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Effect of Estrogen Plus Progestin on Stroke in Postmenopausal Women
The Women's Health Initiative: A Randomized Trial
Sylvia Wassertheil-Smoller, PhD;
Susan Hendrix, DO;
Marian Limacher, MD;
Gerardo Heiss, MD;
Charles Kooperberg, PhD;
Alison Baird, MD, PhD, MPH;
Theodore Kotchen, MD;
J. David Curb, MD;
Henry Black, MD;
Jacques E. Rossouw, MD;
Aaron Aragaki, MS;
Monika Safford, MD;
Evan Stein, MD, PhD;
Somchai Laowattana, MD;
W. Jerry Mysiw, MD; for the WHI Investigators
JAMA. 2003;289:2673-2684.
ABSTRACT
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Context The Women's Health Initiative (WHI) trial of estrogen plus progestin was stopped early because of adverse effects, including an increased risk of stroke in the estrogen plus progestin group.
Objective To assess the effect of estrogen plus progestin on ischemic and hemorrhagic stroke and in subgroups, and to determine whether the effect of estrogen plus progestin was modified by baseline levels of blood biomarkers.
Design Multicenter double-blind, placebo-controlled, randomized clinical trial involving 16 608 women aged 50 through 79 years with an average follow-up of 5.6 years. Baseline levels of blood-based markers of inflammation, thrombosis, and lipid levels were measured in the first 140 centrally confirmed stroke cases and 513 controls.
Interventions Participants received 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate (n = 8506) or placebo (n = 8102).
Main Outcome Measures Overall strokes and stroke subtype and severity were centrally adjudicated by stroke neurologists.
Results One hundred fifty-one patients (1.8%) in the estrogen plus progestin and 107 (1.3%) in the placebo groups had strokes. Overall 79.8% of strokes were ischemic. For combined ischemic and hemorrhagic strokes, the intention-to-treat hazard ratio (HR) for estrogen plus progestin vs placebo was 1.31 (95% confidence interval [CI], 1.02-1.68); with adjustment for adherence, the HR was 1.50 (95% CI, 1.08-2.08). The HR for ischemic stroke was 1.44 (95% CI, 1.09-1.90) and for hemorrhagic stroke, 0.82 (95% CI, 0.43-1.56). Point estimates of the HRs indicate that excess risk of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, use of hormones, statins, or aspirin. Other risk factors for stroke, including smoking, blood pressure, diabetes, lower use of vitamin C supplements, blood-based biomarkers of inflammation, higher white blood cell count, and higher hematocrit levels did not modify the effect of estrogen plus progestin on stroke risk.
Conclusions Estrogen plus progestin increases the risk of ischemic stroke in generally healthy postmenopausal women. Excess risk for all strokes attributed to estrogen plus progestin appeared to be present in all subgroups of women examined.
INTRODUCTION
Stroke is a major health issue for women.1-2 Cerebrovascular diseases are the third leading cause of death in the United States3 and are the leading cause of adult disability. The Women's Health Initiative (WHI), beginning in the early 1990s was designed to examine a number of factors affecting the health of postmenopausal women.4 Recently 1 arm of the WHI, the clinical trial of estrogen plus progestin, was terminated 3 years before its planned completion date because its harmful effects outweighed its benefits.
The overall results in this randomized double-blind clinical trial indicated that women in the estrogen plus progestin group had a 41% increase in locally adjudicated strokes over 5.2 years compared with women in the placebo group.5 Our report provides results over an additional 4 months (average follow-up 5.6 years) on subtypes of stroke, based on central adjudication of stroke events by neurologists, additional data on the effects of estrogen plus progestin in various subgroups of women, and data on the effect of lipid levels and biomarkers of inflammation and thrombosis.
A relationship between stroke and hormone use was suggested in early studies showing that oral contraceptive users had higher stroke rates than those not taking oral contraceptives.6 However, results of subsequent epidemiologic studies have been inconsistent and had small numbers of stroke cases. The WHI is the first randomized trial to show that estrogen plus progestin increases risk of stroke in generally healthy women.5 Stroke is a heterogeneous condition, with differing types, mechanisms, and outcomes. Most prior observational studies and randomized clinical trials reported that stroke risk generally encompassed both hemorrhagic and ischemic strokes without consideration of subtype and mechanism although in more recent studies hemorrhagic and ischemic strokes have been reported separately.7-9 By refined classification of stroke type, it may be possible to elucidate better the mechanism of the increased incidence of stroke in the WHI randomized clinical trial of estrogen plus progestin vs placebo.
The mechanism through which these hormones act has not yet been established, but it has been hypothesized to be through inflammatory or thrombotic effects. The interactions of other risk factors with estrogen and progestin use may enhance or diminish these effects. Although a well-studied set of risk factors (including age, blood pressure, diabetes mellitus, and cigarette smoking)10-11 may permit reasonably accurate predictions of an individual's future risk of ischemic stroke, 40% or more of strokes may remain unexplained after these known risk factors are taken into account.12-13 Even among patients with severe stenosis of the large cerebral arteries, approximately half of all strokes do not originate from lesions in the large arteries.14-15 Exposures that may affect risk of ischemic stroke, which may act through the pathways of inflammation and thrombosis, are smoking,16 hypertension,17 overweight, insulin resistance,18 and physical exertion.19 Therapies known or hypothesized to modify risk of stroke, such as aspirin,20 antihypertensive medications,17 antioxidants,21 oral anticoagulants,22 and omega-3 fatty acids,23 are also associated with changes in biomarkers of inflammation or thrombosis. Our report examines in more detail the effects of estrogen plus progestin on ischemic and hemorrhagic stroke, including a consideration of risk factors and medical therapies that may modify the effect of estrogen plus progestin on stroke.
METHODS
Study Population
Details of the WHI design are reported elsewhere.4 Postmenopausal women aged 50 through 79 years who gave written informed consent were enrolled in the WHI at 40 clinical centers in the United States. Women were considered postmenopausal if they were between the ages 50 and 54 years and had no vaginal bleeding for at least 12 months or were aged 55 through 79 years and had no bleeding in the prior 6 months. To be eligible for the trial of estrogen plus progestin, women had to have an intact uterus. Exclusions were participation in other randomized trials, predicted survival of less than 3 years, alcoholism, drug dependency, diagnosed mental illness, dementia, or other conditions suggesting that a woman would not be adherent to study medicines or other procedures.
Exclusions for safety reasons included prior diagnosis of breast cancer or other cancers within the past 10 years (except nonmelanoma skin cancer). Women with systolic blood pressure (SBP) of 200 mm Hg or higher or diastolic blood pressure (DBP) of 105 mm Hg or higher were advised to see their physician within a specified period depending on blood pressure level and were temporarily excluded from the clinical trials until their blood pressure was determined to be under control. Most women had never taken hormone therapy prior to enrollment. Those who were taking hormones were required to have a 3-month washout period before their baseline visit.
Study Pills
Treatment consisted of combined estrogen and progestin, provided as 1 tablet taken daily, containing 0.625 mg of conjugated equine estrogen and 2.5 mg of medroxyprogesterone acetate (Prempro, Wyeth Ayerst, Philadelphia, Pa), or matching placebo. Details of randomization have been published .4-5 The trial reported herein consists of 8506 participants randomized to take the estrogen plus progestin and 8102 randomized to be in the placebo group. Participants were followed up for an average of 5.6 years.
Study medication was discontinued permanently by protocol for women who developed breast cancer; endometrial hyperplasia not responsive to treatment; atypia or cancer; deep-vein thrombosis or pulmonary embolism; malignant melanoma; meningioma; triglyceride level greater than 1000 mg/dL (11.3 mmol/L); or prescription of estrogen, testosterone, or selective estrogen-receptor modulators by their personal physicians. Medications were temporarily discontinued for participants who had acute myocardial infarction, stroke, fracture, or major injury requiring hospitalization, surgery involving use of anesthesia, or any illness resulting in immobilization for more than 1 week.
Follow-up and End Point Determination
Women were required to come to the clinic annually and have semiannual contacts in the clinic or by telephone. At each semiannual contact, a standardized interview asked them about symptoms, safety, adherence to study pills, and potential outcome events. When a potential outcome was identified, medical records and death certificates were obtained as necessary. Physician adjudicators at clinical sites reviewed the information to determine the cause of the event. Third-party reports directly given to clinic staff were also followed up by obtaining the requisite records. Transient ischemic attacks requiring hospitalization were ascertained and records obtained. One of 3 stroke neurologists centrally adjudicated locally determined strokes, transient ischemic attacks, and women's self-reports of stroke that had been not confirmed by local adjudicators after careful review of the medical records. Of locally adjudicated strokes, 94.5% were confirmed by the central adjudicators. Of centrally adjudicated strokes, 93.8% had been classified as strokes by the local adjudicators. This article presents stroke data centrally confirmed by neurologists. Local and central adjudicators were blinded to treatment assignment.
Stroke diagnosis requiring and/or occurring during hospitalization was based on rapid onset of a neurological deficit attributable to an obstruction or rupture of an arterial vessel system. The deficit was not known to be secondary to brain trauma, tumor, infection, or other cause and must have lasted more than 24 hours unless death supervened or a lesion compatible with acute stroke was evident on computed tomography or magnetic resonance imaging scan. Strokes were classified as ischemic or hemorrhagic based on review of reports of brain imaging studies. A stroke was defined as procedure related if it occurred within 24 hours after any procedure or within 30 days after a cardioversion or invasive cardiovascular procedure.
The 6 categories of stroke were (1) subarachnoid hemorrhage not resulting from a procedure; (2) intracerebral hemorrhage not resulting from a procedure; (3) other or unspecified intracranial hemorrhage not resulting from a procedure (nontraumatic epidural hemorrhage or subdural hemorrhage); (4) occlusion of cerebral or pericerebral arteries with infarction not resulting from a procedure (cerebral thrombosis, cerebral embolism, lacunar infarction); (5) acute, but ill defined, cerebrovascular disease not resulting from a procedure (this option is used only if the adjudicator was unable to code it as hemorrhagic or ischemic); (6) and central nervous system complications during or resulting from a procedure. For analysis purposes, categories 1, 2, and 3 were combined as hemorrhagic strokes; category 4 was classified as ischemic stroke; and categories 5 and 6 were combined as other stroke.
Ischemic strokes were further classified by the central neurologist adjudicators according to the Oxfordshire24 and Trial of Org 10172 Acute Stroke Trial (TOAST)25 criteria to examine stroke subtypes. The TOAST classification focuses on the presumed underlying stroke mechanism; requires detailed investigations (such as brain computed tomography, magnetic resonance imaging, angiography, carotid ultrasound, and echocardiography); and distinguishes 5 categories of stroke, which include large-artery atherothrombosis, cardioembolic, lacunar (small vessel), other, and undetermined mechanism. However, even with the extensive work-up, 39% of strokes were of undetermined mechanism, including cryptogenic stroke (no cause found on work-up), incomplete evaluation to make a determination, and 2 or more causes identified. This classification, the best currently available, shows moderate to good interobserver reliability with training.26-28
For the purpose of analyses, stroke subtypes judged probable or possible are combined. The Oxfordshire classification24 is based on clinical assessment of the patient in whom a computed tomographic brain scan has excluded cerebral hemorrhage and classifies patients into total anterior circulation infarct, partial anterior circulation infarct, lacunar infarct, and posterior circulation infarct. This scale has the advantage that virtually all patients can be classified; it shows a correlation with outcome and severity and has a moderate-to-good interobserver reliability for the classification in practice.28 The Glasgow Outcome Scale score was ascertained by clinical information available at the time of hospital discharge to provide an assessment of stroke outcome.29-30
Definition of Variables
Hypertension was defined as either elevated clinic blood pressure (SBP  140 mm Hg and/or DBP 90 mmHg), a self-report of taking medications for hypertension, or both. Baseline blood pressure was measured at the first clinic visit by certified staff using standardized procedures and instruments using a conventional mercury sphygmomanometer, after the participant was seated and resting for 5 minutes. The average of 2 sitting readings, obtained at least 30 seconds apart, was used for analyses.
Physical activity was assessed by asking about the frequency and duration of walking at various intensities and 3 other types of recreational activity classified by intensity (strenuous, moderate, or light). Data were summarized into episodes per week of moderate or strenuous activity (as defined by a metabolic equivalent score of at least 4.0 as indicated by Ainsworth and colleagues31 of at least 20 minutes' duration). One metabolic equivalent is the amount of energy expended sitting quietly at rest adjusted to body weight, equal to 1 kcal/kg per hour. Women reporting some recreational activity but of shorter duration and/or lesser intensity were classified as engaging in some activity. Vasomotor symptoms were assessed from responses to questions on the presence of hot flashes or night sweats. A 12-lead electrocardiogram was performed at baseline and every 3 years.
Statistical Analyses
Baseline characteristics between placebo and estrogen plus progestin groups were compared using the  2 test. The Fisher exact test was used for comparisons between randomization assignment and stroke-severity classification. The Cochran-Armitage test was used to determine whether treatment assignment was associated with a linear trend in stroke severity.
Outcome comparisons were made from Cox proportional hazards analyses and Kaplan-Meier curves for the entire population. Additional analyses examined effects of estrogen plus progestin in 11 subgroups of special clinical interest: by age group, race or ethnicity, years since menopause, prior history of cardiovascular disease, hypertensive status, duration of prior hormone use, statin and aspirin use, vasomotor symptoms at baseline, vasomotor symptoms within the youngest group, and by tertile of Framingham scores for stroke risk. Framingham risk scores reflect the probability of stroke within 10 years for women aged 55 to 84 years, based on use of antihypertensive medications, as well as SBP, age, diabetes mellitus, cigarette smoking, prior cardiovascular disease, atrial fibrillation, and left ventricular hypertrophy by electrocardiogram.32 In addition, 16 biomarkers were examined, resulting in a total of 27 subgroups. At the .05 level of significance, 1 of 20 comparisons may be statistically significant by chance. Nominal confidence intervals (CIs) are presented throughout, except for stroke outcome, which was 1 of 7 outcomes monitored by the data and safety monitoring board, so we also present the adjusted CIs in this instance.
All primary analyses of time-to-first stroke were based on the intention-to-treat principle. The effect modification of stroke risk with estrogen plus progestin by potential risk factors was assessed by first-fitting univariate Cox proportional hazards models. Variables showing a marginal relationship with stroke (P<.25) were all included in a multivariate Cox model with estrogen plus progestin. Statistical significance of the interaction between estrogen plus progestin and these variables was explored 1 at a time using the score test. All Cox models were stratified on age, prior stroke, and randomization assignment in the dietary modification trial and were adjusted for race or ethnicity. The proportional hazards assumption was verified by testing the interaction of time and estrogen plus progestin and through visual inspection of the survival function.
Secondary analyses were performed to account for participant adherence, to determine if any risk conferred by estrogen plus progestin could not be explained by increases in SBP and if risk differed by stroke type. In the adherence-adjusted analyses, participants' event histories were censored 6 months after they became nonadherent (stopped taking study drugs, were using <80% of study drugs, or, if in the placebo group, started hormone therapy). A Cox model that included follow-up SBP as a time-dependent covariate was used to estimate the additional risk of estrogen plus progestin unrelated to its effect on SBP. Differences in risk between ischemic and hemorrhagic strokes were assessed by competing-risks analysis using Cox models. Significance was based on a Wald 2 test of scaled coefficient differences. Analysis were performed by SAS statistical software version 8.02 (SAS Inc, Cary, NC).
The protocol included a blood draw at baseline after a minimum 10-hour fast. Serum and plasma specimens were maintained at 4°C until separated, aliquoted, and frozen at -70°C, until they were shipped on dry ice to the laboratory (Medical Research Laboratories, Highland Heights, Ky), for analysis. All lipid and lipoprotein fractions were analyzed on EDTA-treated plasma, using methods described elsewhere.33-37 Fibrinogen and factor VIII were measured in frozen citrated plasma using a clot-based turbidometric detection system (MLA Electra 1400c, Pleasantville, NY). Human interleukin 6 (IL-6) was quantitated using a high-sensitivity sandwich enzyme-linked immunoassay (R&D Systems, Minneapolis, Minn). Soluble endothelial leukocyte adhesion molecules (E-selectin) was measured by enzyme-linked immunosorbent assay (R&D Systems). High-sensitivity C-reactive protein was measured using an ultra-sensitive rate immunonephelemetric method (Dade-Behring, Marburg, Germany). Matrix metalloproteinase 9 (MMP-9) was quantitated using an enzyme-linked immunosorbent assay procedure (Quantikine human MMP-9, R&D Systems).
Associations of biomarkers with stroke by randomization group were assessed using logistic regression models on available case-control data. Cases were the first 140 strokes that were locally adjudicated as stroke before February 2001 and later confirmed centrally. There were 513 controls: a control with an intact uterus was selected for each case, matched on age, randomization year, and presence of baseline stroke. Additional controls that had been selected for women who developed coronary heart disease and venous thrombosis were included in these analyses.
RESULTS
Baseline Characteristics
Baseline characteristics of the estrogen plus progestin and placebo groups are shown in Table 1. Both groups were similar with respect to baseline demographic and risk factor characteristics with no significant differences between the 2 groups on any of the variables except for history of transient ischemic attack, which was higher in the placebo group (P = .03) than in the treatment group. The average participant age was 63.3 years; 33% of women were in the 50 through 59 year age group. Before WHI enrollment, 74.3% of participants never used hormones. Ninety-five percent had no history of cardiovascular disease.
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Table 1. Baseline Characteristics of the Women's Health Initiative Estrogen Plus Progestin Trial Participants by Randomization Assignment*
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Stroke and Stroke Subtype Events
There were 151 strokes in the estrogen plus progestin group (1.8%) and 107 in the placebo group (1.3%) as of July 7, 2002, after an average of 5.6 years of follow-up; all women had been enrolled for a minimum of 3.7 years and a maximum of 8.6 years. Ischemic strokes accounted for 79.8% of all strokes (82.8% estrogen plus progestin; 75.7% placebo), and hemorrhagic strokes accounted for 14.8% of strokes (11.9% estrogen plus progestin; 18.6% placebo, Table 2). Three strokes were not classified as ischemic or hemorrhagic, 1 of which resulted from a surgical procedure. Of 38 hemorrhagic strokes, 10 (26.3%) were due to subarachnoid hemorrhage.
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Table 2. Diagnosis, Classification, and Severity of Centrally Adjudicated Stroke in the Women's Health Initiative Estrogen Plus Progestin Trial Participants by Randomization Assignment*
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Of 206 ischemic strokes in both groups, 24 (11.7%) were cardioembolic; 28 (13.6%), large artery; and 58 (28.2%), small vessel. There were 23 stroke deaths, 12 in the estrogen plus progestin and 11 in the placebo groups; 11 of these were reports of cerebrovacular deaths only (6 estrogen plus progestin; 5 placebo) without classification of type. Distributions of ischemic stroke subtypes by Oxfordshire and TOAST classifications did not differ significantly between the 2 treatment groups nor did severity of stroke differ on the Glasgow Outcome Scale.
The hazard ratio (HR) for all stroke subtypes combined was 1.31 (nominal 95% CI, 1.02-1.68). Because 7 end points were monitored by the data and safety monitoring board and examined to assess the global risk vs benefit of estrogen plus progestin,5 the conservative Bonferroni adjusted 95% CI was (0.93-1.84). The HR for ischemic stroke was 1.44 (95% CI, 1.09-1.90), and for hemorrhagic stroke, it was 0.82 (95% CI, 0.43-1.56; Table 3).
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Table 3. Annualized Percentage of Stroke Events and Hazard Ratios of the Women's Health Initiative Estrogen Plus Progestin Trial Participants by Randomization Assignment and in Selected Subgroups*
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Subgroup Analyses
Hazard ratios for all stroke subtypes combined were similar across age groups (Table 3). Women who never used hormones before randomization had a 37% excess risk of stroke with estrogen plus progestin (HR, 1.37; 95% CI, 1.03-1.82). Use of statins or aspirin at baseline did not modify the effect of estrogen plus progestin, and the findings remained similar when participants with prior cardiovascular disease were excluded (n = 24) from the analysis (data not shown). The effect of estrogen plus progestin on stroke risk was similarly increased in women with and without vasomotor symptoms at baseline. Thirteen women taking estrogen plus progestin and 5 women taking placebo who were aged 50 through 59 years and who had vasomotor symptoms had experienced a stroke. Point estimates of HRs were higher for estrogen plus progestin in virtually all subgroups examined and did not differ from the overall HR of 1.31 for total strokes.
Time Trends
Kaplan-Meier cumulative hazard of stroke (all types of stroke combined) begins to diverge between 1 and 2 years after randomization (Figure 1). Cumulative hazards within each of the 3 age groups (50-59, 60-69, 70-79 years), for normotensive and hypertensive women, and within low, medium, and high stroke–risk tertiles as determined from the Framingham equations, indicate that within each of these groups there was an adverse effect of estrogen plus progestin compared with placebo, but the adverse effect of estrogen plus progestin was delayed in the low-risk tertile compared with the middle or highest tertile of Framingham stroke risk and in normotensive compared with hypertensive women (data not shown).
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Figure 1. Estimates of Cumulative Hazards for Strokes
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Other Stroke Risk Factors
Black women were 75% more likely to have a stroke than white women (HR, 1.75; 95% CI, 1.14-2.68). Risk of stroke, adjusted for race or ethnicity, was significantly associated with current smoking (HR, 2.31; 95% CI, 1.61-3.31), hypertension (HR, 1.85; 95% CI, 1.42-2.42), higher baseline SBP (HR, 1.22; 95% CI, 1.14-1.30 per 10 mm Hg increase), or DBP (HR, 1.21; 95% CI, 1.06-1.38 per 10 mm Hg increase), having left ventricular hypertrophy at baseline (HR, 1.73; 95% CI, 1.13-2.66), having diabetes (HR, 2.23; 95% CI, 1.47-3.38), and with Framingham stroke risk score (HR, 6.36; 95% CI, 3.76-10.76 for highest tertile compared with lowest tertile of Framingham stroke risk). Increased white blood cell count (P<.001) and higher hematocrit levels (P<.001) were also significantly related to stroke risk. Reduced risk was associated with taking vitamin C supplements (HR, 0.74; 95% CI, 0.58 -0.95) and physical activity (HR, 0.65; 95% CI, 0.44-0.97 for participants who reported 4 or more episodes a week of moderate or strenuous activity). Prior oral contraceptive use was not related to stroke risk.
Multivariate Analyses
We ran Cox regression models including as independent variables those univariately related to stroke with P<.05 as noted above, plus additional variables with P>.05 and P<.25 (data not shown). To examine potential interactions of variables from this core set with estrogen plus progestin, we included each interaction term 1 at a time. There were no significant interactions (P>.05) of estrogen plus progestin with any of these variables or with the Framingham risk score, which is a composite of some of these variables. Other analyses indicated no significant interactions of estrogen plus progestin with age or use of aspirin, nonsteroidal anti-inflammatory drugs, statins, or prior oral contraceptives.
Use of estrogen plus progestin was not associated with an increase in DBP, but it was associated with an increase in SBP (average <2 mm Hg).5
For women taking estrogen plus progestin, the unadjusted HR was 1.31 (95% CI, 1.02-1.68, Table 4). Adjustment for race or ethnicity and baseline SBP did not affect the risk of stroke for those taking estrogen plus progestin, nor did further adjustments for multiple covariates affect stroke risk. Adjustment for SBP as a time-dependent variable did not appreciably change the HR. Thus, the effect of estrogen plus progestin on SBP did not explain the excess risk of stroke associated with estrogen plus progestin. In an analysis that adjusted for adherence, the HR was higher than in the intention-to-treat analysis (HR, 1.50; 95% CI, 1.08-2.08), and higher HRs were found in all models tested.
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Table 4. Risk of Stroke With Estrogen Plus Progestin vs Placebo
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Blood Biomarkers
In a substudy of blood biomarkers to examine the effects of lipid levels, inflammatory markers, and thrombotic factors on the excess risk associated with estrogen plus progestin, the first 140 stroke cases that were locally adjudicated and centrally confirmed were compared with 513 controls who had no stroke, myocardial infarction, or venous thromboembolism up to that time. The overall odds ratio of estrogen plus progestin in this case-controlled substudy is 1.47 (95% CI, 1.00-2.16).
The odds ratios for each biomarker tertile in relation to the lowest tertile in the placebo group are shown in Figure 2 and Figure 3. Inflammatory markers (C-reactive protein, IL-6, and E-selectin) were associated with increased risk of stroke. For example women in the highest tertile of C-reactive protein in the placebo group had 3.0 times the risk of stroke as those in the lowest tertile, whereas women in the highest tertile of C-reactive protein in the estrogen plus progestin group had 3.9 times the risk of stroke as those in the lowest tertile of the placebo group. However, there were no significant interactions of baseline inflammatory markers and estrogen plus progestin, indicating that the increased risk associated with higher levels of inflammatory markers held true in both placebo and estrogen plus progestin. Factor VIII coagulant activity and fibrinogen concentration were not associated with stroke risk. Of the lipids, only high-density lipoprotein-3 was statistically significantly related to stroke risk with higher levels being protective. Similarly, there were no significant interactions between estrogen plus progestin and lipid levels or thrombosis markers. All odds ratios for estrogen plus progestin vs placebo do not differ significantly from the overall odds ratio of 1.47 in the case-control substudy (Figure 2 and Figure 3).
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Figure 2. Odds Ratios for Blood Inflammatory Markers and Stroke Risk
*Odds ratios for all biomarkers use placebo lowest tertile of that biomarker as the reference group. In the display of confidence intervals, the odds ratios pertain to the effect of estrogen plus progestin within each tertile of biomarker.
 Based on a 2-degree-of-freedom likelihood ratio statistic.
 Placebo group within each tertile is used as the reference group for odds ratios and corresponding 95% confidence intervals (CIs), which are presented as error bars. IL-6 indicates interleukin 6; MMP-9, matrix metalloprotein 9. To convert fibrinogen from mg/dL to µmol/L, multiply by 0.0294.
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Figure 3. Odds Ratios for Blood Biomarkers and Stroke Risk
To convert total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (LDL-C), HDL-2, and HDL-3 from mg/dL to mmol/L, multiply by 0.0259; lipoprotein(a) (Lp[a]), multiply by 0.0357; and triglycerides from mg/dL to mmol/L, multiply by 0.0113.
*Odds ratios for all biomarkers use placebo lowest tertile of that biomarker as the reference group. In the display of confidence intervals, the odds ratios pertain to the effect of estrogen plus progestin within each tertile of biomarker.
Based on a 2-degree-of-freedom likelihood ratio statistic.
Placebo group within each tertile is used as the reference group for odds ratios and corresponding 95% confidence intervals (CIs), which are presented as error bars.
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COMMENT
In this clinical trial involving 16 608 postmenopausal women, those taking estrogen plus progestin had an approximate 31% increase in total stroke risk compared with those taking placebo. This increased risk was significant for ischemic but not hemorrhagic stroke although there were too few hemorrhagic strokes to draw conclusions about the risk of estrogen plus progestin for this subtype. The increase was unrelated to a number of other risk factors, including age and a prior history of cardiovascular disease, hormone use, or hypertension. Furthermore, no interaction was observed between estrogen plus progestin and any stroke risk factor that might allow identification of women at the highest risk of stroke when taking estrogen plus progestin. The increase in risk did not appear until after the first year of treatment. The results extend those published in the first WHI report,5 with the use of central adjudication of strokes, the addition of new cases (from 212 to 258), data on the effects of estrogen plus progestin in various subgroups of women, and assessment of biomarker levels and stroke risk.
Prior case-control, observational studies and randomized clinical trials of postmenopausal hormone therapy have given conflicting results in relation to stroke risk,38 with some showing decreased risk39-42 others showing no effect,43-45 and, yet, others46 including the Framingham study, showing increased risk.47 A recent meta-analysis also reported increased risk.48 Two prior randomized controlled trials have evaluated the effect of estrogen with or without progestin on stroke risk. The Heart and Estrogen/progestin Replacement Study (HERS)9 was a secondary coronary heart disease prevention trial using a combination of 0.625 mg of conjugated equine estrogen and 2.5 mg of medroxyprogesterone acetate. Of the 2763 women with known coronary heart disease, whose mean age was 67 years and who were followed up for a mean of 4.1 years, 149 had strokes. Hormone therapy in HERS was not significantly associated with risk of all strokes (HR, 1.23; 95% CI, 0.89-1.70), and results were similar for ischemic and hemorrhagic strokes. The Women's Estrogen for Stroke Trial (WEST)8 was a secondary stroke prevention trial in which 664 women with a mean age of 71 years using estrogen alone (1 mg of 17B-estradiol), who were followed up for a mean of 2.8 years, had a total of 192 strokes. No difference in the combined end point of recurrent stroke and fatality rate was found; however, there was an increased rate of fatal stroke and an early increase in overall stroke rate in the first 6 months, but this was not sustained.
In WHI, 79.8% of all strokes were ischemic while 14.7% were hemorrhagic. The increased risk with estrogen plus progestin is related to ischemic stroke. Because the numbers of hemorrhagic strokes were very low, no definitive conclusion can be drawn about how or whether hormone therapy affects the risk of hemorrhagic stroke. The distributions of stroke subtypes and stroke severity were similar in the estrogen plus progestin and placebo groups. Determination of ischemic stroke subtype was made from chart review. While chart documentation was adequate for most patients, evaluation was incomplete for some patients. The time trend for stroke differed from WEST, in which the early increase in stroke risk observed in the first 6 months disappeared over time as it did in HERS, in which an early increase in the coronary event rate in the estrogen plus progestin group was reported in the first year of follow-up. Both WEST and HERS were secondary prevention trials involving women at high risk of stroke.
In contrast, WHI is a trial involving predominantly healthy women with only 5% having a history of cardiovascular disease. Their low-baseline risk is illustrated by the fact that even though the WHI cohort was much larger (N = 16 608) than the other 2 studies, only 258 strokes occurred during the 5.6-year follow-up. When considering ischemic stroke, estrogen has been believed to have a neuroprotective effect through perfusion-dependent and independent mechanisms and so may be associated with less severe strokes and better stroke outcome49; however, in our study there were no differences in stroke outcome as classified by the Glasgow Outcome Scale. In prior observational studies, the increased risk involved nonfatal rather than fatal strokes. Similarly in WHI most of the increased elevation was in nonfatal strokes, with only 23 stroke-related deaths occurring in both groups combined.
The WHI trial used a specific combination of hormones: 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate taken daily. The WHI trial studying the effect of estrogen alone on women with no uterus is continuing and is scheduled to be completed in 2005. The question of whether giving estrogen plus progestin to younger women when they first reach menopause would confer the same risks has been raised. Our study does not address the issue of short-term hormone use for postmenopausal symptoms or perimenopausal use of hormones. However, in our youngest age group (50-59 years), the results were similar, if not more extreme than in older women, showing about a 46% increase in risk of stroke. There was no indication that estrogen plus progestin had a different effect in the younger women (aged 50-59 years) who experienced vasomotor symptoms (hot flashes or night sweats). These women showed an HR of 2.42 (95% CI, 0.86 -6.80), but the number of events in this subgroup was very small. Additionally, the effect of estrogen plus progestin did not vary according to years since menopause. Furthermore, defining short-term is problematic. In our study, the excess stroke risk became apparent by the second year. The rates of discontinuation of medication, while similar in both treatment groups, were high (approximately 40%) although comparable with what has been reported in practice. However, our results of excess risk of stroke with estrogen plus progestin in the intention-to-treat analysis were confirmed and strengthened by the per protocol analyses that indicated a relative risk of 1.50 (95% CI, 1.08-2.08).
The case-control substudy of inflammatory, thrombogenic, and lipid biomarkers indicated that inflammation plays a role in increasing stroke risk, but does not do so differentially in women who received estrogen plus progestin than in those who received placebo. Inflammation has been shown to be a risk factor for coronary heart disease,50-51 and our findings demonstrate that it is also a risk factor for stroke. Whether changes brought about by estrogen plus progestin play a role remains to be determined in future analyses of postbaseline biomarker levels.
In summary, the results from this large randomized, double-blind clinical trial, conducted in multiple centers among a generally healthy, ethnically diverse group of postmenopausal women indicate that combined estrogen plus progestin use poses a significant increase in risk of stroke, in particular ischemic stroke, overall, and provide no indication that any of the multiple subgroups examined had a different risk. This increased risk is not accounted for by an increase in blood pressure. Together with other findings reported from WHI5 of increased risk of invasive breast cancer, myocardial infarction, and venous thrombosis, the stroke data indicate that the risks of estrogen plus progestin outweigh the potentially beneficial effects.
AUTHOR INFORMATION
| |
Corresponding Author and Reprints: Sylvia Wassertheil-Smoller, PhD, Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Room 1312 Belfer, Bronx, NY 10461 (e-mail: smoller{at}aecom.yu.edu).
Financial Disclosures: Dr Wassertheil-Smoller owns stock in Eli Lilly Co. Dr Hendrix has received grant support from Bristol-Myers Squibb, 3M, Organon, Merck & Co, TAP, MGI Pharma, Wyeth-Ayerst, and GlaxoSmithKline; has consulted for Eli Lilly & Co, Merck & Co, Proctor & Gamble, GlaxoSmithKline, and Organon; served on the speaker's bureau for Eli Lilly & Co, 3M, and Organon. Dr Black has received research support from Bristol-Myers Squibb, Boehringer Ingelheim, MSD, and Pfizer/Pharmacia; served as a consultant for Abbott Laboratories, Astra-Zeneca, Biovail, Bristol-Myers Squibb, GlaxoSmithKline, MDS, and Pfizer/Pharmacia; and served on the speaker's bureau for Astra-Zeneca, Bristol-Myers Squibb, MSD, Norvartis, Pfizer/Pharmacia, and Wyeth-Ayerst.
Author Contributions: Study concept and design: Wassertheil-Smoller, Curb, Black, Rossouw.
Acquisition of data: Wassertheil-Smoller, Hendrix, Limacher, Baird, Kotchen, Curb, Black, Safford, Stein, Mysiw.
Analysis and interpretation of data: Wassertheil-Smoller, Hendrix, Limacher, Heiss, Kooperberg, Baird, Kotchen, Curb, Black, Aragaki, Laowattana.
Drafting of the manuscript: Wassertheil-Smoller, Hendrix, Baird, Curb, Black, Stein.
Critical revision of the manuscript for important intellectual content: Wassertheil-Smoller, Hendrix, Limacher, Heiss, Kooperberg, Baird, Kotchen, Curb, Black, Rossouw, Aragaki, Safford, Stein, Laowattana, Mysiw.
Statistical expertise: Wassertheil-Smoller, Kooperberg, Aragaki.
Obtained funding: Wassertheil-Smoller, Curb, Black, Rossouw, Safford.
Administrative, technical, or material support: Hendrix, Limacher, Baird, Curb, Black, Rossouw, Aragaki, Stein, Mysiw.
Study supervision: Hendrix, Limacher,Curb, Black, Rossouw.
Cardiovascular disease epidemiology: Heiss.
Stroke adjudication: Laowattana.
Program Office: National Heart, Lung, and Blood Institute, Bethesda, Md: Barbara Alving, Jacques E. Rossouw, Linda Pottern, Shari Ludlam, and Joan A. McGowan.
Clinical Coordinating Center: Fred Hutchinson Cancer Research Center, Seattle, Wash: Ross Prentice, Garnet Anderson, Andrea LaCroix, Ruth Patterson, Anne McTiernan, Barb Cochrane, Julie Hunt, Lesley Tinker, Charles Kooperberg, Martin McIntosh, C. Y. Wang, Chu Chen, Deborah Bowen, Alan Kristal, Janet Stanford, Nicole Urban, Noel Weiss, and Emily White; Bowman Gray School of Medicine, Winston-Salem, NC: Sally Shumaker, Pentti Rautaharju, Ronald Prineas, and Michelle Naughton; Medical Research Labs, Highland Heights, Ky: Evan Stein and Peter Laskarzewski; University of California at San Francisco, San Francisco: Steven Cummings, Michael Nevitt, and Maurice Dockrell; University of Minnesota, Minneapolis: Lisa Harnack; McKesson BioServices, Rockville, Md: Frank Cammarata and Steve Lindenfelser; and University of Washington, Seattle: Bruce Psaty and Susan Heckbert.
Research Laboratory for Biomarker Study: Mary Cushman, Elaine Cornell, Margaret Doyle. Laboratory for Clinical Biochemistry Research, University of Vermont, Burlington.
Clinical Centers: Albert Einstein College of Medicine, Bronx, NY: Sylvia Wassertheil-Smoller, William Frishman, Judith Wylie-Rosett, David Barad, and Ruth Freeman; Baylor College of Medicine, Houston, Tex: Jennifer Hays, Ronald Young, Jill Anderson, Sandy Lithgow, and Paul Bray; Brigham and Women's Hospital, Harvard Medical School, Boston, Mass: JoAnn Manson, Julie Buring, J. Michael Gaziano, Kathryn Rexrode, and Claudia Chae; Brown University, Providence, RI: Annlouise R. Assaf, Richard Carleton, Carol Wheeler, Charles Eaton, and Michelle Cyr; Emory University, Atlanta, Ga: Lawrence Phillips, Margaret Pedersen, Ora Strickland, Margaret Huber, and Vivian Porter; Fred Hutchinson Cancer Research Center, Seattle, Wash: Shirley A. A. Beresford, Vicky M. Taylor, Nancy F. Woods, Maureen Henderson, and Mark Kestin; George Washington University, Washington, DC: Judith Hsia, Nancy Gaba, Joao Ascensao, and Somchia Laowattana; Harbor-University of California Los Angeles Research and Education Institute, Torrance: Rowan Chlebowski, Robert Detrano, Anita Nelson, James Heiner, and John Marshall; Kaiser Permanente Center for Health Research, Portland, Ore: Cheryl Ritenbaugh, Barbara Valanis, Patricia Elmer, Victor Stevens, and Njeri Karanja; Kaiser Permanente Division of Research, Oakland, Calif: Bette Caan, Stephen Sidney, Geri Bailey and Jane Hirata; Medical College of Wisconsin, Milwaukee: Jane Morley Kotchen, Vanessa Barnabei, Theodore A. Kotchen, Mary Ann C. Gilligan, and Joan Neuner; MedStar Research Institute/Howard University, Washington, DC: Barbara V. Howard, Lucile Adams-Campbell, Maureen Passaro, Monique Rainford, and Tanya Agurs-Collins; Northwestern University, Chicago and Evanston, Ill: Linda Van Horn, Philip Greenland, Janardan Khandekar, Kiang Liu, and Carol Rosenberg; Rush-Presbyterian St Luke's Medical Center, Chicago, Ill: Henry Black, Lynda Powell, and Ellen Mason; Stanford Center for Research in Disease Prevention, Stanford University, Stanford, Calif: Marcia L. Stefanick, Mark A. Hlatky, Bertha Chen, Randall S. Stafford, and Linda C. Giudice; State University of New York at Stony Brook, Stony Brook: Dorothy Lane, Iris Granek, William Lawson, Gabriel San Roman, and Catherine Messina; Ohio State University, Columbus: Rebecca Jackson, Randall Harris, David Frid, W. Jerry Mysiw, and Michael Blumenfeld; University of Alabama at Birmingham, Birmingham: Cora E. Lewis, Albert Oberman, Mona N. Fouad, James M. Shikany, and Delia Smith West; University of Arizona, Tucson and Phoenix: Tamsen Bassford, John Mattox, Marcia Ko, and Timothy Lohman; University at Buffalo, Buffalo, NY: Maurizio Trevisan, Jean Wactawski-Wende, Susan Graham, June Chang, and Ellen Smit; University of California at Davis, Sacramento: John Robbins, S. Yasmeen, Karen Lindfors, and Judith Stern; University of California at Irvine, Orange: Allan Hubbell, Gail Frank, Nathan Wong, Nancy Greep, and Bradley Monk; University of California at Los Angeles, Los Angeles: Howard Judd, David Heber, and Robert Elashoff; University of California at San Diego, LaJolla and Chula Vista: Robert D. Langer, Michael H. Criqui, Gregory T. Talavera, Cedric F. Garland, and R. Elaine Hanson; University of Cincinnati, Cincinnati, Ohio: Margery Gass, Suzanne Wernke, and Nelson Watts; University of Florida, Gainesville and Jacksonville: Marian Limacher, Michael Perri, Andrew Kaunitz, R. Stan Williams, and Yvonne Brinson; University of Hawaii, Honolulu: J. David Curb, Helen Petrovitch, Beatriz Rodriguez, Kamal Masaki, and Santosh Sharma; University of Iowa, Iowa City and Davenport: Robert Wallace, James Torner, Susan Johnson, Linda Snetselaar, and Bradley VanVoorhis; University of Massachusetts and Fallon Clinic, Worcester: Judith Ockene, Milagros Rosal, Ira Ockene, Robert Yood, and Patricia Aronson; University of Medicine and Dentistry of New Jersey, Newark: Norman Lasser, Norman Hymowitz, Vera Lasser, Monika Safford, and John Kostis; University of Miami, Miami, Fla: Mary Jo O'Sullivan, Linda Parker, R. Estape, and Diann Fernandez; University of Minnesota, Minneapolis: Karen L, Margolis, Richard H. Grimm, Donald B. Hunninghake, June LaValleur, and Kathleen M. Hall; University of Nevada, Reno: Robert Brunner, Sachiko St Jeor, William Graettinger, and Vicki Oujevolk; University of North Carolina, Chapel Hill: Gerardo Heiss, Pamela Haines, David Ontjes, Carla Sueta, and Ellen Wells; University of Pittsburgh, Pittsburgh, Pa: Lewis Kuller, Arlene Caggiula, Jane Cauley, Sarah Berga, and N. Carole Milas; University of Tennessee, Memphis: Karen C. Johnson, Suzanne Satterfield, Raymond W. Ke, Jere Vile, and Fran Tylavsky; University of Texas Health Science Center, San Antonio: Robert Brzyski, Robert Schenken, Jose Trabal, Mercedes Rodriguez-Sifuentes, and Charles Mouton; University of Wisconsin, Madison: Catherine Allen, Douglas Laube, Patrick McBride, Julie Mares-Perlman, and Barbara Loevinger; Wake Forest University School of Medicine, Winston-Salem, NC: Greg Burke, Robin Crouse, Lynne Parsons, and Mara Vitolins; Wayne State University School of Medicine and Hutzel Hospital, Detroit, Mich: Susan Hendrix, Michael Simon, Gene McNeeley, Pamela Gordon, Paul Makela.
Funding/Support: This study was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services. The active study drug and placebo were supplied by Wyeth-Ayerst Research Laboratories, Philadelphia, Pa.
Acknowledgment: We thank all WHI Centers, their principal investigators and staff for their participation in this research.
Author Affiliations: Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, Bronx, NY (Dr Wassertheil-Smoller); Wayne State University WHI Clinical Center, Detroit, Mich (Dr Hendrix); University of Florida WHI Clinical Center, Gainesville (Dr Limacher); University of North Carolina School of Medicine and Public Health, Durham (Dr Heiss); Fred Hutchinson Cancer Research Center, Seattle, Wash (Drs Kooperberg and Mr Aragaki); National Institute of Neurological Disorders and Stroke, Stroke Neuroscience Unit, Bethesda, Md (Dr Baird); Medical College of Wisconsin, Milwaukee (Dr Kotchen); Women's Health Hawaii, Honolulu (Dr Curb); Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill (Dr Black); National Heart, Lung, and Blood Institute, Bethesda, Md (Dr Rossouw), University of Medicine and Dentistry of New Jersey, Newark (Dr Safford); Medical Research Laboratories, Highland Heights, Ky (Dr Stein); Georgetown Washington University, Washington, DC (Dr Laowattana); and Ohio State University, Columbus (Dr Mysiw).
REFERENCES
1. Bousser MG. Stroke in women: the 1997 Paul Dudley White International Lecture. Circulation. 1999;99:463-7.
FREE FULL TEXT
2. Bonita R. Epidemiology of stroke. Lancet. 1992;339:342-344.
FULL TEXT
|
ISI
| PUBMED
3. Murphy SL. Deaths: final data for 1998. Natl Vital Stat Rep. 2000;48:1-105.
PUBMED
4. Design of the Women's Health Initiative clinical trial and observational study: the Women's Health Initiative Study Group Control Clin Trials. 1998;19:61-109.
FULL TEXT
|
ISI
| PUBMED
5. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-33.
FREE FULL TEXT
6. Gillum LA, Mamidipudi SK, Johnston SC. Ischemic stroke risk with oral contraceptives: a meta-analysis. JAMA. 2000;284:72-78.
FREE FULL TEXT
7. Hulley S, Grady D, Bush T, et al, for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605-613.
FREE FULL TEXT
8. Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med. 2001;345:1243-1249.
FREE FULL TEXT
9. Simon JA, Hsia J, Cauley JA, et al. Postmenopausal hormone therapy and risk of stroke: The Heart and Estrogen-progestin Replacement Study (HERS). Circulation. 2001;103:638-642.
FREE FULL TEXT
10. Hart CL, Hole DJ, Smith GD. Risk factors and 20-year stroke mortality in men and women in the Renfrew/Paisley study in Scotland. Stroke. 1999;30:1999-2007.
FREE FULL TEXT
11. Wolf PA, D'Agostino RB, Kannel WB, Bonita R, Belanger AJ. Cigarette smoking as a risk factor for stroke: the Framingham Study. JAMA. 1988;259:1025-1029.
FREE FULL TEXT
12. Whisnant JP. Modeling of risk factors for ischemic stroke: the Willis Lecture. Stroke. 1997;28:1840-1844.
FREE FULL TEXT
13. Gorelick PB, Sacco RL, Smith DB, et al. Prevention of a first stroke: a review of guidelines and a multidisciplinary consensus statement from the National Stroke Association. JAMA. 1999;281:1112-1120.
FREE FULL TEXT
14. Inzitari D, Eliasziw M, Gates P, et al, for the North American Symptomatic Carotid Endarterectomy Trial Collaborators. The causes and risk of stroke in patients with asymptomatic internal-carotid-artery stenosis. N Engl J Med. 2000;342:1693-700.
FREE FULL TEXT
15. Barnett HJ, Gunton RW, Eliasziw M, et al. Causes and severity of ischemic stroke in patients with internal carotid artery stenosis. JAMA. 2000;283:1429-1436.
FREE FULL TEXT
16. Rohde LE, Hennekens CH, Ridker PM. Survey of C-reactive protein and cardiovascular risk factors in apparently healthy men. Am J Cardiol. 1999;84:1018-1022.
FULL TEXT
|
ISI
| PUBMED
17. Makris TK, Stavroulakis GA, Krespi PG, et al. Fibrinolytic/hemostatic variables in arterial hypertension: response to treatment with irbesartan or atenolol. Am J Hypertens. 2000;13:783-788.
FULL TEXT
|
ISI
| PUBMED
18. Hak AE, Stehouwer CD, Bots ML, et al. Associations of C-reactive protein with measures of obesity, insulin resistance, and subclinical atherosclerosis in healthy, middle-aged women. Arterioscler Thromb Vasc Biol. 1999;19:1986-1991.
FREE FULL TEXT
19. Mustonen P, Lepantalo M, Lassila R. Physical exertion induces thrombin formation and fibrin degradation in patients with peripheral atherosclerosis. Arterioscler Thromb Vasc Biol. 1998;18:244-249.
FREE FULL TEXT
20. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men [published correction appears in N Engl J Med. N Engl J Med. 1997;337:356]. 1997;336:973-979.
FREE FULL TEXT
21. Devaraj S, Jialal I. Low-density lipoprotein postsecretory modification, monocyte function, and circulating adhesion molecules in type 2 diabetic patients with and without macrovascular complications: the effect of alpha-tocopherol supplementation. Circulation. 2000;102:191-196.
FREE FULL TEXT
22. Lip GY, Lip PL, Zarifis J, et al. Fibrin D-dimer and beta-thromboglobulin as markers of thrombogenesis and platelet activation in atrial fibrillation: effects of introducing ultra-low-dose warfarin and aspirin. Circulation. 1996;94:425-431.
FREE FULL TEXT
23. De Caterina R, Cybulsky MI, Clinton SK, Gimbrone MA Jr, Libby P. The omega-3 fatty acid docosahexaenoate reduces cytokine-induced expression of proatherogenic and proinflammatory proteins in human endothelial cells. Arterioscler Thromb. 1994;14:1829-1836.
FREE FULL TEXT
24. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet. 1991;337:1521-1526.
FULL TEXT
|
ISI
| PUBMED
25. Adams HP Jr, Bendixen BH, Kappelle LJ, et al, for TOAST Trial of Org 10172 in Acute Stroke Treatment. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. Stroke. 1993;24:35-41.
FREE FULL TEXT
26. Goldstein LB, Jones MR, Matchar DB, et al. Improving the reliability of stroke subgroup classification using the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria. Stroke. 2001;32:1091-1098.
FREE FULL TEXT
27. Madden KP, Karanjia PN, Adams HP Jr, Clarke WR. Accuracy of initial stroke subtype diagnosis in the TOAST study: Trial of ORG 10172 in Acute Stroke Treatment. Neurology. 1995;45:1975-1979.
FREE FULL TEXT
28. Lindley RI, Warlow CP, Wardlaw JM, Dennis MS, Slattery J, Sandercock PA. Interobserver reliability of a clinical classification of acute cerebral infarction. Stroke. 1993;24:1801-1804.
FREE FULL TEXT
29. Jennett B, Snoek J, Bond MR, Brooks N. Disability after severe head injury: observations on the use of the Glasgow Outcome Scale. J Neurol Neurosurg Psychiatry. 1981;44:285-293.
FREE FULL TEXT
30. Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet. 1975;1:480-484.
ISI
| PUBMED
31. Ainsworth BE, Haskell WL, Leon A. Compendium of physical activities: classification of energy costs of human activities. Med Sci Sports Exerc. 1993;25:71-80.
32. D'Agostino RB, Wolf PA, Belanger AJ, Kannel WB. Stroke risk profile: adjustment for antihypertensive medication: The Framingham Study. Stroke. 1994;25:40-43.
ABSTRACT
33. Steiner P, Freidl J, Bremner W, Stein E. Standardization of micromethods for plasma cholesterol, triglyceride and HDL-cholesterol with the lipid clinics' methodology. J Clin Chem. 1981;19:850.
34. Warnick GR, Albers JJ. A comprehensive evaluation of the heparin manganese precipitation procedure for estimating high-density lipoprotein cholesterol. J Lipid Res. 1978;19:65-76.
ABSTRACT
35. Friedewald WT, Levy RI, Frederickson DS. Estimation of concentration of low-density lipoprotein cholesterol in plasma, without the use of the preparative ultracentrifuge. Clin Chem. 1972;18:499-502.
ABSTRACT
36. Vu Dac N, Mezdour H, Parra HJ, Luc G, Luyeye I, Fruchart JC. A selective bi-site immunoenzymatic procedure for human Lp(a) lipoprotein quantification using monoclonal antibodies against apo[a] and apoB. J Lipid Res. 1989;30:1437-1443.
ABSTRACT
37. Russell WG. Measurement and clinical significance of high-density lipoprotein cholesterol subclasses. In: Rifai-Warnick, ed. Laboratory Measurement of Lipids, Lipoproteins, and Apolipoproteins; 1994:207-222.
38. Paganini-Hill A. Estrogen replacement therapy and stroke. Prog Cardiovasc Dis. 1995;38:223-242.
FULL TEXT
|
ISI
| PUBMED
39. Paganini-Hill A, Ross RK, Henderson BE. Postmenopausal oestrogen treatment and stroke: a prospective study. BMJ. 1988;297:519-522.
FREE FULL TEXT
40. Hunt K, Vessey M, McPherson K. Mortality in a cohort of long-term users of hormone replacement therapy: an updated analysis. Br J Obstet Gynaecol. 1990;97:1080-1086.
ISI
| PUBMED
41. Finucane FF, Madans JH, Bush TL, Wolf PH, Kleinman JC. Decreased risk of stroke among postmenopausal hormone users: results from a national cohort. Arch Intern Med. 1993;153:73-79.
FREE FULL TEXT
42. Falkeborn M, Persson I, Terent A, Adami HO, Lithell H, Bergstrom R. Hormone replacement therapy and the risk of stroke: follow-up of a population-based cohort in Sweden. Arch Intern Med. 1993;153:1201-1209.
FREE FULL TEXT
43. Petitti DB, Sidney S, Quesenberry CP Jr, Bernstein A. Ischemic stroke and use of estrogen and estrogen/progestogen as hormone replacement therapy. Stroke. 1998;29:23-28.
FREE FULL TEXT
44. Pedersen AT, Lidegaard O, Kreiner S, Ottesen B. Hormone replacement therapy and risk of non-fatal stroke. Lancet. 1997;350:1277-1283.
FULL TEXT
|
ISI
| PUBMED
45. Boysen G, Nyboe J, Appleyard M, et al. Stroke incidence and risk factors for stroke in Copenhagen, Denmark. Stroke. 1988;19:1345-1353.
FREE FULL TEXT
46. Lemaitre RN, Heckbert SR, Psaty BM, Smith NL, Kaplan RC, Longstreth WT Jr. Hormone replacement therapy and associated risk of stroke in postmenopausal women. Arch Intern Med. 2002;162:1954-1960.
FREE FULL TEXT
47. Wilson PW, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50: the Framingham Study. N Engl J Med. 1985;313:1038-1043.
ABSTRACT
48. Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy: scientific review. JAMA. 2002;288:872-281.
FREE FULL TEXT
49. Hurn PD, Macrae IM. Estrogen as a neuroprotectant in stroke. J Cereb Blood Flow Metab. 2000;20:631-652.
FULL TEXT
|
ISI
| PUBMED
50. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000;101:1767-1772.
FREE FULL TEXT
51. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836-843.
FREE FULL TEXT
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Disposition of Lasofoxifene, a Next-Generation Selective Estrogen Receptor Modulator, in Healthy Male Subjects
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Drug Metab. Dispos. 2008;36:1218-1226.
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Postmenopausal Hormone Therapy and Stroke: Role of Time Since Menopause and Age at Initiation of Hormone Therapy
Grodstein et al.
Arch Intern Med 2008;168:861-866.
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Lipoprotein-Associated Phospholipase A2, Hormone Use, and the Risk of Ischemic Stroke in Postmenopausal Women
Wassertheil-Smoller et al.
Hypertension 2008;51:1115-1122.
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Health Risks and Benefits 3 Years After Stopping Randomized Treatment With Estrogen and Progestin
Heiss et al.
JAMA 2008;299:1036-1045.
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Heart Disease and Stroke Statistics--2008 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee
Writing Group Members et al.
Circulation 2008;117:e25-e146.
FULL TEXT
Pharmacokinetics and Pharmacodynamics of Drospirenone-Estradiol Combination Hormone Therapy Product Coadministered With Hydrochlorothiazide in Hypertensive Postmenopausal Women
Karara et al.
J Clin Pharmacol 2007;47:1292-1302.
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Management of cardiovascular risk in the peri-menopausal woman: a consensus statement of European cardiologists and gynaecologists
Collins et al.
Eur Heart J 2007;28:2028-2040.
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Neurocognitive Outcomes Are Not Improved by 17{beta}-Estradiol in Postmenopausal Women Undergoing Cardiac Surgery
Hogue et al.
Stroke 2007;38:2048-2054.
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Novel Perspectives for Progesterone in Hormone Replacement Therapy, with Special Reference to the Nervous System
Schumacher et al.
Endocr. Rev. 2007;28:387-439.
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Review Article: Vascular and Metabolic Effects of Sex Steroids: New Insights Into Clinical Trials
Wierman and Kohrt
Reproductive Sciences 2007;14:300-314.
ABSTRACT
Activation of a Membrane-Associated Androgen Receptor Promotes Cell Death in Primary Cortical Astrocytes
Gatson and Singh
Endocrinology 2007;148:2458-2464.
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Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause
Rossouw et al.
JAMA 2007;297:1465-1477.
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Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions
Suzuki et al.
Proc. Natl. Acad. Sci. USA 2007;104:6013-6018.
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Estrogen, cognition and female ageing
Genazzani et al.
Hum Reprod Update 2007;13:175-187.
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Calcium/Vitamin D Supplementation and Cardiovascular Events
Hsia et al.
Circulation 2007;115:846-854.
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Heart Disease and Stroke Statistics--2007 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee
Rosamond et al.
Circulation 2007;115:e69-e171.
FULL TEXT
Selective Activation of Estrogen Receptor-{beta} Transcriptional Pathways by an Herbal Extract
Cvoro et al.
Endocrinology 2007;148:538-547.
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Historical Perspectives in Postmenopausal Hormone Therapy: Defining the Right Dose and Duration
Warren
Mayo Clin Proc. 2007;82:219-226.
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Complex Actions of Sex Steroids in Adipose Tissue, the Cardiovascular System, and Brain: Insights from Basic Science and Clinical Studies
Turgeon et al.
Endocr. Rev. 2006;27:575-605.
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Advancing the Study of Stroke in Women: Summary and Recommendations for Future Research From an NINDS-Sponsored Multidisciplinary Working Group
Bushnell et al.
Stroke 2006;37:2387-2399.
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The Impact of Hormone Replacement Therapy on Menopausal Symptoms in Younger High-Risk Women After Prophylactic Salpingo-Oophorectomy
Madalinska et al.
JCO 2006;24:3576-3582.
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Aspects of the design and analysis of high-dimensional SNP studies for disease risk estimation
Prentice and QI
Biostatistics 2006;7:339-354.
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Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial
Vogel et al.
JAMA 2006;295:2727-2741.
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Differential Modulation of Estrogen Receptors (ERs) in Ischemic Brain Injury: A Role for ER{alpha} in Estradiol-Mediated Protection against Delayed Cell Death
Dubal et al.
Endocrinology 2006;147:3076-3084.
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Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative
Hendrix et al.
Circulation 2006;113:2425-2434.
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The WHI and the Postmenopausal Woman: No Magic Bullet
JWatch Women's Health 2006;2006:1-1.
FULL TEXT
Potentially Inappropriate Prescribing for Elderly Patients in 2 Outpatient Settings
Maio et al.
American Journal of Medical Quality 2006;21:162-168.
ABSTRACT
Novel Mechanisms for Estrogen-Induced Neuroprotection.
Singh et al.
Exp. Biol. Med. 2006;231:514-521.
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Effects of Combination Estrogen Plus Progestin Hormone Treatment on Cognition and Affect
Resnick et al.
J. Clin. Endocrinol. Metab. 2006;91:1802-1810.
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Combined Analysis of Women's Health Initiative Observational and Clinical Trial Data on Postmenopausal Hormone Treatment and Cardiovascular Disease
Prentice et al.
Am J Epidemiol 2006;163:589-599.
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Dismembering the ethical physician.
Genuis
Postgrad. Med. J. 2006;82:233-238.
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Esterified estrogen and conjugated equine estrogen and the risk of incident myocardial infarction and stroke.
Lemaitre et al.
Arch Intern Med 2006;166:399-404.
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Heart Disease and Stroke Statistics--2006 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee
Thom et al.
Circulation 2006;113:e85-e151.
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Medroxyprogesterone acetate binds the glucocorticoid receptor to stimulate {alpha}-ENaC and sgk1 expression in renal collecting duct epithelia
Thomas et al.
Am. J. Physiol. Renal Physiol. 2006;290:F306-F312.
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Hormone replacement therapy and mortality in 52- to 70-year-old women: the Kuopio Osteoporosis Risk Factor and Prevention Study
Pentti et al.
Eur J Endocrinol 2006;154:101-107.
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Harnessing Hormonal Signaling for Cardioprotection
Ballard and Edelberg
Sci Aging Knowl Environ 2005;2005:re6-re6.
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Changes in Women's Use of Hormones After the Women's Health Initiative Estrogen and Progestin Trial by Race, Education, and Income
Wei et al.
J Natl Cancer Inst Monogr 2005;2005:106-112.
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Effects of Estrogen on Platelet Reactivity After Transient Forebrain Ischemia in Rats
Littleton-Kearney et al.
Biol Res Nurs 2005;7:135-145.
ABSTRACT
HIV/AIDS prevention in Uganda: why has it worked?
Genuis and Genuis
Postgrad. Med. J. 2005;81:615-617.
FULL TEXT
Differential regulation of insulin resistance and hypertension by sex hormones in fructose-fed male rats
Vasudevan et al.
Am. J. Physiol. Heart Circ. Physiol. 2005;289:H1335-H1342.
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Gender Differences in the Risk of Ischemic Stroke and Peripheral Embolism in Atrial Fibrillation: The AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) Study
Fang et al.
Circulation 2005;112:1687-1691.
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Risk of adverse drug events by patient destination after hospital discharge
Triller et al.
Am J Health Syst Pharm 2005;62:1883-1889.
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The Proliferation of Clinical Practice Guidelines: Professional Development or Medicine-by-Numbers?
Genuis
J Am Board Fam Med 2005;18:419-425.
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Combined Postmenopausal Hormone Therapy and Cardiovascular Disease: Toward Resolving the Discrepancy between Observational Studies and the Women's Health Initiative Clinical Trial
Prentice et al.
Am J Epidemiol 2005;162:404-414.
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Major Risk Factors for Intracerebral Hemorrhage in the Young Are Modifiable
Feldmann et al.
Stroke 2005;36:1881-1885.
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Does Sex Matter in Musculoskeletal Health? The Influence of Sex and Gender on Musculoskeletal Health
Tosi et al.
JBJS 2005;87:1631-1647.
FULL TEXT
High-soy diet decreases infarct size after permanent middle cerebral artery occlusion in female rats
Schreihofer et al.
Am. J. Physiol. Regul. Integr. Comp. Physiol. 2005;289:R103-R108.
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Sex, Hormones, and Alzheimer's Disease
Baum
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2005;60:736-743.
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Astrocyte-Derived Transforming Growth Factor-{beta} Mediates the Neuroprotective Effects of 17{beta}-Estradiol: Involvement of Nonclassical Genomic Signaling Pathways
Dhandapani et al.
Endocrinology 2005;146:2749-2759.
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Menopause, micronutrients, and hormone therapy
Wylie-Rosett
Am. J. Clin. Nutr. 2005;81:1223S-1231S.
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Are Estrogens Protective or Risk Factors in Brain Injury and Neurodegeneration? Reevaluation after the Women's Health Initiative
Wise et al.
Endocr. Rev. 2005;26:308-312.
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Use of Hormone Replacement Therapy by Postmenopausal Women After Publication of the Women's Health Initiative Trial
Ness et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2005;60:460-462.
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William M. Feinberg Lecture: Cognitive Vitality and the Role of Stroke and Cardiovascular Disease Risk Factors
Gorelick
Stroke 2005;36:875-879.
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Modulation of tumor formation and intestinal cell migration by estrogens in the ApcMin/+ mouse model of colorectal cancer
Javid et al.
Carcinogenesis 2005;26:587-595.
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Estrogen Treatment for Urinary Incontinence: Never, Now, or in the Future?
DuBeau
JAMA 2005;293:998-1001.
FULL TEXT
Time to review all the evidence for hormone replacement therapy
Crawford and Langhorne
BMJ 2005;330:345-345.
FULL TEXT
Decline in Lung Function in Patients With Lymphangioleiomyomatosis Treated With or Without Progesterone
Taveira-DaSilva et al.
Chest 2004;126:1867-1874.
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Hormone Therapy: Making Decisions in the Face of Uncertainty
Peterson et al.
Arch Intern Med 2004;164:2308-2312.
FULL TEXT
Risk Factors for Vascular Dementia and Alzheimer Disease
Gorelick
Stroke 2004;35:2620-2622.
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Estrogen-Like Compounds for Ischemic Neuroprotection
Simpkins et al.
Stroke 2004;35:2648-2651.
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Sex, Steroids, and Stroke: Introduction
Hurn and Sacco
Stroke 2004;35:2642-2643.
FULL TEXT
Risk of ischemic stroke with tamoxifen treatment for breast cancer: A meta-analysis
Bushnell and Goldstein
Neurology 2004;63:1230-1233.
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Estrogen Plus Progestin and Risk of Venous Thrombosis
Cushman et al.
JAMA 2004;292:1573-1580.
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Targeting of the Renin-Angiotensin System as an Adjunct to Estrogen Replacement Therapy
Harrison-Bernard
Hypertension 2004;44:390-391.
FULL TEXT
Effects of estrogen deprivation due to breast cancer treatment
Angelopoulos et al.
Endocr Relat Cancer 2004;11:523-535.
ABSTRACT
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Hormone Replacement Therapy
Lochner and Einhorn
J Am Acad Orthop Surg 2004;12:291-294.
FULL TEXT
The Effect of Menopause on Grip and Pinch Strength: Results from the Chicago, Illinois, Site of the Study of Women's Health Across the Nation
Kurina et al.
Am J Epidemiol 2004;160:484-491.
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A Three-Part Intervention To Change the Use of Hormone Replacement Therapy in Response to New Evidence
Roumie et al.
ANN INTERN MED 2004;141:118-125.
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Postmenopausal hormone therapy and risk of cognitive decline in community-dwelling aging women
Kang et al.
Neurology 2004;63:101-107.
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Estrogen-mediated protection against HIV Tat protein-induced inflammatory pathways in human vascular endothelial cells
Lee et al.
Cardiovasc Res 2004;63:139-148.
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Commentary: The hormone replacement-coronary heart disease conundrum: is this the death of observational epidemiology?
Lawlor et al.
Int J Epidemiol 2004;33:464-467.
FULL TEXT
Measuring Hot Flashes: Summary of a National Institutes of Health Workshop
Miller and Li
Mayo Clin Proc. 2004;79:777-781.
Fracture Incidence in Relation to the Pattern of Use of Hormone Therapy in Postmenopausal Women
Banks et al.
JAMA 2004;291:2212-2220.
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