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Health Prior to Hormone Use: Matthews et al. Reply to Grodstein

American Journal of Epidemiology
Copyright C 1996 by The Johns Hopkins University School of Hygiene and Public Health
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143, No. 10
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Health Prior to Hormone Use: Matthews et al. Reply to Grodstein
Karen A. Matthews,
Lewis H. Kuller,
Rena R. Wing,
Elaine N. Meilahn,
and Pamela Plantinga
Grodstein (1) suggests that the useful questions
raised by our paper (2) are how and to what extent the
differences in cardiovascular health of women who do
and do not use postmenopausal estrogen replacement
therapy (ERT) affect the interpretation of observa-
tional studies on the relation between ERT use and risk
for cardiovascular disease morbidity and mortality.
She argues that the relation is likely to be causal, but
we are not ready to accept that interpretation without
further clinical trial data that would document the
effect of long-term use of ERT according to the wom-
en's characteristics.
Although it is true that many observational studies
show the benefit of ERT on risk for cardiovascular
disease, they also show that the benefit of ERT is
apparent for diseases not thought to be related to
estrogen exposure. For example, among women en-
rolled in the Study of Osteoporotic Fractures, long-
term current ERT users had a lower risk of all-cause
mortality after removal of death due to breast, endo-
metrial, and colon cancer, hip fractures, stroke, and
atherosclerotic heart disease (3). Similarly, Sturgeon et
reported lowered relative risk among current users
(defined as use within 1.9 years or less) for almost all
causes of death, including cancers (4). Grodstein sug-
gests that many physicians stop ERT when women
become ill with cancer, leaving healthy women re-
maining as current users. However, this explanation is
not easily applied to mortality from injuries, which is
also reduced among ERT users (4). The ubiquitous
benefit of ERT suggests that selection factors for ERT
use are important to consider in interpreting ERT-heart
disease associations.
Received for publication October 16, 1995, and in final form
February 23, 1996.
Abbreviation: ERT, estrogen replacement therapy.
Department of Psychiatry, University of Pittsburgh School of
Medicine, Pittsburgh, PA.
Department of Epidemiology, Graduate School of Public
University of Pittsburgh, Pittsburgh, PA.
Reprint requests to Dr. Karen A. Matthews, Department of Psy-
chiatry, University of Pittsburgh School of Medicine, 3811 O'Hara
Street, Pittsburgh, PA 15213.
A key selection factor for ERT use is high socio-
economic status (2, 5, 6). Socioeconomic status is a
powerful predictor of rates of mortality and morbidity
from almost every disease and condition (7). For ex-
ample, Kitagawa and Hauser (8) reported a Linear
relation between mortality and years of education
among white women aged 25-64 years. The ratio of
observed to expected deaths within subgroups ranged
from 0.78 for women with a college education or
better to 1.60 for women with <4 years of education.
Although part of the association between socioeco-
nomic status and health can be accounted for by in-
termediate risk factors, attempts to control statistically
for risk factors do not eliminate the effect of socio-
economic status on coronary disease mortality (e.g., 8,
Because we do not completely understand why
socioeconomic status is related to health, we cannot
adequately introduce appropriate controls for its influ-
Grodstein suggests that the better risk factor profile
of hormone users "reflect sociologic heterogeneity,
and . . . not biologic phenomena." We maintain that
biologic variability also affects both the initiation and
maintenance of hormone use. Women who initiate use
of ERT have had a bilateral oophorectomy, report high
levels of menopausal symptoms, and are lean (2, 5, 6),
suggestive of low endogenous estrogen levels. More-
over, women who discontinue use are frequently those
who bleed intermittently, develop uterine hyperplasia,
or develop adverse symptoms in response to ERT (10).
Indeed, these sequelae of ERT use are not rare. In the
Postmenopausal Estrogen/Progestin Interventions
Trial (PEPI) (11), the cumulative percent of women
with a uterus who discontinued unopposed estrogen
therapy for any reason was 55 percent. Thus, women
who are long-term users are likely to be quite different
biologically from never or former users. Statistical
controls for the biologic as well as the sociologic
differences between ERT users and nonusers can only
be adequate if we have perfect measurement of all
relevant variables that determine the differences.
Grodstein takes issue with the argument that adher-
ence to pill-taking may account for some of the ap-
by guest on September 27, 2012 from
984 Matthews et al.
parent benefit of ERT use because the data that dem-
onstrate the utility of adherence (even to placebo)
come from randomized clinical trials, and not from
observational studies "where the subjects themselves
have chosen to use medication." Clinical trial partici-
pants also choose to take medications. For unknown
reasons, the beneficial effect of adherence is about a
50 percent reduction of rate of mortality among pa-
tients who had a myocardial infarction (12), about the
same reduction of disease rates associated with ERT
Grodstein cites a series of potential mechanisms that
underlie the ERT-coronary disease associations, some
of which are based on studies of the acute effects of
estrogen exposure, often at supraphysiologic dosage.
Our concern is that long-term exposure at physiologic
dosages may have different effects than short-term
exposure. Take several illustrations. Exposure to acute
infusions of 17-beta estradiol improved endothelium-
dependent vasodilation in both the peripheral and cor-
onary circulations of postmenopausal women, whereas
3 weeks of transdermal estradiol administration did
not result in alterations of vasodilator responses (13).
Among ovariectomized cynomolgus monkeys, 30
months of a lipid-lowering diet led to improvements in
coronary and lumen size and dilator responses to ace-
tylcholine, which were not affected by simultaneous
exposure to conjugated equine estrogen alone or with
medroxyprogesterone acetate treatment (14).
In conclusion, we think it prudent to be cautious in
interpreting the ERT-cardiovascular disease associa-
tions until clinical trial data have demonstrated for
whom ERT use is beneficial and for whom it is not. It
is premature to advocate ERT as a universal or wide-
spread preventive therapy for women.
Grodstein F. Can selection bias explain the cardiovascular
benefits of hormone replacement therapy? Am J Epidemiol
Matthews KA, Kuller LH, Wing RR, et al. Prior to use of
estrogen replacement therapy, are users healthier than nonus-
ers? Am J Epidemiol 1996;143:971-8.
Cauley JA, Seeley DG, Browner W, et al. Estrogen replace-
ment therapy and mortality among older women: effects of
age and duration of use. Presented at the Annual Meeting of
the American Heart Association Epidemiology Council, San
Antonio, TX, March 1995.
Sturgeon SR, Schairer C, Brinton LA, et al. Evidence of a
healthy estrogen user survivor effect Epidemiology 1995;6:
Cauley JA, Cummings SR, Black DM, et al. Prevalence and
determinants of estrogen replacement therapy in elderly
women. Am J Obstet Gynecol 1990;163:1438-44.
6. Manolio TA, Furberg CD, Shemanski L, et al. Associations of
postmenopausal estrogen use with cardiovascular disease and
its risk factors in older women. Circulation 1993;88:2163-71.
Adler NE, Boyce T, Chesney M, et al. Socioeconomic ine-
qualities in health: no easy solution. JAMA 1993;269:3140-5.
8. Kitagawa EM, Hauser PM, eds. Differential mortality in the
United States: a study in socioeconomic epidemiology. Cam-
bridge, MA: Harvard University Press, 1973.
9. Rose G, Marmot MG. Social class and coronary heart disease.
Br Heart J 1981;45:13-19.
Kenemans P, Barentsen R, van de Weijer P. Practical HRT.
Bussum, The Netherlands: Medicom Europe BV, 1995.
The Writing Group for the PEPI Trial. Effects of estrogen or
estrogen/progestin regimens on heart disease risk factors in
postmenopausal women. The Postmenopausal Estrogen/
Progestin Interventions (PEPI) Trial. JAMA 1995;27:
Horwitz RI, Viscoli CM, Berkman L, et al. Treatment adher-
ence and risk of death after a myocardial infarction. Lancet
Gilligan DM, Badar DM, Panza JA, et al. Effects of estrogen
replacement therapy on peripheral vasomotor function in post-
menopausal women. Am J Cardiol 1996;75:264-8.
Williams JK, Anthony MS, Honore EK, et al. Regression of
atherosclerosis in female monkeys. Arterioscler Thromb Vase
Biol 1995;15:827-36.
Am J Epidemiol Vol. 143, No. 10, 1996
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... T here have been numerous studies of the relation between hormone replacement therapy (HRT) and coronary heart disease (CHD). 1 2 In observational studies, current users of HRT have consistently been shown to have a better cardiovascular risk factor profile than non-users and to have a lower risk of cardiovascular events. 1 3 However, some studies have shown that users of HRT have a better risk factor profile before HRT, 4 5 and it has therefore been argued that the protective effect of HRT on risk of CHD has been over-estimated. [6][7][8] This argument is reinforced by the failure of two recent randomised trials involving women with established CHD 9 10 to show a protective effect. 11 Results of randomised trials in women without CHD are not yet clear. ...
To compare the demographic, behavioural, and biological correlates of use of hormone replacement therapy (HRT) in women with an intact uterus and women who have undergone hysterectomy. Cross sectional analysis of data from the Busselton Health Study and the 1994 Healthway-National Heart Foundation Risk Factor Survey. Busselton and Perth, Western Australia, 1994. 2540 women aged 35-79 years. Demographic, behavioural, and biological correlates of use of HRT by hysterectomy status. In women with an intact uterus, after adjustment for age and place of residence, current use of HRT was significantly associated with having a professional level of occupation, ever use of alcohol, having a history of smoking, and a lower body mass index. Current users of HRT had significantly lower levels of total cholesterol and higher levels of triglycerides than non-users. In women who had undergone hysterectomy, the only non-biological characteristic associated with use of HRT was having a history of smoking. Current users of HRT had lower levels of systolic blood pressure, lower levels of LDL cholesterol, higher levels of HDL cholesterol, and higher levels of triglycerides. The association between use of HRT and participation in exercise, level of systolic blood pressure, level of HDL cholesterol, and total/HDL cholesterol ratio varied significantly by hysterectomy status. After adjustment for age and place of residence, the mean levels of systolic and diastolic blood pressure, body mass index, waist/hip ratio, LDL cholesterol, and total/HDL cholesterol ratio were highest in women who had undergone hysterectomy and were not using HRT. Demographic/behavioural and biological correlates of use of HRT varied depending on hysterectomy status. Demographic and behavioural characteristics were more important as selection factors for use of HRT in women with an intact uterus than in women who had undergone hysterectomy. Women who had undergone hysterectomy and were not using HRT had a significantly worse profile for CHD than did women with an intact uterus. These results indicate that any bias in estimates of the protective effect of HRT on risk of CHD in observational studies is likely to depend on the prevalence of hysterectomy within the study population. Hysterectomy status needs to be taken into account in any studies that investigate the effect of HRT on risk of CHD.
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The proposals for the medicalization of postmenopausal women with female hormones are based on theories which in summary consider that the fall in estrogenic levels that follows the menopause is either a disease in itself a risk factor that is responsible for the increase in the appearance of many serious diseases. After criticizing the philosophical and scientific basis of these theories, the impact of these proposals on the health of women is discussed. Special attention is paid to the assessment of the impart of the proposals of the long-term medicalization of almost all post menopausal women. As a result of theories pervaded with a male chauvinist rationale, millions of women are recommended treatment with therapies with an impact which is not properly assessed exposed to known and unknown risks and involved in an important unjustified medicalization of their lives. The resources involved should be used in other social programs with a well-assessed positive social impact.
Observational studies have demonstrated that women who have used postmenopausal estrogen replace- ment therapy (ERT) are at reduced risk of coronary heart disease. The authors examined whether premeno- pausal women who subsequently elected to use ERT during menopause had a better cardiovascular risk factor profile prior to use than did nonusers. A total of 541 premenopausal women had their cardiovascular risk factors and psychosocial characteristics evaluated at study entry. After approximately 8 years, 355 women had become postmenopausal, and 157 women reported ERT use during the follow-up period (mean = 93.4 months). The authors compared the premenopausal characteristics of users with those of nonusers. Relative to nonusers, ERT users were better educated (63 vs. 81 % with at least some college), and prior to the use of ERT had higher levels of high density lipoprotein (HDL) cholesterol (1.49 vs. 1.59 mmol/liter), HDL2 (0.50 vs. 0.57 mmol/liter), HDL3 (0.98 vs. 1.02 mmol/liter), leisure physical activity (5,122 vs. 7,158 Kjoules), and alcohol intake (7.5 vs. 9.7 g/day), and lower levels of apolipoprotein B (0.97 vs. 0.90 g/liter), systolic blood pressure (112.1 vs. 107.1 mmHg) and diastolic blood pressure (73.8 vs. 71.4 mmHg), weight (68.5 vs. 64.2 kg), and fasting insulin (9.10 vs. 7.66 /xU/iiter). Prior to use of ERT, in comparison with nonusers, subsequent users reported on standardized questionnaires that they more often exhibited Type A behavior, were more aware of their feelings, motives, and symptoms, and had more symptoms of stress. Women who elect to use ERT have a better cardiovascular risk factor profile prior to the use of ERT than do women who subsequently do not use this treatment during the menopause, which supports the hypothesis that part of the apparent benefit associated with use of ERT is due to preexisting characteristics of women who use ERT. This study underscores the widely recognized importance of randomized clinical trials to estimate the direct benefit of postmenopausal ERT for protecting women from cardiovascular disease. Am J Epidemiol 1996;143:971-8. cardiovascular diseases; estrogen replacement therapy; menopause; risk factors
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Socioeconomic status (SES) is a significant sociodemographic correlate of noncontraceptive hormone therapy, yet multiple dimensions of SES have not been examined systematically in previous studies of hormone therapy. This study examined the lifetime incidence of noncontraceptive hormone therapy, how usage varied by type of reproductive organ surgery, and the bivariate and net associations between a large array of SES indicators and the likelihood of ever using hormones by age 53-54 years in a population sample (n = 3,612) of non-Hispanic white female participants in the Wisconsin Longitudinal Study (1957-1993). Approximately half of the women had ever used noncontraceptive hormones; 38.5% were current users. In multivariate logistic regression analyses, the most robust SES predictor of hormone therapy was a woman's husband's occupational status (higher status associated with higher rates of use), after adjustment for all other measured sociologic and biomedical factors (e.g., other SES measures, other health behaviors, menopausal symptoms, age at menopause, health insurance). The association of hormone therapy with education differed between women who underwent hysterectomy and/or oophorectomy (higher odds for less educated women) and those with intact reproductive organs (lower odds for less educated women). Additionally, a woman's own earnings and household net worth were positive net correlates of noncontraceptive hormone therapy.
The advancement of access and opportunities for girls and women in health enhancing physical activity in recent decades is a matter of record. Yet despite burgeoning interest and increased female participation in sport and recreational physical activity, few women are active enough to benefit their health. Even after extensive government campaigns are repeatedly used to educate the public, fewer women than men participate in every age group. Something is drastically wrong when exercise is said to be associated with so many health benefits, yet only a small portion of the female population exercises sufficiently to accrue these benefits. It is important to critically evaluate the challenges inherent in achieving social equity in opportunities for healthy physical activity for all women. As we gain new understandings about how health gains can be achieved by reducing social inequality rather than providing more medical care, we can see how involvement in healthy exercise is closely entwined with the social and economic status of women, disempowering stereotypes of the female body and the issue of control over women's bodies. This paper explores central tensions in the current debate about promoting female health through physical activity across the lifespan by focusing upon (i) the continued medicalization of the female body; (ii) adolescence and the tyranny of physical appearance over health and physical activity choices; (iii) menopause and the perpetuation of disempowering stereotypes into old age; and (iv) issues of diversity and the impact of ‘race’ and ethnicity upon female health and physical activity. These issues are then examined in light of the discourses of recent population health strategies in Canada and the U.S. Surgeon General's Report on Physical Activity and Health (1996) which both (in differing degrees) demonstrate a continued preoccupation with individual lifestyle change and cautious medical prescription for exercise as recipes for better female health.
Advantages and disadvantages of postmenopausal oestrogen replacement therapy (ERT) are still not clear. We aimed to analyse the relation between postmenopausal oestrogen replacement therapy (ERT), cardiovascular disease, and cancer. We examined 7944 women born between 1923 and 1930, who participated in a mammography screening for breast cancer, and who were followed up from 1987 to 1995. The follow-up consisted of 53,305 person-years. 988 women were current users and 757 were former users of ERT. Information about hormone use and health events was obtained through biennial questionnaires and recording and linking information from the hospital discharge registers of the region, the national cancer register, the social insurance reimbursement register, and the national death register. We used proportional-hazards models to calculate risk ratios and 95% CIs, adjusted for eight confounding variables. Current ERT was associated with decreased cardiovascular mortality and a decrease in sudden cardiac death. Adjusted risk ratio (RR) for cardiovascular mortality in current users was 0.21 (95% CI 0.08-0.59) and in former users 0.75 (0.41-1.37). Absolute risk per 1000 person-years for deaths from acute myocardial infarction (AMI) was 1.1 in never users, 1.2 in former users, and 0.45 in current users (p=0.197). Corresponding absolute risk for other coronary-artery-disease (CAD) deaths was 1.0, 0.81, and 0 (p=0.009), and for deaths from stroke 1.2, 1.0, and 0.15 (p=0.012). Absolute risk for sudden cardiac death was 1.6 in never users, 1.0 in former users, and 0 in current users (p<0.001). Cardiovascular morbidity was not decreased by ERT: the RR for current use was 1.07 (0.86-1.32) and for former use 1.11 (0.89-1.39). Incidence of cardiovascular disease per 1000 person-years was 24.9 in never users, 23.4 in former users, and 20.9 in current users (p=0.153). Breast-cancer morbidity did not increase with current ERT--the RR was 0.57 (0.27-1.20). Incidence of breast cancer was 1.8, 1.6, and 1.0 in never, former, and current users (p=0.242). Endometrial cancer increased with current ERT--the RR was 5.06 (2.47-10.41). Incidence of endometrial cancer was 0.52 in never users, 0.51 in former users, and 2.1 in current users (p<0.001). Current ERT reduced primarily sudden cardiac death and predicted reduced cardiovascular mortality, but did not reduce morbidity. ERT did not increase the risk of breast cancer, but was associated with increased risk of endometrial cancer.
Short-term estrogen administration improves vasodilation and has been shown to improve exercise capacity. However, it is unknown whether long-term estrogen replacement therapy is associated with improved exercise capacity in postmenopausal women without known coronary artery disease. We studied 248 postmenopausal women without known coronary artery disease (mean age 63.5 years); 158 (64%) were current or past hormone replacement therapy (HRT) users and 108 (44%) were current users of HRT. Attributes potentially affecting exercise capacity and cardiac risk factors were carefully measured. These included duration of estrogen replacement therapy, all variables in the Framingham risk index, physical activity level, body mass index, waist-to-hip ratio, presence of osteoporosis, and family history of heart disease. We measured maximal oxygen uptake (MVO (2)) and anaerobic threshold as objective markers of exercise capacity. The relation between exercise capacity and use of HRT was analyzed with the use of logistic regression, controlling for confounding variables. We found that fitness, as measured by MVO (2) and anaerobic threshold, was significantly greater in women who had used HRT currently or in the past compared with women who had never used HRT. This difference in fitness was not confounded by age or physical activity level. Estrogen replacement therapy is associated with increased exercise capacity as measured by MVO (2) and anaerobic threshold in postmenopausal women without coronary artery disease. This finding is consistent with the beneficial effect of short-term estrogen administration on improved endothelium-dependent and endothelium-independent vasodilation.
Previous economic evaluations of hormone replacement therapy (HRT) have restricted positive effects to alleviation of postmenopausal symptoms and negative effects to drug side effects. We studied the association between HRT use and postmenopausal women's valuation of both health-related quality of life and potential treatment side effects. Postmenopausal women with either a documented first vertebral fracture within the past 5 years or no history of osteoporotic fractures were recruited from Olmsted County, Minnesota, and from Dartmouth-Hitchcock Medical Center in New Hampshire to participate in a study to assess quality of life and women's attitudes toward osteoporosis prevention. Women's valuations of their current health and potential HRT-related side effects were quantified as quality-adjusted life years (QALYs) assessed by an automated utility assessment instrument (U-Titer) and the time tradeoff technique, by a vertical rating scale, and by estimated quality of well-being (QWB) scores. Health status was measured using the Medical Outcomes Study SF-36. Regression methods were used to assess the impact of current HRT use on health-related quality of life and valuation of side effects. There were 106 women with vertebral fracture and 180 with no history of hip, wrist, or vertebral fractures. Altogether, 116 (40.6%) women were currently taking HRT, 64 (22.2%) had taken HRT in the past, and 106 (37.1%) women had never taken HRT. Current HRT users had higher time tradeoff QALYs than never and past HRT users, with gains ranging from 15.0 to 83.7 days per year for current users relative to the others. Benefits were largest for women with a vertebral fracture and limitations in activities. The secondary QALY measures also showed significantly higher values for current HRT users compared with other women, as did SF-36 subscales for general health, physical function, role-emotional function, and vitality. There was substantial variability in women's perceptions of HRT side effects. Overall, the proportion of women willing to trade time to avoid bleeding was largest, at 95.5%, followed by breast tenderness, weight gain, and endometrial biopsy at 90.4%, 87.4%, and 82.7%, respectively. Current HRT users had higher health-related quality of life than past or never users according to all measures studied. Women's perceptions of potential side effects were highly variable and should be considered by physicians when prescribing an HRT regimen. If, as our results suggest, postmenopausal therapy has positive effects beyond the immediate postmenopausal years, previous economic studies may have underestimated the value of HRT.
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An analysis was performed to determine the risks and benefits of a 10-year hormone replacement therapy regimen that had been applied to all women at 50 years of age in 8 countries. Cumulative mortality with and without hormone replacement therapy over 20 years was estimated, with both current and predicted total and disease-specific secular mortality trends and the influence of a generational cohort effect taken into account. In countries with high ischemic heart disease frequency and predictable relative predominance of ischemic heart disease rates over breast cancer rates for the next 20 years, hormone replacement therapy could result in benefits with regard to overall mortality; this advantage decreases in younger-generation cohorts. In countries in which breast cancer mortality predominates over ischemic heart disease in early postmenopause and in which the predictable trends for both diseases reinforce this condition, a negative effect on overall mortality would be observed. In the United States, the effect of large-scale hormone replacement therapy would change over time. The long-term effect of hormone replacement therapy on life expectancy of postmenopausal women may vary among countries.
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Over the past 40 years in England and Wales the rise in mortality from coronary heart disease has continued unabated among working-class men, whereas among professional men the rate has changed little for the past 20 years. As a result it is now 26 per cent higher in social class V compared with social class I. The difference in women is larger (+ 152%), and it has been present for at least 40 years. The social class gradient for men was confirmed in a survey of 17530 London civil servants aged between 40 and 64 (the Whitehall Study). When men in the lowest employment grade were compared with those in the top (administrative) grade, the age-adjusted prevalence rate was 53 per cent higher for angina, 77 per cent higher for ischaemic-type electrocardiographic abnormalities, and 75 per cent higher for the prevalence of electrocardiographic abnormality among men with angina. At follow-up, the seven-and-a-half year coronary mortality was 3.6 times higher in the lowest than in the top grade. This social class difference was partly explained by known coronary risk factors: men in the lower grades smoked more and exercised less, they were shorter and more overweight, and they had higher blood pressures and lower levels of glucose tolerance. Most of the difference, however, remains unexplained. It seems that there are major risk factors yet to be identified, and that these may throw light on how it is possible for members of a highly-placed social group to have a relatively low risk of coronary heart disease.
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Socioeconomic status (SES) is strongly associated with risk of disease and mortality. Universal health insurance is being debated as one remedy for such health inequalities. This article considers mechanisms through which SES affects health and argues that a broader and more comprehensive approach is needed. Published articles surveyed using MEDLINE and review articles and bibliographies. Research is reviewed on the association of SES with health outcomes in different countries, including those with universal health coverage. Socioeconomic status relates to health at all levels of the SES hierarchy, and access to care accounts for little of this association. Other mechanisms are suggested and implications for policy and clinical practice are discussed. Health insurance coverage alone is not likely to reduce significantly SES differences in health. Attention should be paid both in policy decisions and in clinical practice to other SES-related factors that may influence patterns of health and disease.
The relation of treatment adherence to mortality after a myocardial infarction was investigated among 2175 participants in the Beta Blocker Heart Attack Trial, which had data for measures of treatment adherence, clinical severity, and the psychological and social features that may influence post-infarction mortality. Overall, patients who did not adhere well to treatment regimen (ie, who took less than or equal to 75% of prescribed medication) were 2.6 times more likely than good adherers to die within a year of follow-up (95% confidence interval, 1.2, 5.6). Poor adherers had an increased risk of death whether they were on propranolol (OR = 3.1) or placebo (OR = 2.5). Furthermore, this increased risk of death for poor adherers was not accounted for by measures of the severity of myocardial infarction, sociodemographic features (eg, race, marital status, education), smoking, or psychological characteristics (high life-stress or social isolation).
To better understand which women use estrogen replacement therapy, we examined the prevalence and determinants of estrogen replacement therapy in 9704 nonblack women, age greater than or equal to 65 years, who participated in the multicenter prospective Study of Osteoporotic Fractures. Overall, 13.7% of women reported current use of oral estrogen; 10.9% took estrogen alone and 2.8% took estrogen opposed by progestin. Four percent currently used parenteral estrogen compounds. Current use declined sharply with age from 17% at age 65 to 4% at age greater than or equal to 85. The primary determinant of estrogen replacement therapy was the type of menopause; the odds of using estrogen replacement therapy in current users compared with never users were approximately five times higher in women with a surgical menopause. Estrogen use was more common among women who had higher levels of education and were less obese. Furthermore, estrogen replacement therapy users were more likely to drink alcohol and to participate in sports and recreation. A diagnosis of osteoporosis was the major determinant of continued estrogen use, but only 24% of women with a diagnosis of osteoporosis used estrogen replacement therapy. We conclude that only a small proportion of elderly women in the United States use estrogen replacement therapy. Selection factors for use of estrogen are evident and may introduce bias in studies of estrogen and disease. In consideration of the distribution of these selection factors, estrogen users will tend to be at lower risk of coronary disease and possibly breast cancer but at greater risk for hip fractures.
The objective of this study was to determine the structural and functional changes that occur in the artery wall in response to plasma lipid lowering and hormone replacement in surgically postmenopausal monkeys with established coronary artery atherosclerosis. Eighty-eight surgically postmenopausal cynomolgus monkeys were fed an atherogenic diet for 24 months and were then allocated into 4 groups: group 1 (n = 20), a baseline necropsy group; group 2 (n = 25), a lipid-lowering diet only; group 3 (n = 22), lipid lowering plus conjugated equine estrogen treatment equivalent to 0.625 mg/d for a woman; and group 4 (n = 21), lipid lowering plus conjugated equine estrogen and medroxyprogesterone acetate treatment (equivalent to 2.5 mg/d for a woman). Treatment was for 30 months. Histomorphometric analysis of perfusion-fixed coronary arteries revealed that plaque size did not change significantly in any of the groups compared with group 1 (P > .20). Plasma lipid lowering permitted coronary artery remodeling to occur (coronary artery and lumen size doubled compared with group 1) (P < .05); however, hormone therapy did not augment remodeling. Quantitative angiographic analysis of coronary artery reactivity revealed that lipid lowering improved dilator responses to acetylcholine by 22 +/- 4% (P = .01) but not to nitroglycerin (P = .23). Hormone replacement did not further affect vascular reactivity to the agonists tested (P > .4), but addition of medroxyprogesterone acetate diminished the beneficial effects of conjugated estrogens on coronary flow reserve (P = .03). In summary, the major arterial sequelae of lipid lowering in female monkeys were artery and lumen enlargement and improved reactivity of large epicardial coronary arteries. Addition of hormone replacement to the dietary modification did not further augment these improvements, except for the dilator capacity of the coronary microcirculation.
We examined the relation between menopausal estrogen use and all-cause and cause-specific mortality in a cohort of over 49,000 women followed between 1979 and 1989 in the Breast Cancer Detection Demonstration Project (BCDDP) Follow-Up Study. We found a lower all-cause mortality rate among women who took estrogens [rate ratio (RR) = 0.7; 95% confidence interval (CI) = 0.7-0.8], particularly current users (RR = 0.3; 95% CI = 0.2-0.4), than among women who never took them. Additional analyses, however, revealed that women who had recently stopped taking estrogens had a higher all-cause mortality rate than women who had never taken them (RR = 1.4; 95% CI = 1.2-1.7). Women who had recently stopped taking estrogens also had higher mortality rates from circulatory disease (RR = 1.3; 95% CI = 1.0-1.8) and cancer (RR = 1.6; 95% CI = 1.2-2.2) than women who never took them. The most likely explanation for these results is that women stop taking estrogens when they develop symptoms of serious illness. As a consequence of this "healthy estrogen user survivor effect," nonexperimental studies are susceptible to overestimating the benefits of menopausal estrogen use, particularly current use, on mortality.
Hormone replacement therapy is associated with a reduction in cardiovascular events in postmenopausal women. We have recently found that acute 17 beta-estradiol administration improves endothelium-dependent vasodilation in both the peripheral and coronary circulations of postmenopausal women. The current study was undertaken in 33 estrogen-deficient postmenopausal women (mean age 59 +/- 7 years) to determine if short-term estrogen replacement therapy also improves endothelium-dependent vasodilation in peripheral circulation. Acute intraarterial infusion of estradiol, which increased forearm venous estradiol levels from 16 +/- 11 to 345 +/- 202 pg/ml, potentiated forearm vasodilation induced by the endothelium-dependent vasodilator acetylcholine by 49 +/- 67% (p < 0.001). Acute estradiol also potentiated vasodilation induced by the endothelium-independent vasodilator nitroprusside by 5 +/- 31% (p = 0.04). However, after 3 weeks of transdermal estradiol administration (0.1 mg/day), which achieved an estradiol level of 120 +/- 57 pg/ml, the vasodilator responses to acetylcholine and to sodium nitroprusside were unchanged from initial measurements obtained before acute administration of estradiol. Repeat intraarterial infusion of estradiol in 8 women, while receiving transdermal estradiol, increased forearm venous estradiol levels to 268 +/- 105 pg/ml and again potentiated the vasodilator response to acetylcholine to a similar degree as that observed in the initial study after acute administration of estradiol. Thus, although acute intraarterial infusion of 17 beta-estradiol potentiates endothelium-dependent vasodilation in the forearms of postmenopausal women, this effect is not maintained with a 3-week cycle of systemic estradiol administration. The different effects of acute and chronic estradiol may be due to the lower plasma levels achieved with chronic estrogen administration.
Postmenopausal estrogen replacement therapy has been associated with favorable levels of cardiovascular disease risk factors, but these associations and the relations between estrogen use and subclinical disease have not been examined in large samples of older women. Present and past estrogen use was ascertained in 2955 women > or = 65 years old in the Cardiovascular Health Study, a study of risk factors for coronary heart disease and stroke in the elderly. Present estrogen use was reported by 12% of these women and past use by an additional 26.5%. Estrogen use (past or present) was strongly associated with lower low-density lipoprotein cholesterol, fibrinogen, glucose, insulin, obesity, and age and higher high-density lipoprotein cholesterol and socioeconomic status (all P < .0001). Estrogen users also had lower levels of subclinical disease as measured by carotid intimal-medial thickness, carotid stenosis grade, ECG left ventricular mass, and Doppler mitral peak flow velocities (each P < .02). Relations were similar in younger and older women (65 to 74 versus > or = 75 years) and smokers and nonsmokers and were unchanged after women with poor medication compliance were excluded. After adjustment for other factors, estrogen use was associated with decreased carotid wall thickness, although this association was of borderline significance after further adjustment for lipids. Postmenopausal estrogen use in this sample of older women was associated with favorable cardiovascular disease risk factor profiles and with lower measures of subclinical disease. These findings suggest that postmenopausal estrogen use may be associated with lower risk of cardiovascular disease in women well into the eighth decade of life.