Prospective Assessment of Estrogen Replacement Therapy and Cognitive Functioning: Atherosclerosis Risk in Communities Study
Suzana Alves de Moraes1,
Moyses Szklo1,
David Knopman2 and
Eunsik Park3
1 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
2 Department of Neurology, Mayo Clinic, Rochester, MN.
3 Collaborative Studies Coordinating Center, Department of Biostatistics, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC.
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ABSTRACT
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Studies of humans have not confirmed the suggestion from animal studies that estrogen replacement therapy may have an inverse relation with cognitive function decline. Because many of these studies have been marred by design or methodological problems, such as a small sample size, failure to control for confounding variables, or the use of a cross-sectional design, the present study was conducted in a large cohort of middle-aged postmenopausal women participating in the Atherosclerosis Risk in Communities (ARIC) Study. The study population consisted of 2,859 women aged 4867 years, whose cognitive function was tested at the second (19901992) and fourth (19961998) visits of the ARIC Study using three instruments: the Delayed Word Recall Test, Digit Symbol Subtest of the Wechsler Adult Intelligence Scale-Revised, and Word Fluency Test. After multiple adjustment, no consistent patterns of cognitive changes between the two cohort visits could be detected according to current use or duration of use of estrogen replacement therapy. Thus, the results of the present study do not support the hypothesis that estrogen replacement therapy may slow age-related cognitive decline, at least as it applies to relatively young postmenopausal women.
cognition disorders; cohort studies; estrogen replacement therapy; menopause; women's health
Abbreviations:
ARIC, Atherosclerosis Risk in Communities; DSS/WAIS-R, Digit Symbol Subset of the Wechsler Adult Intelligence Scale-Revised; DWR, Delayed Word Recall Test; WF, Word Fluency Test
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INTRODUCTION
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Evidence supporting a relation between estrogen and cognitive function is largely indirect. In animal models, it has been demonstrated that estradiol alters the number of muscarinic cholinergic receptors in some preoptic nuclei in rats (1
). In addition, cyclic changes in spine density have been observed during the estrous cycle of rats, suggesting that there is a continual formation and destruction of new synapses in areas of the brain that are important for cognitive function, such as the basal forebrain, hippocampus, and cerebral cortex (2
).
Most studies of the influence of estrogens on the cognitive function of humans have had limitations, including small sample sizes and failure to control for confounders (1




7
). A recent report from the Nurses' Health Study could not detect a protective effect of hormone therapy in a cohort of over 2,000 nurses followed up since 1976 (8
). Recent randomized clinical trials with follow-up times of 315 months in patients with Alzheimer's disease have also been inconsistent: Although a small trial (n = 12) suggested an improvement of cognitive function with estrogen replacement therapy in these patients (9
), two larger trials have failed to do so (10
, 11
). In a previous cross-sectional analysis of the Atherosclerosis Risk in Communities (ARIC) Study based on its second clinic examination, which included relatively young women, no clearcut associations were found between estrogen replacement therapy and cognitive function (12
). In the present report, we extend the analysis of cognitive functioning in relation to estrogen replacement therapy by assessing cognitive changes between the ARIC Study's second (19901992) and fourth (19961998) clinic visits. Thus, the present report differs from the previous one not only because it is based on prospective data but also because it allowed for a 6-year aging of the cohort.
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MATERIALS AND METHODS
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Study population
The ARIC Study is a prospective investigation of the etiology and natural history of atherosclerosis and of the etiology of clinical atherosclerotic disease in four US communities: 1) Forsyth County, North Carolina; 2) Jackson, Mississippi; 3) selected suburbs of Minneapolis, Minnesota; and 4) Washington County, Maryland. At the first visit (19871989), 15,792 persons aged 4564 years were selected, of whom 8,685 were women. The study participants were recruited using probability samples from population-wide lists or area sampling. Fourteen percent of the participants in Forsyth County were African American, reflecting the county's ethnic composition. In Jackson, they were exclusively African American. In the other sites, participants were predominantly White. Details of the study design, objectives, and procedures have been published (13
).
Cognitive function testing was carried out in the second (19901992) and fourth (19961998) cohort visits. During the cohort's visit 2, 7,944 African-American and White women were examined. For the purposes of the present paper, we excluded four women who had primary amenorrhea, 645 who were less than 55 years of age and who had had a hysterectomy without bilateral oophorectomy (because their menopausal status could not be determined), and 207 with a history of stroke or transient ischemic attack. From the remaining 7,088 women, 1,554 were excluded because they had missing values for one or more cognitive tests in the second (19901992) or the fourth (19961998) visit. Thus, a total of 5,534 women completed all cognitive tests in both visits. Among these, 1,701 women were excluded because information on self-reported health status (n = 1,031) or hormone use (n = 670) was unavailable. After the exclusion of records with missing values for other variables (n = 257), Indians or Asians (n = 8), those who were taking medications that may affect the central nervous system (n = 556), and former users of estrogen replacement therapy (n = 153), the final study population on which the present report was based comprised 2,859 women.
Study variables
The main outcome investigated in these analyses was the cognitive test score difference between the two visits (visit 4 minus visit 2 values). The estrogen replacement therapy status and potential confounders were those measured at visit 2, with the exception of sports index, self-reported health status, plasma fibrinogen, and educational level, which were measured at visit 1 (19871989).
Estrogen replacement therapy. Data on current or past use of estrogen replacement therapy (estrogens only, or estrogens plus progestin) after menopause were obtained by a trained interviewer. Women were initially classified as "never," "former," or "current" users. However, because there were only 153 women in the category "former" users, the final analysis considered only two categories: "never" and "current" users. The duration of estrogen replacement therapy use in menopausal women was classified by three levels, according to the tertiles of duration: "04 years," "510 years," and ">10 years."
Cognitive function. Three neuropsychological tests were applied at both visits: the Delayed Word Recall Test (DWR) (14
), the Digit Symbol Subtest of the Wechsler Adult Intelligence Scale-Revised (DSS/WAIS-R) (15
), and the Word Fluency Test (WF) (16
) of the Multilingual Aphasia Examination. The DWR, WF, and DSS/WAIS-R were administered by trained interviewers. The fact that all ARIC Study interviews were tape recorded allowed the study coordinator in each field center to monitor interviewers' performances by reviewing a random sample of the taped interviews.
The DWR is a test of verbal learning and recent memory. It requires the respondent to recall 10 common nouns after a 5-minute interval during which another test is given. To standardize the elaborative processing of the words to be recalled, persons are required to compose sentences incorporating the nouns as presented. Test scores range from zero to 10 words recalled. This test has been shown to have a high 6-month test-retest reliability (Pearson's correlation coefficient, r = 0.75) (14
).
The DSS/WAIS-R is a pencil-and-paper test requiring timed translation of numbers 19 to symbols using a key. The test measures psychomotor performance and is relatively unaffected by intellectual ability, memory, or learning for most adults (15
). It appears to be a sensitive and reliable marker of brain damage (17
). This test was scored as the number of numbers correctly translated to symbols within 90 seconds (the maximum score possible is 93). Short-term test-retest reliability has been found to be high in middle-aged persons (r = 0.82) (15
).
The WF requires the participant to generate as many words as possible in 60 seconds beginning with a letter from the alphabet. Three trials using the letters F, A, and S were conducted, and the WF score was the total number of words generated over the three trials. The test is particularly sensitive to linguistic impairment (16
, 18
) and early mental decline in older persons (19
). It is also a sensitive indicator of damage to the left lateral frontal lobe (16
, 18
). The immediate test-retest correlation coefficient based on an alternate test form has been found to be high (r = 0.82) (20
).
Covariates. Menopausal status was classified as premenopausal, perimenopausal, and postmenopausal (natural or surgical menopause). Premenopausal women were those who reported having menstruated in the 2 years before visit 2 and who labeled themselves as premenopausal. Perimenopausal women were those who had menstruated in the 2 years before the examination, but who labeled themselves as postmenopausal or as uncertain menopausal. Postmenopausal women included women who had not menstruated in the last 2 years. Menopause was classified as surgical, if women had had a bilateral oophorectomy, or as natural menopause. Natural menopause also included women aged >55 years who had had a hysterectomy without oophorectomy.
The educational level was classified as "incomplete high school," "complete high school or vocational school," or "college or more"; self-reported health status as "excellent," "good," "fair," or "poor"; race as "White" or "Black"; marital status as "married," "widowed," "divorced/separated," or "never married"; smoking status as "never smoker," "former smoker," or "current smoker"; and drinking status as "never drinker," "former drinker," or "current drinker." Diastolic and systolic blood pressure levels were calculated as the average of the second and third of three consecutive measurements with a random zero sphygmomanometer. Hypertension was defined on the basis of a systolic blood pressure of
140 mmHg, a diastolic blood pressure of
90 mmHg, or the use of antihypertensive medication. Women were classified as diabetic if they self-reported diabetes, were taking medications for diabetes, had a 12-hour fasting plasma glucose level of
126 mg/dl, or had a nonfasting glucose level of
200 mg/dl.
Fasting plasma fibrinogen and lipids (cholesterol and its fractions, triglycerides) were measured and expressed as mg/dl (13
). Age was that reported at the second visit; it ranged from 48 to 67 years. The median age was 56 years. Body mass index was calculated as weight (kg)/height (m)2. Carotid intimal-medial thickness was the overall average (µm) for six sites of the carotid artery measured by B-mode ultrasound (13
). Vital exhaustion was assessed by the Maastricht Questionnaire, a 21-item, pencil-and-paper test that assesses mental and physical exhaustion, hopelessness, and symptoms of depression. The Maastricht Questionnaire is a scored test, and its validity as a predictor of myocardial infarction has been established from prospective data provided by the Rotterdam Civil Servants Study (21
). The sports index, using a modified version of the questionnaire of Baecke et al. (22
), measures sports activity during leisure time, taking into consideration intensity, time, frequency, and kind of activity.
Statistical analysis
Linear regression modeling was done using Stata version 6.0 software (23
). Dummy variables were derived for categorical variables. The analyses proceeded in three steps (24
):
- 1. Univariate analyses were carried out to identify the relations between each independent variable and each outcome (changes in DWR, DSS/WAIS-R, and WF). Variables that showed a p value of
0.25 were included in the multivariate models.
- 2. Potential confounders were added to the multivariate models and excluded only if the beta coefficient for the main variable had not materially changed.
- 3. The final models for each cognitive function test estimated the predicted values for the outcomes (adjusted mean between-visit change), according to menopausal status, estrogen replacement therapy use, or estrogen replacement therapy duration, in two age strata using the approximate median age as the cutoff point.
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RESULTS
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The baseline characteristics of the subjects included in the evaluation of cognitive differences between ARIC Study visits 2 and 4 and those of women in whom these differences could not be assessed because relevant information on one or more cognitive tests was missing from one or both visits are shown in table 1. Women with information on cognitive function between-visit changes were found to be slightly younger, better educated, and more often White, and they had better health and cardiovascular risk profiles, a thinner average carotid intimal-medial wall, and higher average cognitive test scores than those with insufficient information to examine temporal differences in cognitive function. In addition, as expected from the age difference, the study sample had a slightly lower proportion of postmenopausal women (about 74 percent) than women excluded from the analysis (84 percent).
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TABLE 1. Baseline characteristics (visit 2) of women in the study sample and women with missing information on cognitive test differences, the Atherosclerosis Risk in Communities Study, 19901998
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At the time of visit 2, there was a greater proportion of women who were surgically menopausal than naturally menopausal who were current users of estrogen replacement therapy (297/430 (69 percent) and 372/1,691 (22 percent), respectively).
Selected characteristics of postmenopausal women included in the analyses according to use of estrogen replacement therapy are shown in table 2. Current users of estrogen replacement therapy were on average younger, more educated, and more often White than were never users of estrogen replacement therapy. In addition, except for triglyceride levels, they had more favorable health and cardiovascular risk profiles and a thinner carotid intimal-medial wall. Vital exhaustion scores were slightly lower for current users of estrogen replacement therapy. Unadjusted mean DSS/WAIS-R between-visit declines were similar for current and never users of estrogen replacement therapy; for DWR, they were close to zero regardless of estrogen replacement therapy use; for WF, they were slightly higher for current users.
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TABLE 2. Distribution of selected variables by use of estrogen replacement therapy among 2,121 postmenopausal women, the Atherosclerosis Risk in Communities Study, 19901998
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The adjusted mean cognitive differences according to menopausal status and estrogen replacement therapy use or according to menopausal status and estrogen replacement therapy duration for each test, using the final models and stratified by the approximate median age at visit 2 (
56 years vs. >56 years), are shown in tables 3 and 4, respectively. The cognitive change patterns for women in the pre- or perimenopause could be examined only for women aged
56 years, because there were only 57 women in these categories who were older than 56 years. On average, the adjusted age declines in cognitive scores between visits 2 and 4 were fairly homogeneous across all categories of menopause and estrogen replacement therapy use. (The results did not materially change when the category "former use" was added to the category "current use.") A similar pattern was detected for estrogen replacement therapy duration, with the exception of the upper tertile of the WF score in naturally menopausal women aged
56 years: Compared with never users, the average decline in the WF score was significantly larger (-5.9) in women who had used the estrogen replacement therapy for 1144 years. Additional adjustment for cognitive test scores at baseline, recommended by some (25
), had no material influence on these results.
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TABLE 3. Adjusted* mean cognitive score differences between visits 4 and 2 by menopausal status and use of estrogen replacement therapy, stratified by median age at visit 2, the Atherosclerosis Risk in Communities Study, 19901998
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TABLE 4. Adjusted* mean cognitive score differences between visits 4 and 2 by duration of use of ERT in menopausal women who are current ERT users, stratified by median age at visit 2, the Atherosclerosis Risk in Communities Study, 19901998
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Finally, differences in cognitive function scores measured at baseline (visit 2 of the cohort) between current estrogen users and nonusers were examined in the persons included and in those excluded, because cognitive data were not available for visit 4. These cross-sectional differences between estrogen users and nonusers were very small, statistically nonsignificant, and very similar in both groups.
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DISCUSSION
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In the present study, with the exception of a significantly larger WF score decline, possibly due to chance resulting from multiple testing, among naturally menopausal women aged
56 years who had used estrogen replacement therapy between 11 and 44 years (compared with nonusers), no associations were observed between estrogen replacement therapy use or duration and 6-year changes in cognitive functioning. This was true for both older (>56 years) and younger (
56 years) women in this cohort aged 4867 years at baseline.
Failure to observe an inverse association between estrogen replacement therapy use and cognition is inconsistent with evidence from animal studies that suggest possible mechanisms whereby estrogens could slow down the age-related cognitive decline in humans (1
, 26
28
). However, it is consistent with results of some recent longitudinal studies (29

32
) and randomized clinical trials (10
, 11
, 33


37
), although by no means all (9
, 38
) studies in humans. The results of the present prospective study are also consistent with the cross-sectional results found in a previous evaluation of ARIC Study data (12
).
The present study used a prospective design, thus making it easier to evaluate temporality when assessing the associations between estrogen replacement therapy and cognitive functioning. In addition, the study was based on a large sample size, making it easier to detect weak associations. Although only 70 percent of the eligible cohort were available for the present analyses, differences in baseline variables between women who were included versus those excluded were taken into consideration in regression models. In addition, when the relation between estrogen use and cognitive function at baseline (visit 2) was assessed both in women who were included in the temporal trend analyses and in those who were excluded because data on cognitive function for visit 4 were missing, the patterns were found to be very similar. Thus, selection bias does not seem to be a likely explanation for the study's failure to show associations between estrogen replacement therapy and differences in mean cognitive scores measured 6 years apart. Furthermore, given the extensive characterization of ARIC Study participants in terms of demographic, medical, and physical factors, we were able to take into consideration the effect of potential confounding variables related to either estrogen replacement therapy use or cognitive functioning, such as vital exhaustion measured by the Maastricht Questionnaire (21
), education, diabetes, smoking, and carotid intimal-medial thickness.
In spite of efforts to adjust for selection and confounding factors, residual negative confounding resulting from variables unaccounted for or from misclassification of variables entered into the regression models cannot be excluded as an explanation for the null findings in the present study. Another potential limitation of the present study is the relatively young age of the ARIC Study cohort, who may be expected to have less cognitive decline over a 6-year interval than that of an older cohort. On the other hand, the relatively young age of the ARIC Study cohort is also a strength in that it avoids confounding by comorbidities that have plagued previous studies of the elderly. An additional problem is that, although the tests used in the current study are known to be sensitive to changes in cognitive function, a broader assessment of cognitive function by the use of additional tests may have revealed different effects.
The prospective nature of the present study, which makes it easier to establish true associations, the fact that careful adjustment for confounding was done, and the lack of a consistent pattern of associations regardless of age would seem to indicate that, at least for women in the age range included in the study, use of estrogen replacement therapy is not associated with age-related cognitive declines.
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ACKNOWLEDGMENTS
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This research was supported by contract N0I-HC-55020 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland, with the Morbidity/Mortality Follow-up Field Center of the Atherosclerosis Risk in Communities Study. Additional support was provided by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Brazil, to S. A. M.
The authors thank the staff and participants in the ARIC Study for their important contributions.
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NOTES
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Reprint requests to Dr. Suzana Moraes, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., Room W6009, Baltimore, MD 21205 (email: smoraes{at}jhsph.edu).
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Received for publication November 29, 2000.
Accepted for publication May 10, 2001.