Effect of Body Mass on the Association between Estrogen Replacement Therapy and Mortality among Elderly US Women

Carmen Rodriguez1, Eugenia E. Calle1, Alpa V. Patel1, Lilith M. Tatham1,2, Eric J. Jacobs1 and Michael J. Thun1,2

1 Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA.
2 Present address: Assisted Reproductive Technology Epidemiology Unit, Women's Health and Fertility Branch, Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, GA.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In observational studies, estrogen replacement therapy is associated with decreased cardiovascular disease rates and increased breast cancer rates. Recent evidence suggests that the impact of estrogen use on disease outcomes may vary by body mass. In a prospective study of 290,827 postmenopausal US women with no history of cancer or cardiovascular disease at enrollment in 1982, the authors examined the association between postmenopausal estrogen use and all-cause, coronary heart disease, stroke, all-cancer, and breast cancer death rates and whether these associations differed by body mass. After 12 years of follow-up, results from Cox proportional hazards models showed that all-cause death rates were lower among baseline estrogen users than never users (rate ratio (RR) = 0.82, 95% confidence interval (CI): 0.78, 0.87). The lowest relative risk was found for coronary heart disease (RR = 0.66, 95% CI: 0.58, 0.77). The inverse association between estrogen use and coronary heart disease mortality was strongest for thin women (body mass index <22 kg/m2) (RR = 0.49, p for interaction = 0.02). Breast cancer mortality did not increase with estrogen use overall, and no increased risk was observed for thin or heavy women. In this population, the reduction in coronary heart disease mortality among estrogen users was greatest for thinner women. Additional studies are needed to confirm or refute these results.

body mass index; cardiovascular diseases; estrogen replacement therapy; mortality

Abbreviations: BMI, body mass index; CI, confidence interval; ICD-9, International Classification of Diseases, Ninth Revision; RR, rate ratio


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Observational studies consistently show that postmenopausal women who use estrogen have lower overall death rates than those who do not use estrogen (1GoGoGoGoGoGoGo–8Go); the largest decrease is for cardiovascular disease mortality (2Go, 4Go, 7Go). The net impact of estrogen therapy on all-cause mortality remains uncertain, however, because of the observed increase in breast cancer incidence rates among current and long-term users (9Go, 10Go) and the likelihood that the lower death rates among users may be due partly to estrogen users having a healthier lifestyle than nonusers do (11GoGo–13Go).

Recent evidence suggests that the magnitude of the increased risk of breast cancer associated with estrogen use may vary by body mass index (BMI) (9Go) and that thin women have higher risks. Little is known about whether the associations between estrogen use and all-cause and coronary heart disease mortality also vary according to characteristics such as BMI. These questions are important, since individual women, together with their physicians, must decide whether to use estrogen replacement therapy, and thin women are more likely to seek or to be prescribed such therapy (11Go).

We measured death rates from all causes, coronary heart disease, stroke, other circulatory diseases, all cancer, and breast cancer in relation to postmenopausal estrogen use and the extent to which age, BMI, and smoking modify these associations. Our large, prospective cohort study included 290,827 postmenopausal, primarily elderly, US women.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Women in this study were selected from the 676,306 female participants in Cancer Prevention Study II, a prospective mortality study of about 1.2 million US men and women begun by the American Cancer Society in 1982 (14Go). Participants were identified and were enrolled by more than 77,000 American Cancer Society volunteers in all 50 states, the District of Columbia, and Puerto Rico. Study subjects completed a confidential, self-administered questionnaire in 1982 that included personal identifiers, demographic characteristics, personal and family history of cancer and other diseases, reproductive history, and various behavioral, environmental, occupational, and dietary exposures.

The vital status of study participants was determined from the month of enrollment through December 31, 1994, by using two approaches. Volunteers made personal inquiries in September 1984, 1986, and 1988 to determine whether their enrollees were alive or dead and to record the date and place of all deaths. Automated linkage with the National Death Index was used to extend follow-up through December 31, 1994 (15Go) and to identify deaths among 13,219 women (2 percent) lost to follow-up between 1982 and 1988. At completion of mortality follow-up in December 1994, 86,374 women (12.8 percent) had died and 587,855 (86.9 percent) were still living; for 2,077 women (0.3 percent), follow-up was truncated on September 1, 1988, because of insufficient data for National Death Index linkage. Death certificates were obtained for 98.0 percent of all women known to have died.

Underlying causes of death were coded from the death certificates according to the International Classification of Diseases, Ninth Revision (ICD-9) (16Go). We first assessed the association between estrogen use and total mortality, and then we grouped the observed deaths into four main diagnostic categories: coronary heart disease (ICD-9 codes 410.0–414.9), stroke (ICD-9 codes 430–438), other circulatory diseases (ICD-9 codes 390.0–405.9, 415.0–429.9, and 440.0–459.9), any cancer (ICD-9 codes 140–195.9 and 199–208.9), and breast cancer (ICD-9 codes 174.0–174.9).

We excluded from the analysis 57,107 women who had prevalent cancer (except nonmelanoma skin cancer) at study entry in 1982, 41,163 who reported prevalent heart disease, 4,316 who reported a history of stroke, 116,308 who were premenopausal, 81,208 whose menopausal status or age at menopause was unknown, 65,905 with incomplete data on estrogen use, and 19,472 who reported use of estrogen in cream or injection form exclusively. After the exclusions and 12 years of follow-up, 31,011 eligible deaths were observed among 290,827 postmenopausal women who were free of cancer or heart disease at baseline.

In the baseline questionnaire, women were asked whether they had "ever used female hormones (estrogens) other than oral contraceptives," the reason for their use, their age at first use, the number of years of use, and the method of use (i.e., injection, cream, or pill). Two definitions of hormone use were investigated for their potential relation with mortality: baseline and former use at study entry. Women missing information on years of use who indicated they were "still using" hormones in 1982 (1.4 percent of ever users) were assigned the difference between their age at enrollment and age at first use as their years of use. Baseline users were defined as those women who either said they were still using these products or whose total years of use, added to their age at first use, were within 1 year of their age at enrollment. Former users were defined as those women whose total years of use, added to their age at first use, were less than their age at enrollment.

To assess the association between estrogen use and death rates, we used age-adjusted death rates directly standardized to the age distribution of the entire female study population. Cox proportional hazards modeling (17Go) was used to compute rate ratios, adjusting for potential confounders. All Cox models stratified on exact year of age at enrollment and adjusted for race (White, Black, other), marital status (single, married, widowed, separated/divorced), education (less than high school, high school graduate, some college, college graduate), BMI (weight in kilograms/(height in meters)2 <22, 22–<25, 25–<30, >=30), consumption of vegetables (frequency per week of consuming six items, divided into quartiles) (18Go), total fat consumption (estimated grams per week, categorized into quartiles) (18Go), physical activity at work or play (none, slight, moderate, heavy), parity (none, 1, 2 or 3, >=4, number unknown), oral contraceptive use (ever, never), age at menopause (<40, 40–44, 45–49, 50–54, >=55 years), hysterectomy (yes, no), smoking (never, current, former, ever smoker but status at entry unknown), prevalent diabetes (yes, no), prevalent high blood pressure (yes, no), alcohol intake (none, occasional, daily), daily aspirin intake (yes, no), and vitamin C supplement use (yes, no). Rate ratios reported in this paper were obtained from multivariate analyses.

To test whether these factors modified the association between estrogen use at baseline and all-cause, coronary heart disease, and breast cancer mortality, we entered multiplicative interaction terms between estrogen status (baseline use, never use) and each covariate into separate multivariate models. In the multiplicative interaction terms, we categorized BMI into four strata (<22, 22–<25, 25–<30, >=30 kg/m2). Attained age also was categorized into four strata (<60, 60–69, 70–79, >=80 years). The statistical significance of each interaction was assessed at the p = 0.05 level by using the likelihood ratio test (19Go).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A history of estrogen use was reported by 34.1 percent of all women in this cohort. Among ever users, 35 percent reported use at baseline (12 percent of the total cohort) and 65 percent reported past use (22 percent of the total cohort). Estrogen use varied considerably across levels of some covariates (table 1). Compared with never users, women who ever used estrogen were more likely to be White, be more educated, have fewer children, report earlier age at menopause, have had a hysterectomy, have used oral contraceptives, be a former smoker, exercise more, be thinner, eat more vegetables, drink alcohol daily, and take aspirin and vitamin C.


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TABLE 1. Demographic characteristics of women, by estrogen replacement therapy (ERT) use at study entry, Cancer Prevention Study II, United States, 1982–1994

 
The all-cause mortality death rate was lower among women who were baseline estrogen users (rate ratio (RR) = 0.82, 95 percent confidence interval (CI): 0.78, 0.87) and among former users (RR = 0.86, 95 percent CI: 0.84, 0.89) compared with women who never used estrogen (table 2). For specific causes of death, the largest decrease in risk was found in mortality rates from coronary heart disease and from other circulatory diseases among estrogen users at baseline (RR = 0.66 for coronary heart disease, RR = 0.70 for other circulatory diseases (table 2)). The absolute decrease in death rates (rate difference) from these conditions combined for baseline users was 108.6 deaths per 100,000 women. Estrogen use also was associated with a lower risk of stroke mortality, although the relative risk of death from stroke was not different between baseline (RR = 0.81, 95 percent CI: 0.67, 1.00) and former users (RR = 0.82, 95 percent CI: 0.73, 0.92) (table 2).


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TABLE 2. Total mortality, by estrogen use and various specific causes of death, Cancer Prevention Study II, United States, 1982–1994

 
Death rates from all cancer combined were modestly lower among estrogen users at baseline (RR = 0.91, 95 percent CI: 0.84, 0.98) and former users (RR = 0.92, 95 percent CI: 0.87, 0.96) compared with never users (table 2). As reported previously, based on 9 years of follow-up in this cohort (20Go), the risk of breast cancer mortality did not increase with estrogen use for baseline users (RR = 0.83, 95 percent CI: 0.69, 1.01), even for women who used estrogen for 10 years or more (data not shown).

BMI significantly (p for interaction = 0.02) modified the association between estrogen use at baseline and coronary heart disease mortality, in both relative and absolute terms (table 3). The rate ratio for coronary heart disease mortality associated with estrogen use was lower for the leanest women (BMI <22 kg/m2) (RR = 0.49, 95 percent CI: 0.37, 0.65) than for the heaviest women (RR = 0.95, 95 percent CI: 0.65, 1.39). Estrogen use did not seem to decrease the risk of coronary heart disease for women whose BMI was >=30 kg/m2. The joint association of BMI and estrogen use with coronary heart disease mortality is illustrated in table 4. The referent group consisted of women whose BMI was <22 kg/m2 and who never used estrogens. Overall, coronary heart disease mortality risk increased with increasing BMI and decreased with estrogen use. However, estrogen use was not associated with a decreased risk for the heaviest women (BMI >=30 kg/m2). In contrast to coronary heart disease, BMI did not seem to modify the association between estrogen use and death from all causes or breast cancer.


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TABLE 3. Risk of death from all causes, coronary heart disease, and breast cancer for baseline estrogen users* compared with never users, according to body mass index, Cancer Prevention Study II, United States, 1982–1994

 

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TABLE 4. Risk of death from coronary heart disease associated with the combination of body mass index and estrogen use, Cancer Prevention Study II, United States, 1982–1994

 
The relation between estrogen use at baseline and coronary heart disease mortality was significantly modified (p for interaction = 0.03) by attained age. Table 5 illustrates that estrogen use was inversely associated with coronary heart disease mortality across all age groups for women younger than age 80 years. In absolute terms, the reduction in death rates associated with estrogen use became larger with age (14.8 per 100,000 person-years among women less than 60 years of age vs. 312.25 per 100,000 among those aged 80 years or more). In relative terms, however, the rate ratio estimate was lowest for women less than 60 years of age (RR = 0.42, 95 percent CI: 0.25, 0.69). No other significant modifications of the association between estrogen use and all-cause, coronary heart disease, and breast cancer mortality were observed (data not shown).


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TABLE 5. Risk of death from all causes, coronary heart disease, and breast cancer for baseline estrogen users compared with never users, according to attained age, Cancer Prevention Study II, United States, 1982–1994

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This large prospective study corroborates many other studies in finding lower death rates (particularly from coronary heart disease) for women who use estrogen than for those who do not. It also suggests that the inverse association between coronary heart disease mortality and estrogen use may be stronger for lean women.

An important limitation of many observational studies of postmenopausal estrogens and mortality is that estrogen users typically have healthier lifestyles and a better cardiovascular profile than nonusers do, which may explain, at least in part, the lower mortality rates for estrogen users (11Go, 12Go). This finding has been referred to as the "healthy user effect." The relative homogeneity of our cohort, exclusion of women with cancer and cardiovascular disease at entry, and the ability to control for a variety of confounders may reduce, although not eliminate, this potential bias. Residual confounding or confounding by factors such as screening practices, however, cannot be excluded. Posthuma et al. (12Go) have suggested that the association between hormone replacement therapy and lower mortality from all cancers combined, found in many observational studies, provides an indirect index of this healthy user effect. In our study, the net association between estrogen use and all-cancer mortality reflected a substantially decreased risk of colorectal cancer death (21Go, 22Go), partially offset by an increased risk of ovarian (23Go) and uterine cancer. When we excluded deaths from colorectal, ovarian, and uterine cancer, a small inverse association between baseline estrogen use and all other cancer remained (RR = 0.91, 95 percent CI: 0.84, 0.99). This finding would imply a "healthy estrogen user effect" in this cohort consistent with at least a 9 percent reduction in risk.

To further explore the healthy estrogen user effect, we examined the association of estrogen use with deaths due to external causes (ICD-9 codes E800–E999). Risk of death due to external causes was not associated with former estrogen use (RR = 1.04, 95 percent CI: 0.90, 1.20), and no statistically significant decreased risk was observed for baseline users (RR = 0.90, 95 percent CI: 0.90, 1.20). The magnitude of the reduction in risk for current users is consistent with the estimated healthy estrogen user effect in our cohort.

The lower risk of coronary heart disease mortality for baseline estrogen users observed in this study (about 34 percent) is similar to that observed in other studies (2Go, 6Go, 7Go). This inverse association is larger than would be explained solely by a "healthy user bias."

Women who already had a lower risk of coronary heart disease mortality by virtue of their lean body mass (24Go) had the largest decreased risk associated with estrogen use, while no decrease was observed among women with grade II obesity (BMI >=30 kg/m2). The stronger inverse association between estrogen use and coronary heart disease mortality observed for thin women is consistent with the effect of adiposity on estrogen metabolism. Adipose tissue is the primary source of endogenous estrogen after menopause, and circulating levels of estrogen are considerably higher in postmenopausal women who are heavy (25Go). Thus, the addition of exogenous estrogen may have less of an effect on estrogen availability in heavy women than in lean women. A similar modifying effect of obesity on the association between hormone use and breast cancer has been observed; the increased risk of breast cancer associated with hormone use is found for lean women but not for heavy women (9Go, 26Go).

Breast cancer mortality did not increase with estrogen use, a finding consistent with several (4GoGo–6Go, 27Go) but not all prospective mortality studies (7Go). Because estrogen use is associated with an increased risk of incident breast cancer (9Go), the general lack of association found in mortality studies could be due to surveillance bias or the possibility that estrogen replacement therapy promotes development of less-aggressive tumors (28Go). In our analyses, we controlled for many lifestyle and reproductive variables but had no information on screening behaviors or on stage at diagnosis.

Several observational prospective studies (1GoGo–3Go, 5Go, 7Go, 8Go, 29Go), each with certain limitations, have assessed the association between estrogen use and all-cause mortality. In all studies, risk of death was found to be lower for estrogen users, with relative risks of 0.40 to 0.80. However, the association between current estrogen use and all-cause mortality may have been biased downward in studies that did not exclude women with prevalent cardiovascular disease and cancer (1Go, 3Go, 5Go). Other studies included only a small number of women (1Go), had a short follow-up period (2Go), or used an external comparison group (8Go). In a study of nurses, Grodstein et al. (7Go) excluded women with cancer and cardiovascular disease and updated information on estrogen use every 2 years; they found a relative risk of 0.63 (95 percent CI: 0.56, 0.70) for all-cause mortality associated with current estrogen use. We observed a significant, decreased risk for former estrogen users. This decreased risk may be due to a combination of residual confounding because of the healthy user effect and the fact that some former users in 1982 may have started using hormone therapy again. A repeat survey, conducted in 1992, of a subgroup of almost 98,000 women found that at the 1982 baseline, 28 percent of former estrogen users had re-adopted hormone therapy.

The Heart and Estrogen/Progestin Replacement Study (30Go) was a randomized controlled clinical trial designed to assess the effectiveness of hormone replacement therapy for secondary prevention of coronary heart disease among women with established coronary heart disease. In that study, the rate of subsequent coronary heart disease events was not lower for women using hormones. These important findings do not necessarily conflict with the large body of observational data on estrogen use and heart disease, because observational studies have looked at primary prevention, that is, the effect of hormone use in women with no preexisting heart disease. It is possible that hormone use may cause a transient increase in risk among women with established heart disease but not among healthy women. Our finding that estrogen replacement therapy does not seem to appreciably reduce the risk of coronary heart disease for obese women may offer another explanation for the difference between results from the Heart and Estrogen/Progestin Replacement Study trial and observational studies. Unlike participants in observational studies or the general population, the majority of women in the Heart and Estrogen/Progestin Replacement Study trial (55 percent) were obese (BMI >27 kg/m2) (30Go) and therefore may have received relatively little benefit from hormone replacement therapy.

Our study has several important limitations, including lack of information on screening practices. First, no data were available on type of hormone replacement therapy used, and baseline estrogen users in this analysis represented a mix of women taking estrogens alone and women receiving combination therapy. Until the late 1970s, when use of estrogen alone was shown to increase a woman's risk of endometrial cancer, most hormonal treatment contained only estrogenic compounds. Since then, a combination of estrogen and progesterone is prescribed for women with an intact uterus. Second, assessment of exposure was based on information from a single self-administered questionnaire in 1982; thus, we were unable to assess risk of death in relation to duration of estrogen use, and some misclassification of estrogen use is expected with increasing follow-up time. However, in the subgroup of women who completed the 1992 questionnaire, we found that 69 percent of baseline users in 1982 remained current users. In addition, we found no empirical evidence that increasing misclassification of exposure with time substantially biased our results; in a reanalysis of the data comparing the first 6 years of follow-up with years 7–12, estimates of risk remained stable. For the first and second follow-up periods for baseline users, the rate ratios were 0.81 and 0.82 for all-cause mortality, 0.65 and 0.67 for coronary heart disease mortality, and 0.78 and 0.86 for breast cancer, respectively.

In summary, the inverse association between estrogen use and coronary heart disease mortality appears to be stronger for lean than for heavier women. These findings, together with those on breast cancer, suggest that body size should be considered when the potential risks and benefits of exogenous hormone use in an individual woman are estimated. Results from the large, ongoing Women's Health Initiative randomized trial (31Go), as well as observational studies, are needed to confirm or refute these results.


    NOTES
 
Reprint requests to Dr. Carmen Rodriguez, Epidemiology and Surveillance Research, American Cancer Society, National Home Office, 1599 Clifton Road NE, Atlanta, GA 30329-4251 (e-mail: crodrigu{at}cancer.org).


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication October 13, 1999. Accepted for publication March 31, 2000.