* The Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts; and
Technology Assessment Group, Department of Health Policy and Management, Harvard School of Public Health, Boston, Massachusetts
Accepted 19 July 1990
Received 21 May 1990
Considerable epidemiological evidence has accumulated regarding the effect of post-menopausal estrogens on coronary heart disease risk. Five hospital-based case-control studies yielded inconsistent but generally null results; however, these are difficult to interpret due to the problems in selecting appropriate controls. Six population-based case-control studies found decreased relative risks among estrogen users, though only 1 was statistically significant. Three cross-sectional studies of women with or without stenosis on coronary angiography each showed markedly less atherosclerosis among estrogen users. Of 16 prospective studies, 15 found decreased relative risks, in most instances, statistically significant. The Framingham study alone observed an elevated risk, which was not statistically significant when angina was omitted. A reanalysis of the data showed a nonsignificant protective effect among younger women and a nonsignificant increase in risk among older women. Overall, the bulk of the evidence strongly supports a protective effect of estrogens that is unlikely to be explained by confounding factors. This benefit is consistent with the effect of estrogens on lipoprotein subfractions (decreasing low-density lipoprotein levels and elevating high-density lipoprotein levels). A quantitative overview of all studies taken together yielded a relative risk of 0.56 (95% confidence interval 0.500.61), and taking only the internally controlled perspective and angiographic studies, the relative risk was 0.50 (95% confidence interval 0.430.56).
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Introduction |
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Methods for quantitative overview |
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Separate analyses were performed within each category of study design, and an additional analysis was conducted including the internally controlled cohort and cross-sectional angiography studies (which are less prone to bias). When they were given, we used estimates adjusted for confounding factors. Where several disease endpoints were studied, we chose the one closest to major CHD (nonfatal myocardial infarction (MI) and death due to CHD, or, for the angiography studies, the highest category of occlusion). For comparability, we used estimates associated with ever use of estrogens whenever possible. These analyses make the assumption that each of the studies was estimating the same underlying parameter. We recognize that the requirements for this assumption are not strictly met, because the studies were conducted using different designs among different populations. Despite these and other limitations in the metaanalysis of observational data,4 this approach can provide a meaningful guide to the strength of the evidence.
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Hospital-based case-control studies |
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The only case-control study which showed an increased risk for CHD was conducted by Jick et al.6 who observed a relative risk of 7.5 among women less than age 46. Among postmenopausal women, the relative risk was 4.2 (95% confidence interval 1.018.8). Of the 14 cases, at least 13 were current smokers. In the larger study of which that analysis was part, of 954 initially eligible patients, only 95 enrolled, which may have introduced a bias. The small sample size and the restriction to women under age 46 render the findings difficult to interpret. In a parallel paper, Jick et al.9 studied estrogen users under age 46 with a high CHD risk profile, and observed a relative risk of 0.5 (0.13.4).
La Vecchia et al.10 reported an Italian study of women under age 55. Because the majority were premenopausal and no analysis was presented for postmenopausal women, these results are not included in the quantitative overview.
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Population-based case-control studies |
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In another case-control study in the same retirement community, Ross et al. used medical records to assess use of estrogens.13 They observed a relative risk of 0.4 (0.20.8) compared with living controls and 0.6 (0.31.0) compared with deceased controls. In the overview, we used the higher (less protective) estimate based on dead controls, since all the cases were dead, and ignored the small correlation between results induced by overlap of patients with the previous study.
Thompson et al.17 used a combined endpoint of MI and stroke in a practice-based case-control study of women ages 4569 years. Cases were matched to controls by age and practitioner, which would tend to drive the results toward the null if the physicians differed in their usual practice for prescribing hormone therapy. For estrogens alone, they observed a relative risk of 1.1 (0.71.8), and for estrogen plus progesterone, the relative risk was 1.2 (0.43.1). In this study from the UK, conjugated estrogen use was less predominant than in the United States. In the overview, we use these risk estimates, but their weight was decreased by 244/603 (the fraction of strokes among the cases). Results from this study were not presented separately for MI and stroke.
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Cross-sectional studies |
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Gruchow et al.19 examined the records of 933 postmenopausal women with coronary angiography; 17% were current users of estrogens. The degree of occlusion among estrogen users was significantly lower than that among nonusers (P <0.01). After controlling for a variety of coronary risk factors, the relative risk for severe coronary occlusion for current estrogen users was 0.4 (0.30.5). For moderate occlusion it was 0.6 (0.50.7). Controlling for cholesterol and triglycerides in the regression model had no material effect on the inverse association between estrogen use and coronary occlusion. However, when high-density lipoprotein cholesterol (HDL-C) was added to the model, it substantially reduced that association such that it was no longer statistically significant. This suggests that elevations in HDL-C and a decrease in low-density lipoprotein cholesterol (LDL-C) are the most likely mechanisms for the benefit of estrogen. In most analyses, it is inappropriate to adjust for HDL since it is in the causal pathway.
McFarland et al.20 used a design identical to that of Sullivan et al.18 Estrogen exposure was defined as ever use, but since the mean age of the postmenopausal women was 52 years, most of the use was probably current and of fairly short duration. Comparing 70% or more occlusion with no stenosis, they observed a relative risk of 0.5 (0.30.8)
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Prospective studies |
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Most prospective studies followed women with and without estrogen exposure, and thus had an internal control group. Such a design is preferable because the exposed and unexposed individuals are generally comparable. These studies are summarized in Table 4. In three studies,22,23,26 summarized in Table 5, the entire cohort was taking estrogens, and their morality was compared with national statistics. Usually estrogen users will be healthier than the general population, in part by virtue of their connection with the medical care system. Despite the estrogen exposure misclassification that would attenuate the apparent benefit, the bias due to a comparison with general population statistics is likely to be more important; hence these studies probably overstate the benefit of estrogen. The findings from several prospective studies with internal controls, including the Framingham Study, are reviewed below.
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Stampfer et al. reported results from the Nurses' Health Study.27 The Nurses' Health Study was established in 1976 when 121 700 nurses ages 30 to 55 completed a mailed questionnaire regarding health status and a variety of lifestyle practices. This information was updated by a follow-up questionnaire sent in 1978. A total of 32 317 postmenopausal women without prior CHD were followed for an average of 31/2 years for a total follow-up of 105 786 person-years. Nonfatal MI was reported by the participants on the 1978 and 1980 questionnaires. Only cases documented by medical records or other confirmatory information are included in the analysis. Deaths from CHD were documented by medical records. Follow-up was nearly complete. Ever users of estrogens had a relative risk of 0.5 (0.30.8). Adjustment for a variety of coronary risk factors including hypercholesterolemia, family history of heart disease, hypertension, diabetes, obesity, and smoking did not alter these relative risk estimates.
Results from the Leisure World Study were reported by Henderson et al.33 In this study, 8841 women ages 40 through 101 completed a health survey in 1981. After 51/2 years of follow-up (40 919 person years) 1019 deaths (149 due to MI) had occurred. For all-cause mortality, the relative risk was 0.8 (0.70.91) for ever users of estrogen compared with never users, and for fatal MI it was 0.59 (0.420.82). Estrogen use was defined on the baseline questionnaire and was not updated. Adjustment for several CHD risk factors did not appreciably change the results.
A cohort of 6093 women, ages 18 to 54 from the Kaiser Permanente Medical Program, was followed for an average of 10 to 13 years.31 The mortality rate from cardiovascular disease was slightly lower among estrogen users, with a relative risk of 0.9, 95% confidence intervals, 0.23.3. After adjustment for a variety of cardiovascular risk factors including age, hypertension, obesity, and smoking, the apparent benefit was more marked, with a relative risk of 0.6, 95% confidence interval, 0.31.1. Estrogen use was defined at the baseline in 19681972 and was updated through 1977, but not thereafter.
In contrast to all other cohort studies, Wilson et al.28 from the Framingham Heart Study reported an increase in risk for cardiovascular disease associated with estrogen use. A participant was classified as an estrogen user if that was included on the medication form during an 8-year period, between biennial examinations 8 and 12. Follow-up began at the end of that 8-year interval for 1,234 women who were postmenopausal and 50 years of age or older. Of these, 302 had used estrogens at some time. They were followed for an additional 8 years. After adjustment for age, hypertension, obesity, total cholesterol, HDL-C, smoking, and alcohol consumption, the relative risk for all cardiovascular disease among ever users of estrogen was 1.8 compared with never users. This endpoint included CHD, angina pectoris, intermittent claudication, transient ischemic attack, MI, congestive heart failure, and coronary and sudden death. The apparent elevation in risk was not statistically significant when only MI was considered.
A reanalysis of the Framingham data demonstrated that the results were sensitive to the choice of the baseline examination. Eaker et al. state that after careful analysis of the data, it was evident that the relationships observed between estrogen use or nonuse and cardiovascular disease were present only for examination 12.29 The second analysis29 was limited to CHD without angina, and considered two time periods instead of just one (i.e., using examination 12 and examination 11 as the baseline for assessing estrogen use for the subsequent 10-year follow-up). Taking the average of the findings using the two baselines, there was a nonsignificant protective effect among women ages 50 to 59 with a relative risk of 0.4 (0.12.3). Among older women, there was a nonsignificant adverse effect, with a relative risk of 1.8 (0.56.9). Both Framingham analyses presented findings adjusted for HDL-C, which is probably inappropriate as that is the most plausible mechanism of action for estrogen. For the overview, we used the results reported by Wilson et al. Because no standard error or confidence interval was given for MI, we assumed that the nonsignificant relative risk of 1.87 from the multivariate analysis for MI had a P value of 0.10.
There has been only one clinical trial of estrogen use and coronary disease.25 Eighty-four pairs of women matched for age and medical condition were randomly assigned to take 2.5 mg conjugated estrogen daily and 10 mg Medroxylprogesterone for 7 days a month or placebos. The women were all residents of a long-term chronic care hospital. After 10 years of follow-up, the relative risk for estrogen users was 0.3 (0.12.8) for fatal and nonfatal MI. With only four MIs in this small trial, the results, while intriguing, are difficult to interpret on their own.
In a recent study, Sullivan et al.38 assessed the survival of women with serious, moderate, or no coronary stenosis on angiography according to estrogen use. Estrogen users had a substantially reduced mortality rate, particularly among those with more severe coronary disease.
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Results of the quantitative overview |
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Figure 1 shows the relative risks for each study according to its weight, based on its precision. The first analysis included all studies, whenever possible using estimates for ever use. This yielded a summary relative risk of 0.56, with estimated 95% confidence intervals of 0.500.61. Because the estimate of the standard error for the summary relative risk requires the assumption that the same quantity is being measured (clearly untenable here), the confidence intervals should be taken only as a rough guide to the precision rather than as strict 95% intervals.
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Discussion |
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A positive association does not necessarily imply causality. Physicians and patients decide upon estrogen therapy, and in many instances the health status of the patient has an important influence, so perhaps estrogen use is merely a marker rather than a cause of good health. One way to assess this is to evaluate the risk profile of estrogen users and nonusers. In the Nurses' Health Study27 the distribution of coronary risk factors was quite similar among current and never users of estrogens.27 Generally similar findings were observed in other studies (see Table 6). Moreover, multivariate analyses yielded the same results as age-adjusted analyses in most studies,27,30,20,13,33,34 suggesting lack of confounding by known risk factors. In others,18,14,5,17,32 the relative risk estimates increased slightly after multivariate analysis. In general, the change was modest; the largest difference was in the hospital case-control study of Rosenberg et al.5 where the relative risk increased from 0.71 to 0.97. In contrast, Petitti et al.31 found that multivariate control revealed a stronger protective effect, which could occur only if estrogen users had a somewhat higher underlying risk; the estimate changed from 0.9 to 0.6. Szklo et al.8 and Rosenberg et al.7 also found a decrease in the relative risk following multivariate analysis. Thus, the findings are inconsistent. In some populations, the risk factor profiles of users and nonusers are similar, and in others they vary somewhat in either direction. There are thus substantial data to suggest that no more than a fraction of the benefit of estrogen can be explained by selection of healthier women for its use.
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Current users of estrogens appeared to enjoy greater protection than past users.5,7,12,14 Only the study of Adam et al.15 found a (nonsignificantly) higher risk, but this was based on only two cases among current users. Only two of the prospective studies directly compared current and past use. Henderson et al.33 observed a relative risk of 0.47 for current use and 0.62 for past use. Stampfer et al.27 reported a relative risk of 0.30 for current use and 0.59 for past use. A summary of these two yielded a relative risk of 0.37 (0.210.65) for current use and 0.61 (0.450.84) for past use. In all three cross-sectional studies, the use was current. In many of the cohort studies, current use was defined at baseline and not updated, leading to misclassification of the exposure variable which attenuated the relative risk. The difference in effect of current or recent use and past use may partly explain the greater apparent protection in the cross-sectional studies.
Few studies have examined the effect of duration of estrogen use on CHD risk. Both Henderson et al.33 and Stampfer et al.27 observed no effect of duration. Specific estrogen preparations have generally not been studied. Most studies were in the United States where oral conjugated estrogens (specifically Premarin) were by far the most common form of estrogen used.
Few reports have provided data on the effects of different doses. Ross et al.13 found a nonsignificant trend for greater protection from doses of 0.625 mg/day of conjugated estrogens compared with 1.25 or more. However, Henderson et al.,33 in a prospective study in the same population, found no effect of dose; neither did Stampfer et al.27
Age has been suggested as a possibly important modifier of the estrogen effect, especially since a trend toward benefit was observed in the Framingham study for younger but not older women. Stampfer et al.27 and Bush et al.35 observed a benefit at all ages in their studies. Sullivan et al.18 found slightly greater protection among younger women, while Gruchow et al.19 found the opposite; in both studies, all age groups experienced an apparent benefit. Henderson et al.33 observed substantial benefit in a population with a median age of 73.
The effect of type of menopause was investigated in several studies. Gruchow et al.19 and Henderson et al.33 found no differences. Bain et al.14 found a protective effect only among those with bilateral oophorectomy in a fairly young population (under age 55); in all other studies, a benefit was observed regardless of type of menopause, but the magnitude of protection was greater among those with a surgical menopause.8,20,27,35
Several studies have observed more protection from estrogens among non-smokers or light smokers.13,18,33 Wilson et al.28 observed no effect among nonsmokers and an adverse affect of estrogens among smokers. Criqui et al.32 observed the opposite, with a benefit only among current smokers, and an adverse effect among past smokers.
A plausible biological mechanism for the protective effect of estrogen is its impact on the lipid profile. Among postmenopausal women, estrogens lower the levels of LDL-C and raise the concentration of HDL-C.39 In their review, Bush and Miller found that on average, 0.625 mg/day of conjugated estrogens led to a 10% increase in HDL and a 4% increase in LDL.39 A 1 mg/dl increase in HDL is associated with approximately a 35% decrease in risk for coronary disease, and 1 mg/dl decrease in LDL is associated with about a 2% decline in risk; hence, the changes induced by estrogen could lead to a relatively large decrease in risk.40 Estrogens have other effects on the cardiovascular system which may play important roles in mediating this protective effect [reviewed in (41)].
In nearly all of the epidemiological studies, the use of progestins was uncommon. Progestins are now often recommended to reduce or eliminate the excess risk of developing endometrial cancer due to unopposed estrogen. Unfortunately, most progestins tend to lower HDL-C and raise LDL-C. Although one can devise regimens in which some of the estrogen benefit on lipids remains apparent, it is nonetheless attenuated by the addition of most progestins. An important challenge in this area is to develop a progestin regimen or formulation that will maintain protection of the uterus, yet not impair the benefits of estrogen on lipids.
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Conclusion |
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Acknowledgments |
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Notes |
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2 Presented at the Workshop on Antiestrogen Prevention of Breast Cancer, October 23, 1989, Madison, WI. Proceedings cosponsored by the National Cancer Institute (Grant 1 R13 CA4956101) and the American Cancer Society (Grant RD 291).
3 To whom reprint requests should be addressed at the Channing Laboratory, 180 Longwood Avenue, Boston, MA 02115.
© Preventive Medicine 1991. Meir J Stampfer and Graham A Colditz. Prev Med 1991;20:4763.
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