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Given the strong link between use of unopposed estrogens and development of endometrial cancers, estrogens are usually prescribed with a progestin, particularly for women with intact uteri. Some studies suggest that sequential use of progestins may increase risk, but the moderating effects of usage patterns or patient characteristics, including body mass index (BMI) are unknown. We evaluated menopausal hormone use and incident endometrial cancer (n=885) in 68,419 postmenopausal women with intact uteri enrolled in the NIH-AARP Diet and Health study. Participants completed a risk factor questionnaire in 1996–1997 and were followed through 2006. Hazard rate ratios (RR) and 95% confidence intervals (CI) were estimated using Cox regression. Among 19,131 women reporting exclusive estrogen plus progestin use, 176 developed endometrial cancer [RR 0.88; 95% CI: 0.74, 1.06]. Long duration (≥10 years) sequential (<15 days progestin/month) estrogen plus progestin use was positively associated with risk [RR 1.88; 95% CI: 1.36–2.60], whereas continuous (>25 days progestin/month) estrogen plus progestin use was associated with a decreased risk [RR 0.64; 95% CI: 0.49–0.83)]. Increased risk for sequential estrogen plus progestin was seen only among thin-to-normal weight women (BMI <25 kg/m2) [RR 2.53]. Our findings support that specific categories of estrogen plus progestin use increases endometrial cancer risk, specifically long durations of sequential progestins; while decreased endometrial cancer risk was observed for users of short duration continuous progestins. Risks were highest among thin-to-normal weight women, presumably reflecting their lower endogenous estrogen levels, suggesting that menopausal hormones and obesity increase endometrial cancer through common etiologic pathways.
Endometrial cancer, a known hormone-associated cancer, ranks 4th in most common cancers in women in the U.S., with approximately 40,000 cases diagnosed annually.1 Unopposed estrogens, from either endogenous or exogenous sources, stimulate endometrial cell proliferation thereby increasing the likelihood of genetic errors and malignant transformation.2 Given the strong link between use of unopposed estrogens and development of endometrial cancers,3–6 it has been standard practice to prescribe estrogens in conjunction with progestins, particularly for women with intact uteri. Although it is widely assumed that this type of hormone therapy is safe with respect to endometrial cancer risk, some studies suggest that sequential estrogen plus progestin use may actually increase risk,7–15 although precise relationships according to detailed usage patterns and interactions with other risk factors remain unclear.
Obese women have three- to five-times the risk of endometrial cancer compared with women of normal weight,6,16 reportedly reflecting increased conversion of androgens to estrogens and higher circulating estradiol concentrations.17 The effects of unopposed estrogens on endometrial cancer risk have been shown to be modified by body mass index (BMI), with enhanced risks among thin women. It is less well established whether similar modifications are seen for estrogen plus progestin use.
To address these issues further, we conducted an analysis within the large prospective National Institutes of Health-AARP (NIH-AARP) Diet and Health Study. An increased risk of endometrial cancer with unopposed estrogen use, and modification of this association by BMI, has been previously reported using data from this cohort with follow-up through 2000.18,19 Given six additional years of follow-up and twice as many endometrial cancer cases, we were able to evaluate risks associated with estrogen plus progestin regimen (sequential vs. continuous use of progestins) and duration of use with increased power. Specifically, this large dataset allowed us to analyze the association between estrogen plus progestin use and risk of endometrial cancer within subgroups of BMI.
The NIH-AARP Diet and Health Study design and methodology have been described previously.20 Briefly, the cohort was established during 1995–1996 when 3.5 million AARP members aged 50 to 71 years and residing in one of six states (California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania) or two metropolitan areas (Atlanta, Georgia and Detroit, Michigan) were invited to complete a questionnaire ascertaining information on demographics, dietary intake, and health-related behaviors. In total 617,119 individuals (17.6%) returned the self-administered questionnaire, 566,401 were non-duplicate and satisfactorily completed. Between 1996 and1997 a second questionnaire collecting detailed information on family history of cancer, physical activity, and menopausal hormone therapy use was mailed to baseline questionnaire respondents who did not have self-reported colon, breast, or prostate cancer. This questionnaire was returned by 337,075 individuals (62%). We excluded participants who died (n=1619) or moved out of the study area (n=547) before their completed second questionnaires were scanned. We also excluded male participants (n=188,117), participants who used a proxy respondent for the baseline (n=6959) or second questionnaire (n=3424), and participants who had no follow-up at the time of the second questionnaire (n=2). The study population included 136,407 potentially eligible women. The Special Studies Institutional Review Board of the U.S. National Cancer Institute approved the study and all participants gave informed consent.
Study participants were followed by periodic matching with the U.S. Postal Service National Change of Address database and through processing of undeliverable mail, other address update services and direct participant responses. Vital status was ascertained by linkage to the U.S. Social Security Administration Death Master File with verification in the National Death Index Plus. Follow-up time began at the scan date of the second questionnaire and continued until diagnosis of endometrial cancer, date of death, date moved out of registry ascertainment area, or December 31, 2006, whichever came first.
After exclusions for a previous diagnosis of cancer other than non-melanoma skin cancer (n=9394); being premenopausal at baseline (n=4425); having a prior hysterectomy (n=51,356), or unknown hysterectomy status (n=1492), or menstrual periods that stopped due to surgery (n=1059) or radiation/chemotherapy (n=57); having developed non-epithelial endometrial cancer (n=69) or non-primary endometrial cancer (n=76) during follow-up; or having missing values for menopausal hormone use (n=60), the analytic cohort consisted of 68,419 women.
As detailed elsewhere,18,20 menopausal hormone exposure for the present analysis was defined via information from the second questionnaire. The questionnaire asked about estrogen and progestin use separately and did not ask about the combined estrogen plus progestin pill, which was first marketed in 1995. For each pill type, participants reported the dates of first and last use, total duration of use, usual dose and name of the pill that they took for the longest time. Therefore the categorization of sequential and continuous regimen use was based on the type of hormone used for the longest time. Current use was based on use at time of second questionnaire (1996–1997).
Incident endometrial cancers were identified through probabilistic linkage with cancer registries in the original recruitment areas and two common relocation states (Arizona and Texas). The North American Association of Central Cancer Registries certifies the 10 cancer registries serving the NIH-AARP Cohort. Of the 68,419 postmenopausal women available for analysis, 885 were diagnosed with incident epithelial endometrial cancer after completing the second questionnaire and on or before December 31, 2006. The majority of cancers, 85.6% (n=758) were endometrioid. We further classified the incident epithelial endometrial cancers as type I and type II tumors based on International Classification of Diseases for Oncology (ICD-O) morphology codes.
Cox proportional hazards regression was used to estimate rate ratios (RR) and 95% confidence intervals (CI) with age as the time metric and ties handled by complete enumeration. Estrogen plus progestin only was defined if the reported date of progestin therapy use was within 90 days of unopposed estrogen use. In our estrogen plus progestin only analyses, we excluded women who used unopposed estrogen followed by estrogen plus progestin to avoid any residual influence on risk of former unopposed estrogen use. The sequential regimen included estrogen plus progestin use for less than 15 days per month, and the continuous regimen refers to estrogen with ‘daily’ use of progestin (> 25 days progestin per month). A variable for progestin use of 15–25 days per month was included as a separate category in statistical models; however, the number of women was small and results were intermediate between sequential and continuous regimens and are reported only as a category for ‘days on progestin’ and are not reported for analyses evaluating regimen of use.
We created combination exposure variables (e.g. recency and duration), based on cross-tabulations. We also evaluated the joint effect of duration (estrogen plus progestin) and days on progestin per month by including both covariates in a single multivariable model restricted to women who used estrogen plus progestin menopausal hormone therapy. All models were adjusted for age at entry, race, and duration of oral contraceptive use at baseline. Adjustment variables were coded as defined in Table 1 and main effects were categorized as presented in Tables 2 and and3.3. Tests for linear trends across hormone use categories were calculated using an ordinal categorical variable. Likelihood ratio tests for interaction across levels of a priori effect modifiers (BMI, parity, smoking history and oral contraception use) were computed based on cross-product terms with hormone use measures categorized as presented in the tables. We tested the assumption of proportional hazards for each adjustment variable and main effect using a likelihood ratio test of interaction with the time-scale (continuous) based on cross-product terms.
We computed age-standardized incidence rates across categories of menopausal hormone use and BMI category. We used the age-distribution of women in the analytic cohort as the standard population. To account for potential changes in menopausal hormone therapy use or prescribing patterns following the results of the Women’s Health Initiative (WHI) trial that menopausal hormones should not be prescribed for chronic disease prevention in postmenopausal women,21,22 we conducted one analysis truncating follow-up at June 30, 2002. This shortened follow-up period allowed us to evaluate the menopausal hormone-endometrial cancer association when the potential for exposure misclassification was the smallest.
P-values for all comparisons were two sided and an alpha less than 0.05 indicated statistical significance. SAS statistical software, version 9.2 (SAS Institute Inc., Cary, NC) was used for all analyses.
A total of 68,419 women contributed 606,903 person-years, with mean follow-up of 4.8 years for endometrial cancer cases and 8.9 years for non-cases. The mean ages at entry were 63.1 years (SD = 4.8) and 62.4 years (SD = 5.2) for cases and non-cases, respectively; while comparable mean ages at study exit were 68.4 years (SD = 5.4) and 71.8 years (SD = 5.6). The cohort included primarily non-Hispanic white women in their early 60’s. Endometrial cancer was associated with increasing BMI,19 early age at menarche and later age at natural menopause and inversely associated with duration of oral contraceptive use, increasing parity, and current smoking (results not shown).
Fifty-two percent (n = 35,580) of the postmenopausal women with intact uteri reported never using menopausal hormones, whereas 7.0% (n = 4810) reported using estrogen-only, 37.6% (n = 25,739) any estrogen plus progestin, and 3.3% (n = 2290) other or unknown type of hormone therapy. Of the women who used any estrogen plus progestin, 74.3% (n = 19,131) reported using estrogen plus progestin only, 12.3% (n = 3178) reported using estrogen alone followed by some combination of estrogen plus progestin, and the remaining 13.3% (n = 3430) used other combinations of hormones.
Baseline characteristics of the women included in our analyses are presented in Table 1 according to menopausal hormone use (never/ever) and type/regimen (estrogen-only/sequential estrogen plus progestin only/continuous estrogen plus progestin only). Compared with non-hormone users, women who used unopposed estrogen tended to be older, current or former smokers and more frequent users of oral contraceptives, while women who used sequential or continuous estrogen plus progestins tended to be younger and white, have lower BMIs and older ages at natural menopause, were more often current or formers smokers and more frequent users of oral contraceptives.
Sixty-eight endometrial cancers developed among the 4810 women (7.0% of the analytic population) who reported having ever used unopposed estrogen hormone therapy only [RR 1.13, 95% CI: 0.88, 1.46] (Table 2). Compared with women who never used menopausal hormones, current use of unopposed estrogen only was associated with increased endometrial cancer risk [RR 1.74, 95% CI: 1.20, 2.54]. The risk was also substantially elevated among women who reported long duration (≥ 10 years) use [RR 3.93, 95% CI: 2.62, 5.89] with the largest increase in endometrial cancer risk associated with current, long duration use of unopposed estrogen [RR 5.04, 95% CI: 3.18–7.99].
Among 19,131 women (28.0% of analytic population) who reported having used only estrogen plus progestin regimens, 176 developed endometrial cancer [RR 0.88; 95% CI: 0.74, 1.06] (Table 3). Women who reported using unopposed estrogens followed by estrogen plus progestin were at increased endometrial cancer risk [RR 2.64; 95% CI: 2.10, 3.32]. Compared with women who never used hormones, long duration (≥ 10 years) estrogen plus progestin use was associated with elevated risk [RR 1.43; 95% CI: 1.11–1.83]. This was driven by the risk related to long duration sequential (<15 days/month) progestin use [RR 1.88; 95% CI: 1.36–2.60]. To enable comparison with other studies that defined sequential use as <10 days of progestin per month or 10–14 days of progestin per month we further evaluated long duration sequential use in these categories and found that the increased risk of endometrial cancer was apparent within both categories of long duration sequential use [<10 days progestin/month and ≥ 10 years duration: RR 2.49; 95% CI: 1.51–4.11; 10–14 days progestin/month & ≥ 10 years duration: RR 1.62; 95% CI: 1.07–2.44].
Shorter duration continuous estrogen plus progestin use was inversely associated with endometrial cancer risk [RR 0.53; 95% CI: 0.39, 0.73)]. Increasing days on progestin per month was inversely associated with risk (p-trend < 0.01). The inverse relationship with days of progestin used per month was independent of the direct association with long duration estrogen plus progestin. For a fixed number of days on progestin per month, long duration estrogen plus progestin use was associated with a substantially elevated endometrial cancer risk compared with short duration estrogen plus progestin users (<5 years) [RR 1.70; 95% CI: 1.19, 2.43].
Among thin and normal weight women (BMI < 25 kg/m2), unopposed estrogen as well as sequential estrogen plus progestin use was associated with substantially increased risk of endometrial cancer [unopposed estrogen: RR 2.39, 95% CI: 1.52–3.78; sequential estrogen plus progestin: RR 2.53; 95% CI: 1.71–3.74] (Table 4). The latter association was apparent among estrogen plus progestin users who reported long duration sequential [RR 3.80; 95% CI: 2.37–6.12] usage.
Unopposed estrogen use was associated with increased, albeit not statistically significant, endometrial cancer risk among overweight women (BMI = 25–29.9 kg/m2) [RR 1.37; 95% CI: 0.88–2.14], with higher risks observed for current and long duration usage patterns (Table 4). Estrogen plus progestin use was not associated with any alteration in risk among overweight women [RR 0.98; 95% CI: 0.71–1.36]. Further, women in the overweight BMI category showed no increase or decrease in endometrial cancer risk with regimen of estrogen plus progestin.
Among obese women (BMI ≥ 30 kg/m2), unopposed estrogen [RR 0.64, 95% CI: 0.40–1.02] and sequential estrogen plus progestin [RR 0.76, 95% CI: 0.46–1.27] use were inversely, albeit not significantly, associated with endometrial cancer risk. Continuous estrogen plus progestin use was inversely associated with risk among obese women [RR 0.34, 95% CI: 0.20–0.58] (Table 4).
The associations between menopausal hormone use and endometrial cancer were not significantly modified by other factors associated with endometrial cancer risk including parity, smoking history and oral contraceptive use (data not shown).
We performed several sensitivity analyses of the menopausal hormone-endometrial cancer association (data not shown). The overall associations between unopposed estrogen and estrogen plus progestin and the associations stratified by BMI were similar when restricted to type I endometrial cancer cases. The results were essentially unchanged after further adjustment for calendar time, and several additional endometrial cancer risk factors, including education, age at menarche, age at natural menopause, parity, smoking history, diabetes and physical activity. Results were also not substantially different when we truncated the follow-up at June 30th, 2002 to account for potential changes in menopausal hormone therapy use or prescribing patterns after the WHI trial reported that menopausal hormones should not be recommended for chronic disease prevention in postmenopausal women.21,22
The incidence of epithelial endometrial cancer in the cohort was 14.6 per 10,000 woman years, as compared with 15.2 per 10,000 among women who reported no hormone use. Current and long duration, unopposed estrogen use was associated with the highest incidence [61.1 per 10,000]. Among estrogen plus progestin only users, incidence rates were lowest for short duration use of continuous progestins [6.0 per 10,000] and highest for long duration use of sequential progestins [22.9 per 10,000] (data not shown).
When stratified by BMI, the incidence of endometrial cancer among never users was 7 times higher in obese women [35.9 per 10,000] than normal weight women [5.5 per 10,000] (Figure 1). The incidence of endometrial cancer generally rose with increasing BMI category; for example, the endometrial cancer incidence for continuous regimen estrogen plus progestin users increased from 6.0 per 10,000 for normal weight women to 8.8 per 10,000 for overweight women to 11.9 per 10,000 for obese women.
Our study clearly demonstrates an increased risk of endometrial cancer related to current or long duration use of sequential estrogen plus progestin therapy. Our results expand upon previous studies that have reported some increases in endometrial cancer risk with current7 or long duration use7,8,11,12,14,15 of sequential progestins and refute the contention that this therapeutic approach is completely safe for endometrial cancer risk.23
In line with the notion that progestins ameliorate the adverse effects of estrogens on endometrial tissue 24 we found that risk diminished with increasing days per month that progestins were prescribed. Consistent with our results, continuous regimen estrogen plus progestin use was similarly associated with decreased endometrial cancer risk in a number of recent studies.10,25,26 Endometrial cancer rates, however, were not associated with 5 years of continuous regimen estrogen plus progestin use in the WHI study [RR 0.83, 95% CI: 0.47–1.47].21 In other studies continuous regimen estrogen plus progestin was associated with null9 and increased risk7,13 of endometrial cancer. Further, in our study, the decreased risk of endometrial cancer associated with the continuous regimen estrogen plus progestins diminished with long duration use, whereas a recent case-control study in Washington State reported that the decreased risk of endometrial cancer persisted with long duration continuous regimen use.26 Other studies have not reported risk estimates for long duration estrogen plus progestin use by regimen; therefore further studies are needed to determine risk associated with these preparations.
Obese postmenopausal women have higher levels of circulating estrogens and many studies have found varying effects of hormone therapy according to body mass indices.19,26–30 In line with previous findings from our cohort, that unopposed estrogens exerted the strongest risks among thin women,18,19 we found a similar relationship for sequential estrogen plus progestin regimen use. Increased risk of endometrial cancer among thin-to-normal weight estrogen plus progestin users has also been observed in the Nurses’ Health Study9 and the European Prospective Investigation in Cancer and Nutrition (EPIC)10 studies, however these studies did not report results by regimen. Endometrial cancer risk among thin-to-normal weight women in our study was highest for users of sequential preparations, where the risk was 2.5-times higher than among non-users. Additional support for a potentially adverse effect of sequential use of progestins among thin-to-normal weight women derives from the U.K. Million Women study,30 which assessed current usage, and a case-control study in Washington state,14 which found the association most enhanced among long-term sequential users. Conversely, obese women who used continuous estrogen plus progestin were at reduced risk of endometrial cancer, this finding is consistent with other studies that have reported results stratified by BMI19,26–30 and provides a growing body of evidence that exogenous sources of progestin may also oppose the proliferative effects of endogenous estrogens.
Stronger associations between exogenous hormones and risk of endometrial cancer among thin-to-normal weight women could indicate that there is an endogenous estrogen threshold beyond which exogenous estrogen exposures fail to increase risk. Alternatively, the effective dose of exogenous estrogens may be affected by hemodilution and be markedly reduced in obese women compared with normal weight women.31 Given the extremely high rate of endometrial cancer among obese non-hormone therapy users, it is plausible that these women have higher endogenous estrogen levels and therefore have no need for menopausal hormone therapy to relieve symptoms. However, in our data the median BMI among obese women did not vary markedly by type of therapy used, ranging from 33.7 kg/m2 for never users, 33.0 kg/m2 for unopposed estrogen use and 33.1 kg/m2 for estrogen plus progestin use.
The major strengths of the current study include the use of a large, prospective cohort with extensive data on menopausal hormone therapy use. The detailed questionnaire also provided information on potential confounders and effect modifiers, which allowed for a thorough assessment of the independence of menopausal hormone use from other related factors and the joint effects between menopausal hormones and BMI. The menopausal hormone therapy information in our study is likely accurate, given that previous validation research demonstrated greater than 95% agreement between self-reported data and prescriptions for menopausal hormone therapy.32
Study limitations include exposure ascertainment at only one time point, evaluation of “current use” based on exposure assessment in 1996–1997, lack of information regarding hysterectomy status during follow-up, and use of self-reported BMI. We could not evaluate whether cessation of or changes in menopausal hormone usage patterns after baseline differed by exposure or endometrial cancer status. Hormone usage patterns among our cohort participants likely changed during follow-up given increases in hormone use in the United States leading up to the WHI announcement in 2002 and changes in prescribing patterns after 2002. Further, the reported duration of use at baseline would have systematically underestimated the true total duration of menopausal hormone therapy use in the population during the study period. “Current use” in the context of this study was based on usage patterns at the time of the administration of the risk factor questionnaire in 1996–1997. Since the early 1960’s the use of menopausal hormone therapy has changed dramatically. Thus, these dynamic exposures pose major challenges to accurate assessment of risk, especially for outcomes with long latency periods, such as endometrial cancer. The increased risk of endometrial cancer observed in this population among current estrogen only users, long duration/current estrogen only and current sequential regimen users, is likely more a function of the long duration of use or use of sequential regimen than the effect of recency of use and should therefore be interpreted given this limitation.
Lack of follow-up information regarding hysterectomy status was also a study limitation. The inability to censor women who have had a hysterectomy, and were more likely to use menopausal hormones, would result in bias of the effect estimates towards the null. Hysterectomy rates decline markedly after menopause,33 therefore the expected number of NIH-AARP study participants with a hysterectomy after baseline and included in the current analysis is likely small. Our measure of BMI was based on self-reported weight and height at baseline, and results could have been affected by inaccurate reporting. In general, self-reported height and weight are quite accurate, with correlations between measured and self-reported BMIs typically being greater than 0.9.34 Because participants of the NIH-AARP study represent mainly white, postmenopausal women who consented to participate, the results of the current study may not apply to all women. Some of the menopausal hormone therapy-endometrial cancer analyses by BMI were based on small numbers, requiring a cautious interpretation.
Although some previous studies support a null association between estrogen plus progestin hormone therapy and endometrial cancer risk, there appears to be growing evidence that certain regimens of use confer increased risk. Long durations of sequential progestins are associated with increases in risk—particularly for thin-to-normal weight women. Such women have lower endogenous estrogen levels, supporting the notion that menopausal hormones and obesity increase endometrial cancer through common etiologic pathways. Although obese women have the highest risk of endometrial cancer, and among obese women risks are higher for non-hormone than hormone users, the reverse is true for sequential therapy use among thin-to-normal weight women. In the context of this accumulating evidence, it may be time to reconsider optimal hormone prescribing patterns in thinner women, especially given that their menopausal symptoms often support the greatest need for therapy.
Our findings support that specific categories of estrogen plus progestin use increases endometrial cancer risk, specifically long durations of sequential progestins; whereas, short durations of continuous progestins reduce risk. Increased risks were highest among thin-to-normal weight women, presumably reflecting their lower endogenous estrogen levels, suggesting that menopausal hormones and obesity increase endometrial cancer through common etiologic pathways.
Financial support: This work was supported by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services.
In memory of Dr. Arthur Schatzkin, visionary investigator who founded the NIH-AARP Diet and Health Study.
We thank the participants of the NIH-AARP Diet and Health Study for their outstanding cooperation.
Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System under contract to the Department of Health (DOH). The views expressed herein are solely those of the authors and do not necessarily reflect those of the contractor or DOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services.
Disclosures: The authors have nothing to disclose