Obstetrics & Gynecology:
Endometrial Cancer Risk Among Younger, Overweight Women
Thomas, Cheryll C. MSPH1; Wingo, Phyllis A. PhD, MS1; Dolan, Mary S. MD, MPH2; Lee, Nancy C. MD1; Richardson, Lisa C. MD, MPH1
From the 1Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia; and the 2Department of Obstetrics and Gynecology, Emory University School of Medicine, Atlanta, Georgia.
See related articles on pages 7, 16, and 100.
The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
The Cancer and Steroid Hormone Study was supported by interagency agreement 3-Y01-HD-8-1037 between the Centers for Disease Control and Prevention and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with additional support from the National Cancer Institute.
Corresponding author: Cheryll C. Thomas, MSPH, Centers for Disease Control and Prevention, Division of Cancer Prevention and Control, Cancer Surveillance Branch, 4770 Buford Hwy NE, MS K-53, Atlanta, GA 30341; e-mail: CCThomas@cdc.gov.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To examine the risk for endometrial cancer among overweight women using the World Health Organization's clinical definitions of obesity based on body mass index (BMI).
METHODS: Conducted in the early 1980s, the Cancer and Steroid Hormone study was a multicenter, population-based, case–control study of breast, ovarian, and endometrial cancers among women aged 20–54 years. Participants for the case group (n=421) were identified through cancer registries and had histologically confirmed endometrial cancer. Participants for the control group (n=3,159) were chosen by random-digit dialing methods in the same regions as those in the case group. Those in the case and control groups responded to the same questions during in-person interviews. Unconditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs).
RESULTS: The relationship between endometrial cancer and BMI (calculated as weight [kg]/[height (m)]2) was modified by age at last menstrual period (LMP). Of women who were younger than 45 years at LMP, those with BMIs of at least 35.0 had a greater risk of endometrial cancer (56%, 30/54) than did those with normal BMIs (4%, 59/1,492, adjusted OR 21.7, 95% CI 11.3–41.7). Of women age 45 or older at LMP, those with BMIs of at least 35.0 also had a greater risk (40%, 24/60) than did those with normal BMIs (14%, 168/1,235, adjusted OR 3.7, 95% CI 2.0–6.6). Women younger than 45 years at LMP and those with BMIs of at least 25.0 at 18 years and as adults (25%, 31/123) had an approximately sixfold increased risk (adjusted OR 5.8, 95% CI 3.4–9.8) compared with those with normal BMIs at 18 and as adults (4%, 58/1,460).
CONCLUSION: Very obese women aged 20–54 years have an elevated endometrial cancer risk, which appears heightened by early menopause.
LEVEL OF EVIDENCE: II
Endometrial cancer manifests itself differently among premenopausal and postmenopausal women.1 Irrespective of menopausal status, obesity is a known risk factor for endometrial cancer1–21 and accounts for approximately 40% of the disease burden.1 Whereas previous researchers have studied the relationship between obesity and endometrial cancer among women of all ages, few have focused on younger women.11,19
In the early 1980s, the Cancer and Steroid Hormone study examined the relationship between oral contraceptive use and breast, ovarian, and endometrial cancers in women aged 20–54 years.22 Because a substantial number of the patients with endometrial cancer were overweight,23 the Cancer and Steroid Hormone study provided an opportunity to examine the risk for endometrial cancer among overweight women using the World Health Organization's clinical definitions of obesity based on body mass index (BMI).24
The methods of the Centers for Disease Control and Prevention's Cancer and Steroid Hormone study have been described elsewhere.22 Briefly, patients (case group) were diagnosed with endometrial cancer between December 1, 1980, and December 31, 1982, ranged in age from 20–54 years, and lived in one of the eight data-collection centers. Participants for the control group were identified by random-digit dialing in the same study center location as the patients in the case group and during the time frame that those in the case group were diagnosed. The random-digit dialing process identified potential candidates, ranging in age from 20–54 years, for the study. The stratified sample from this group was frequency-matched by study-center location and the 5-year age distribution of breast cancer cases; the Cancer and Steroid Hormone study also included cancers of the breast and ovary. The study received institutional review board approval through the Centers for Disease Control and Prevention. Endometrial cancer cases were limited to tumors that occurred in the epithelium because sarcomas and other tumor types are rare.2 An expert panel of three pathologists specializing in endometrial cancer confirmed and characterized disease status independent of each cancer registry; if there was disagreement on the diagnosis, the experts discussed until consensus was reached.22,23 Study participants from New Mexico and four urban counties in Utah were excluded because histologic specimens were unavailable to confirm the endometrial cancer diagnoses.22 Control participants who had had hysterectomy also were excluded from the analysis because they were not at risk of developing endometrial cancer.
Interviewers asked two questions about weight and one question about height: 1) What has been your usual weight as an adult? 2) How much did you weigh when you were 18 years old? 3) How tall are you? Because all responses were self-reported and no measurements were taken, eight participants in the case group and 25 in the control group with unknown weight or height measurements were excluded. The BMI that was calculated by using usual weight as an adult in the numerator will be referred to as adult BMI; the BMI that was calculated by using weight at age 18 in the numerator will be referred to as BMI at age 18 (BMI is calculated24 as weight (kg)/[height (m)]2). The BMI categories that were outlined by international24 and national25 guidelines were used in this study: 1) BMI less than 25.0 (normal weight); 2) 25.0–29.9 (overweight); 3) 30.0–34.9 (class I obesity)24; and 4) BMI 35.0 or higher (class II–III obesity).24 The difference between BMI at age 18 and as an adult (labeled as BMI change in the tables and text) was divided into four categories: 1) normal weight at age 18 and normal weight as an adult (referent group); 2) normal weight at age 18 and BMI 25.0 or higher (overweight or obese)25 as an adult; 3) overweight or obese at age 18 and normal weight as an adult; 4) overweight or obese at age 18 and overweight or obese as an adult.
All analyses were conducted using SAS 8.1 for Windows.26 Preliminary analyses showed that the relationship between BMI and endometrial cancer was modified by age at last menstrual period (LMP). This variable characterizes the age at LMP for women whose menstruation has ceased because of menopause and for women who continue to menstruate. The age at LMP for women who continue to menstruate is generally the same as their current age. Five participants in the case group and eight in the control group with unknown age at LMP were excluded from further analysis. The final study population comprised 421 participants in the case group and 3,159 in the control group; the exclusions, as discussed above, were based on cancer cell type, hysterectomy status, and unknown weight, height, and LMP.
Unconditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs).27 Because final models included statistically significant (at P<.05) interaction terms between BMI and age at LMP,27 the data presentations are stratified by age at LMP (less than 45 years, 45 years or older). All models were adjusted for age (20–44 years, 45–54 years), race (non-Hispanic white, all other races and ethnicities combined), education (no high school degree, completed high school, some college, college degree or greater), oral contraceptive use (never, less than 2 years, 2 years or more), parity (nulliparous, one–two pregnancies, three or more pregnancies), estrogen therapy (never, ever), menopausal status (premenopausal, perimenopausal, postmenopausal), and history of high blood pressure (yes, no). Menopausal status was defined as: 1) still having periods but the LMP was more than 6 months previously, 2) periods that had stopped and the LMP was more than 6 months previously, or 3) periods that were stopped owing to an operation. Age, education, parity, and history of high blood pressure were covariates that had a small number for unknown categories, and these unknowns were not included in the final models. Because there were two variables based on age (age at diagnosis or interview and age at LMP), collinearity diagnostics using PROC CORR in SAS were examined. No correlations were observed to be statistically significant.
The characteristics of those in the endometrial cancer case and control groups have been described elsewhere.23 In short, those in the endometrial cancer case group were significantly more likely than those in the control group to be older, non-Hispanic white, nulliparous, never used oral contraceptives, postmenopausal, used estrogen therapy, and have a history of high blood pressure.
Those in the case group were more likely to be overweight or obese (class I, II, III) at age 18, as adults, and during both periods (Table 1) regardless of age at LMP. In general, the estimates of endometrial cancer risk for obese women who had their LMPs before age 45 were much higher than the estimates of endometrial cancer risk for women who had their LMPs at age 45 or older (Table 2). Among women who had their LMPs before age 45, the risk of developing endometrial cancer increased substantially with increasing adult BMI (Table 2). Those in the case group whose adult BMIs were class I obese had a sixfold (adjusted OR 6.0, 95% CI 3.3–10.7) increased risk of developing endometrial cancer than did those in the control group. Those in the case group whose adult BMIs were class II–III obese had a greater than 20-fold (adjusted OR 21.7, 95% CI 11.3–41.7) increased risk. The elevated risks also were seen for women who had been overweight or obese at age 18 and who had their LMPs before age 45, although these findings are based on small numbers of women in the case and control groups (Table 1). Among women who had their LMPs before age 45, those who were overweight or obese at age 18 and as adults had a sixfold (adjusted OR 5.8, 95% CI 3.4–9.8) increased risk for endometrial cancer. Similar risks were observed for women who had normal BMIs at age 18 but who became overweight or obese as adults.
Among women whose LMPs occurred at age 45 or older, the risk for endometrial cancer also increased with increasing adult BMI (Table 2) but not to the same extent as that seen in women whose LMPs occurred at a younger age. Change in BMI from age 18 to adult showed a similar but attenuated pattern to that in women with an earlier age at LMP.
Because the age at LMP variable in this study combines women who currently are menstruating with women who have stopped menstruating, we further stratified our analyses by menopausal status (Table 3). With one exception, the analysis showed that the risk for endometrial cancer increased with increasing BMI. Among women with LMP before age 45, the risk estimates were similar regardless of menopausal status. Among women with LMP at age 45 and older, being overweight or obese had little effect on endometrial cancer risk for premenopausal or perimenopausal women, whereas risk estimates for postmenopausal women were significantly elevated.
In summary, endometrial cancer risk was increased for women whose BMIs were class I or II–III obese as adults, at age 18, or at both periods. In addition, risk increased for women who were normal weight at age 18 and classified as overweight or obese as adults. This study found a statistically significant interaction between BMI and age at LMP and showed that women who had their LMPs before age 45 had the highest risk of developing endometrial cancer associated with being overweight or obese.
The strengths of this study include a large number of endometrial cancer cases, a population-based methodology, and a review of the original pathology diagnosis by a panel of experts. Previous studies of endometrial cancer among younger women had fewer cases of cancer and were conducted at single facilities.11,19 For example, Henderson and others had 31 patients who weighed at least 190 lb each, and La Vecchia and others had 29 premenopausal patients who had BMIs of 25 or higher.11,19 A separate panel of expert pathologists assessed diagnoses independent of the community pathologists, thereby reducing potential misclassification. Previous analyses from the Cancer and Steroid Hormone study indicated that diagnoses of endometrial cancer made by community pathologists were not as reproducible as were ovarian cancer diagnoses.22
The limitations of this study are that the data were collected in the early 1980s, that the measures for determining BMI were self-reported, and that the measures for menstrual history were self-reported. Although we acknowledge the potential concern about the vintage data, weight and height have been longstanding measures for overweight assessment and the questions used to obtain self-reported information have changed little since data collection for the Cancer and Steroid Hormone study.28 Additionally, we know of no physiologic or clinical trends that would change the relationship between BMI and endometrial cancer. The BMIs for women in the case group may have been lower than expected because of possible weight loss from cancer treatment or the cancer itself, but the questionnaire attempted to minimize this bias by asking for “usual adult weight.” Because bias and unreliability in self-reports increase directly with the magnitude of overweight status,29 more recent studies address the potential biases related to self-reported current weight with weight and height verification using scales, tape measures, and trained personnel.5,15 We were unable to verify the self-reported weight and height. In addition, the study did not collect other anthropometric measures such as waist or hip circumference or subscapular measures. Furthermore, previous research has shown that overweight women with predominant central adiposity may be at greater risk for endometrial cancer than overweight women with predominant gynecoid adiposity.3 We had no information on adipose distribution. Age at LMP may be biased because bleeding secondary to the cancer could not be distinguished in the analysis from menstrual bleeding. This may have yielded a shorter time since LMP, an older LMP age, and the misclassification of women who were perimenopausal or naturally menopausal as premenopausal. Given the magnitude of the relative risks, these limitations are unlikely to have affected the findings materially.
Postmenopausal women who report a younger age at LMP and, therefore, a younger age at menopause may be more likely to have irregularities in their menstrual cycles, which may be related to endocrine abnormalities.1 Some of the endocrine abnormalities related to endometrial cancer risk are the same as those for polycystic ovary syndrome, such as chronic hyperinsulinemia, low insulin-like growth factor binding protein-1, low sex hormone-binding globulin, elevated androgens, and lack of luteal-phase progesterone production.1 Kaaks and others hypothesize that the presence of menstrual cycle irregularities or elevated androgen levels may change the relationship between BMI and endometrial cancer among premenopausal women because obesity causes elevated androgens and chronic anovulation.1 Women in our study with class II–III obesity might be more likely to have chronic anovulation leading to extended menstrual cycles and to report early menopause more often. We do not have the data to quantify chronic anovulation.
Our study agrees with other studies—being overweight or obese increases endometrial cancer risk, and the risk increases as BMI increases. One earlier study showed that being overweight in childhood or adolescence increased the risk for endometrial cancer,30 but that study used different BMI definitions and results may not be comparable. Another study that looked at BMI at different ages reported no effect,31 but a small sample size may have contributed to this conclusion. Weight loss has been shown to bring endocrine levels to a normal state to help menstrual cycles return to normal.1
The rapidly increasing prevalence of overweight and obese children, adolescents, and adults in the United States32,33 is of public health and clinical concern because obesity is a risk factor for several chronic disease conditions, including endometrial cancer. Current trends show that, although endometrial cancer trends are decreasing in women older than 50 years, they are increasing in women younger than 50 years.34 The high risk that we observed in this study underscores the need for clinicians to counsel young women on the benefits of maintaining or achieving a normal weight throughout childbearing years and before entering menopause. Maintaining or achieving normal weight affects the risk for endometrial cancer, other reproductive functions, and other chronic conditions, including diabetes and cardiovascular disease.35
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