Therefore, since we only found an increased risk of endometrial cancer for thiazide diuretics, and not for other anti-hypertensive drugs, it is unlikely that the results observed in our study could be explained by residual confounding from diabetes or other cardiovascular-related pro-inflammatory conditions.
The protective effect of osteoporosis was not modified by the medication used to treat it (i.e., calcitonin or biphosphonates), suggesting that the relationship between the condition and the risk of cancer is independent of the treatment used. The effect of potential residual confounding by obesity or estrogen levels remains to be elucidated.
Finally, in our study, NSAID use was related to a marginally significant decreased risk of endometrial cancer (after adjustment for age and BMI, OR= 0.7, 95%CI= 0.5–0.97) whereas other analgesics (i.e., paracetamol and phenacetin), which are prescribed for similar indications as NSAIDs but lack their anti-inflammatory capacity, were not related to a decreased risk of endometrial cancer. Also, the fact that conditions for which NSAIDs are frequently used, such as migraine or rheumatoid arthritis, were not related to a decreased risk of endometrial cancer, argues against confounding by indication. No overall differences were seen between aspirin and non-aspirin NSAIDs. One previous case-control study found that regular use of aspirin was related to a significantly decreased risk of endometrial cancer, although only among obese women (OR= 0.50, 95%CI= 0.27–0.92)(9
); other NSAIDs were not studied. A recent cohort study has reported a decreased risk of endometrial cancer among current users of aspirin who were obese or postmenopausal and had not taken postmenopausal hormones, but no risk modification among other NSAID users (10
). In contrast, the effect we noted in our study was similar in obese and non-obese women. Interestingly, one recent study has reported that use of NSAIDs is related to lower levels of circulating estrogens, offering a mechanistic hypothesis by which anti-inflammatories could reduce the risk of endometrial cancer(32
). Also, factors related to an increased risk of endometrial cancer, such as obesity, insulin resistance, aging or menorrhagia have been linked to higher inflammation levels, whereas protective factors such as pregnancy or regular menses have been related to lower inflammation levels(2
In our study no evidence was found for a significant interaction between BMI and the conditions and medications assessed. Nevertheless, we found a suggestion of a greater risk of endometrial cancer among obese diabetics than among non-obese diabetics, something that others have also observed (33
The EDGE Study has several strengths: a population-based design, relatively large sample size, high quality exposure and pathology assessment, and expert evaluation and classification of drug use. Use of population controls is especially important for studies assessing conditions and medications to limit selection bias. However, to further assess the possibility of selection bias, we compared the characteristics of our controls with other available data. In our study, 55% of control women were overweight, obese, or very obese at the interview date (i.e., BMI of 25–<30, 30–<35, or ≥35 respectively). This finding is similar to the 59.3% estimation of overweight or obesity prevalence among women aged more than 45 in the US in 2005(35
). Type 2 DM and hypertension were reported respectively by 8% and 37% of our controls, somewhat lower than the estimated values of 12.5% and 43.5% among women older than 45 years old in the US in 2005 in the Behavioral Risk Factor Surveillance Survey(35
). In our study, 13% of the control women reported having used thiazides for at least 6 months. In the US Nurses’ Health Study, regular use of thiazides among participants in 1980 was 8%(36
) and in a 2004 Danish study, 22% of the controls reported having ever used a thiazidic diuretic(28
). Since differences in the definition of user exist across studies, we consider the prevalence of thiazide use in our study to be in general agreement with the published data. Finally, in our controls we found a prevalence of NSAID use for at least 6 months of 24%, consistent with the 26% prevalence of daily use for at least 2 months in a recent breast cancer study in a population similar to ours(37
). We therefore consider control subjects included in our study to be representative of the similarly aged, general US female population in terms of the studied conditions and medications.
On the other hand, our analysis may suffer from some potential shortcomings. The novel findings of associations with thiazide diuretics and anemia may be due to chance, since we examined a large number of conditions and medications in this study. However, given the exploratory nature of this analysis -designed to reveal potential new associations- we consider that all the signals from our data were important to capture. As in most interview-based case-control studies, information on study subjects is based on self-report. Therefore, recall bias is a potential threat to the validity of the study results. In our study, however, we do not expect recall bias to be an issue, as patients are unlikely to relate most of the conditions and medications assessed to a modified risk of endometrial cancer. Also, the fact that we have focused on medications chronically used (i.e., for at least 6 months) should help to enhance general recall of use, regardless of disease status. Recall bias is probably lower for drugs used on a daily basis (i.e., hydrochlorothiazides) than for drugs used sporadically (i.e., NSAIDs) or drugs whose use was suspended by the subject a long time ago. However, a residual degree of misclassification for medication use and presence of medical conditions cannot be completely ruled out. Bias due to an increased probability of diagnosis of the conditions assessed or treatments prescribed because of medical consultation due to an undiagnosed endometrial cancer is possible in this kind of study. However, we think it is unlikely that this bias would differentially affect drugs used to treat the same condition (i.e., thiazide diuretics and loop diuretics for hypertension), which, in our opinion, argues against a strong effect of a diagnostic bias on our data. We did not ask specifically about time since last use of medications, so could not account for recency in our analyses. In addition, we did not ask about some conditions associated with use of NSAIDs, such as osteoarthritis. Larger numbers of cases and controls are needed to further investigate interactions of conditions and medications with BMI.
In conclusion, obesity, history of fibroids, and thiazide diuretic use were associated with an increased risk of endometrial cancer. A diagnosis of anemia and use of NSAIDs were related to decreased risk of endometrial cancer. The novel findings related to thiazide diuretics and anemia need to be confirmed in other studies.