Results from our prospective cohort demonstrate that the association between obesity and type 1 endometrial cancer risk in postmenopausal women differs by HT use and type. Among women who never used HT, risk was strongly positively related to obesity and may have been influenced more by abdominal than overall adiposity; however, the latter finding should be interpreted with caution due to small numbers. Among women who ever used ET, being overweight at baseline predicted higher risk, while use of EPT mitigated any effect of obesity.
The associations between endometrial cancer risk and HT use and type in our study were consistent with results from a more detailed analysis of specific HT preparations in a subgroup of the CTS [23
]. Only a few studies have investigated the joint effects of obesity and HT use on endometrial cancer risk. Recently, three cohort studies found results similar to ours. In the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, several measures of obesity (weight, BMI, waist circumference, hip circumference and WHR) were positively associated with endometrial cancer risk in postmenopausal women who never used HT, but were not associated with risk in those who ever used HT; however, the investigators did not stratify risk associations by HT type [24
]. In the Cancer Prevention Study II Nutrition Cohort (CPS II), BMI was significantly associated with increased endometrial cancer risk in postmenopausal women who never used HT (RR 3.7, 95% CI: 2.4–5.7 for BMI 30.0–34.9 kg/m2
and RR 4.4, 95% CI: 2.7–7.2 for BMI ≥35.0 kg/m2
each compared to 22.5–24.9 kg/m2
), but not among those who ever used EPT (RR 1.5, 95% CI: 0.68–3.3 for BMI ≥30.0 vs. 22.5–24.9 kg/m2
]. In the NIH-AARP Diet and Health Study Cohort, obesity was strongly associated with increased endometrial cancer risk in postmenopausal women who never used HT (RR 5.4, 95% CI: 4.0–7.3 for BMI ≥30 vs. <25 kg/m2
]. The obesity association was diminished in those who formerly used HT (RR=2.5, 95% CI: 1.2–8.3) and was only marginally significant in those who currently used HT (RR=1.4 95% CI: 1.0–2.1) (P
-interaction<0.001). Within a subgroup who filled out a later questionnaire with information about HT formulation, overall obesity (RR 1.6, 95% CI: 0.69–3.8 and RR 1.4, 95% CI: 0.66–2.8, respectively) was not associated with endometrial cancer risk among women who exclusively used ET or continuous EPT, but risk was significantly elevated (RR=2.2, 95% CI: 1.0–4.8) among obese women who used a sequential EPT regimen. A similar pattern was seen for weight gain since age 18, i.e., a positive association in those who never used HT and no association in those who ever used HT. Taken together, the results of these cohort studies and our own suggest that the addition of progestin as part of HT can mitigate the effects of obesity on endometrial cancer risk, perhaps because progestins suppress endometrial proliferation that occurs as a result of higher circulation of estrogens in overweight and obese women. In addition, our study, which investigated HT type, showed the obesity effect in those who used ET was less strong than in those who never used HT. This suggests a threshold (rather than a multiplicative) effect beyond which additional exogenous and endogenous estrogens did not continue to increase risk. This could also imply that obesity and ET promote carcinogenesis through the same mechanism [27
]. However, these results must be interpreted with caution, as the ever ET group contained both past users (53%) and users who at one time used EPT (41%).
The three recent cohort studies also examined the independent effects of BMI with other measures of obesity on endometrial cancer risk in women overall, but not within strata of HT use (and the EPIC cohort included women who were not postmenopausal). The EPIC cohort found that waist circumference remained significantly associated with increased risk after adjustment for BMI, but hip circumference and WHR did not [24
]. In the CPS II, BMI at age 18, weight gain and tendency to gain weight centrally were not significantly associated with risk when adjusted for BMI [25
]. In the NIH-AARP Diet and Health Study Cohort, BMI at age 50 remained significantly positively associated with risk after adjustment for baseline BMI, but BMI at age 18 and 30 and weight gain did not [26
]. In our cohort, among postmenopausal women who never used HT, we found the positive associations with waist circumference, WHtR (a measure of visceral adiposity independent of height) and WHR (a measure of the distribution of muscle and adipose tissue) were independent of BMI, consistently suggesting that abdominal adiposity is an important risk factor for type 1 endometrial cancer in the absence of HT use. Furthermore, we observed the effects for BMI to be substantially diminished in models that included waist circumference or WHtR, suggesting that abdominal adiposity may be a more important indicator of risk than overall obesity. However, some care must be taken in interpreting these results, as waist and WHtR were moderately correlated with BMI, and thus these models could have collinearity problems. On the other hand, WHR was not correlated with BMI, yet is not strictly an indicator of abdominal adiposity. In addition, the sample size was limited for these analyses, as reflected in the wide confidence intervals. The number of cases was too small to assess the joint effects of BMI and abdominal adiposity and restricted the interpretation of their simultaneous assessment. Finally, BMI was not reassessed on the follow-up questionnaire, and thus its value was from approximately two years before the waist circumference measure, which could have played a role in the relative strength of the later measure. Nonetheless, of the four cohort studies, ours provides the strongest evidence for the possible relative importance of abdominal versus overall obesity in the absence of HT use and thus, the importance of the aromatization of androgen precursors to estrogens in abdominal adipose tissue [4
]. Similar to the CPS II and NCI-AARP cohorts, we did not find an association with BMI at age 18 independent of BMI at baseline. This finding implies a late-stage (promotional) effect, since it is later life obesity, rather than early obesity, that is important.
A potential limitation of our study is the possibility of error in self-reported anthropometric measurements. Such error could be the result of lack of knowledge, the desire to report a socially more normative value, or measurement error (for waist and hip circumferences). However, to improve the accuracy of measured waist and hip circumferences, participants were provided with specific written and pictorial instructions and a standard tape measure and were asked to take and record their measurements twice. In addition, the prospective study design eliminated recall bias and, thus, if measurement error occurred, it was unlikely to differ systematically between cases and non-cases. Also, socially desirable responses would have been likely to attenuate elevated risk estimates. Finally, in an ancillary validation study conducted within the cohort, comparison of the self-reported measurements to measurements taken by trained interviewers suggested excellent validity, with Pearson correlation coefficients of 0.87, 0.93, 0.85, and 0.87 for weight, height, waist circumference, and hip circumference, respectively.
Another limitation of the study was the relatively small sample size which prohibited analyses further stratified by duration of use or current use of each HT type and limited our ability to assess the joint effects of different aspects of body size. In addition, a large number of women were excluded due to missing data. However, in a comparison of the 28,418 women included in the present analysis with the 8,987 women excluded from analyses for missing data, none of the body size measures differed (data not shown); thus there was no evidence of inclusion bias. Finally, we were unable to update cohort members’ anthropometric and HT data during the decade-long follow-up period included in this analysis.
Strengths of our study include the prospective design minimizing recall bias, detailed exposure information, and virtually complete case ascertainment minimizing selection bias due to loss to follow-up.
In conclusion, in this prospective cohort we found that obesity was strongly positively associated with an increased risk of type 1 endometrial cancer in postmenopausal women who never used HT, and that abdominal obesity may be more important to risk than overall obesity; however, due to small numbers, this latter finding requires replication. Among postmenopausal women who used ET, recently being overweight was a significant risk factor. In contrast, obesity was not associated with risk of endometrial cancer in women who exclusively used EPT. Given the epidemic of obesity in the United States and the recent cessation of HT use by many women resulting from the widely-publicized Women’s Health Initiative results, understanding the associations between various aspects of obesity, modifying factors, and endometrial cancer risk is important. Furthermore, understanding the differential impact of abdominal versus overall obesity on endometrial cancer risk and how these associations differ by type of HT can provide insight into the etiology of this malignancy.