(Circulation. 2001;103:638.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Postmenopausal Hormone Therapy and Risk of Stroke
The Heart and Estrogen-progestin Replacement Study (HERS)
From the General Internal Medicine Section, Medical Service, Veterans Affairs Medical Center (J.A.S.), San Francisco, Calif; Division of Clinical Research, Department of Epidemiology and Biostatistics, School of Medicine, University of California (J.A.S., F.H., J.F., S.B.H.), San Francisco, Calif; Department of Medicine, George Washington University (J.H.), Washington, DC; Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh (J.A.C.), Pittsburgh, Pa; Wyeth-Ayerst Research (C.R.), Radnor, Pa; Department of Family Medicine and Preventive Medicine, School of Medicine, University of California (E.B.-C.), San Diego.
Correspondence to Dr Joel A. Simon, General Internal Medicine (111A1), San Francisco VA Medical Center, 4150 Clement St, San Francisco, CA 94121. E-mail jasimon{at}itsa.ucsf.edu
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Abstract |
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Background—Observational studies have shown that postmenopausal hormone therapy may increase, decrease, or have no effect on the risk of stroke. To date, no clinical trial has examined this question. To investigate the relation between estrogen plus progestin therapy and risk of stroke among postmenopausal women, we analyzed data collected from the Heart & Estrogen-progestin Replacement Study (HERS), a secondary coronary heart disease prevention trial.
Methods and Results—Postmenopausal women (n=2763) were randomly assigned to take conjugated estrogen plus progestin or placebo. Primary outcomes for these analyses were stroke incidence and stroke death during a mean follow-up of 4.1 years. The number of women with strokes was compared with the number of women without strokes. A total of 149 women (5%) had 1 or more strokes, 85% of which were ischemic, resulting in 26 deaths. Hormone therapy was not significantly associated with risk of nonfatal stroke (relative hazard [RH] 1.18; 95% CI 0.83 to 1.66), fatal stroke (RH 1.61; 95% CI 0.73 to 3.55), or transient ischemic attack (RH 0.90; 95% CI 0.57 to 1.42). Independent predictors of stroke events included increasing age, hypertension, diabetes, current cigarette smoking, and atrial fibrillation. Black women were at increased risk compared with white women, and unexpectedly, body mass index was inversely associated with stroke risk.
Conclusions—Hormone therapy with conjugated equine estrogen and progestin had no significant effect on the risk for stroke among postmenopausal women with coronary disease.
Key Words: cerebrovascular disorders • hormones • stroke
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Introduction |
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Strokes are an important cause of disability and death among older women. Because many women use hormone therapy for the control of perimenopausal symptoms and to prevent osteoporosis after menopause, establishing whether such therapy has other health effects is of considerable clinical importance. A decision to use hormone therapy for osteoporosis could be influenced, for example, by effects it might have on other medical conditions, such as the risk of heart disease and stroke.
Based on observational studies, the effect of postmenopausal hormone therapy on the risk of stroke is uncertain. Recent case-control studies and cohort studies have reported that postmenopausal hormone therapy increases,1 decreases,2 3 4 5 6 or has no significant effect7 8 9 10 11 12 13 14 15 on stroke risk. Because observational studies of postmenopausal hormone therapy may be confounded by differences in the characteristics of women who use postmenopausal hormones, eg, women who use postmenopausal hormones tend to be healthier than nonusers,16 17 clinical trial data are essential for discerning the unconfounded relation between postmenopausal hormone therapy and risk of stroke.
To examine the relation of postmenopausal hormone therapy to risk of stroke and transient ischemic attack (TIA), we analyzed data collected from the Heart & Estrogen-progestin Replacement Study (HERS), a secondary coronary heart disease (CHD) prevention study among postmenopausal women with known coronary artery disease.18 Stroke and TIA were prespecified secondary outcomes. HERS is the first clinical trial of postmenopausal hormone therapy to examine whether such therapy affects the risk of TIAs and stroke.
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Methods |
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Subjects
Between February 1993 and October 1994, 2763 postmenopausal women with CHD were recruited from 20 clinical centers across the United States for a randomized, blinded study of the effect of hormone therapy with conjugated equine estrogen (0.625 mg/d) and medroxyprogesterone acetate (2.5 mg/d) on recurrent CHD events. Baseline data were collected during the screening and randomization visits and included demographic characteristics, medical history, risk factors for CHD, physical examination, and laboratory data. Participants were monitored by phone interview 3 times per year and were seen in clinic yearly for a physical examination and for evaluation of interval events. Details of the study rationale, design, and recruitment procedures have been described elsewhere.18 HERS was approved by the institutional review board at each clinical center, and informed consent was obtained from all participants before enrollment.
Measurements
Baseline data included self-reported information on
participants’ age, ethnicity, marital status, highest grade or year of
school completed, number of pregnancies, past use of postmenopausal
estrogen therapy, level of physical activity, alcohol consumption,
smoking habits, and history of diabetes mellitus and hypertension.
Women with a history of gestational diabetes were not classified as
having diabetes mellitus. Data were also obtained on all current
prescription and nonprescription medications and vitamin preparations.
Participants were considered to have hypertension based on
self-reported history, a baseline systolic blood pressure >140 mm Hg,
or a baseline diastolic blood pressure >90 mm Hg. Women with a
history of thrombotic events or with uncontrolled hypertension or
diabetes were not enrolled. Details regarding the questionnaires,
physical examination, and laboratory procedures used in HERS have been
published
previously.18
Outcome Adjudication
Outcome adjudication for stroke and TIA events was
conducted after a careful review of medical records by 2 physician
adjudicators at the coordinating center who were blinded to treatment
status. Stroke events were defined as the rapid onset of a neurological
deficit attributed to an obstruction or rupture of the arterial system
not known to be caused by a brain tumor, infection, or other cause. The
neurological deficit had to last >24 hours or be confirmed by a lesion
compatible with an acute stroke on CT or MRI of the brain. Stroke
events were further classified as fatal or nonfatal and as ischemic or
hemorrhagic based on a review of brain imaging studies. A total of 10
strokes (6 nonfatal and 4 fatal) could not be classified as either
ischemic or hemorrhagic because of the absence of imaging
documentation. Adjudication of these strokes was based on a review of
all other available medical records. These events were excluded from
the analyses that examined the relation of hormone therapy to type of
stroke (ie, hemorrhagic versus ischemic) but were included in the
analyses of fatal and nonfatal stroke. TIA events were defined as the
rapid onset of a neurological deficit attributed to an embolus or
obstruction of the arterial system not known to be caused by a brain
tumor, infection, or other cause. Adjudication of TIA events was based
on documented neurological symptoms that lasted <24 hours and the lack
of an acute stroke on CT or MRI scan of the brain. The main study
results published in 1998 were based on the near-final data available
at the time.18 This article
includes the updated and final HERS results for cerebrovascular disease
events.19
Statistical Methods
We used unpaired 2-tailed
t tests to compare continuous
variables and 
2 tests to compare
categorical variables. To analyze the association between hormone
therapy and incident stroke events, we used Cox proportional hazards
models. To examine the predictors of stroke, treatment assignment and
variables that were associated with stroke at the
P
0.20 significance level were
entered into each multivariate model. We used stepwise regression
procedures to retain variables associated with stroke at
P0.05. We calculated the
hazard ratio and 95% CI to estimate the risk of TIA and stroke
(categorized as ischemic versus hemorrhagic and fatal versus nonfatal).
Participants who were judged to have had TIAs during the study were not
excluded from the analyses of stroke incidence. However, women who
suffered >1 nonfatal stroke (n=9) were excluded from the analyses of
nonfatal stroke after their first stroke event. Women who had 
1
nonfatal stroke followed by a subsequent fatal stroke (n=7) were
included in analyses of predictors of fatal stroke. We also performed
survival analysis using Kaplan-Meier curves to compare time to all
incident stroke events (nonfatal and fatal stroke). Log-rank tests were
used to compare differences in survival
curves.
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Results |
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The baseline characteristics of the HERS participants had similar distributions in the 2 randomized study arms (Table 1
). HERS participants were on average
67-year-old white, married women with a high likelihood of being
hypertensive and using aspirin. A total of 165 strokes occurred in 149
participants over of the course of the study. As expected, most (85%)
of the strokes were ischemic; 8% were hemorrhagic strokes, and 6%
could not be classified. A total of 139 nonfatal strokes and 26 fatal
strokes occurred over a mean follow-up of 4.1 years. The incidence
rates for any stroke event were 12/1000 person-years among women taking
placebo and 15/1000 person-years among women taking postmenopausal
hormone therapy.
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In analyses that examined the relation of hormone therapy to
risk of stroke, we found that hormone therapy was not significantly
associated with either risk of nonfatal stroke events (relative hazard
[RH] 1.18; 95% CI 0.83 to 1.66) or fatal stroke events (RH 1.61;
95% CI 0.73 to 3.55)
(Table 2). Kaplan-Meier survival curves display the
cumulative percentage of strokes for both hormone therapy and placebo
groups over the entire duration of follow-up
(Figure).
By the end of the study, 
7% of women assigned to the hormone
therapy group experienced a fatal or nonfatal stroke compared with 5%
of women in the placebo group. This 2% absolute difference in stroke
risk, however, was not statistically significant
(P=0.20). The relation between
hormone therapy and risk of stroke was similar for ischemic or
hemorrhagic strokes, neither of which was significantly associated with
the use of hormone therapy
(Table 2). Postmenopausal hormone therapy had no discernible
effect on risk of TIAs (RH 0.90; 95% CI 0.57 to 1.42), nor was it
associated with the risk for all combined cerebrovascular disease
events (any stroke or TIA) (RH 1.09; 95% CI 0.84 to 1.43).
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Using multivariable stepwise regression models, we examined
predictors of stroke events adjusting for treatment assignment
(Table 3). A number of variables were significantly
associated with risk of stroke. As expected, older women and
participants with hypertension, atrial fibrillation, or diabetes, as
well as current smokers, were at increased risk for stroke. Black women
had approximately twice the risk of stroke as white women. Increasing
body mass index was associated with a decreased risk for stroke; a
1-unit increase in body mass index was independently associated with a
4% decrease in stroke risk. Additional multivariate models that
included all the variables noted in
Table 1
also found body mass index inversely associated
with risk of stroke. Baseline atrial fibrillation was the strongest
predictor of stroke among HERS participants and conferred a 6.5-fold
increased risk of stroke, even after controlling for the effects of
aspirin and warfarin therapy. Among participants with baseline atrial
fibrillation, stroke incidence did not differ by treatment assignment.
We examined whether statin use might affect the risk of stroke or TIA
and found no relation with either cerebrovascular disease
outcome.
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With the exception of level of education, there were no statistically significant interactions with postmenopausal hormone therapy. Additional adjustment for level of education and level of educationxtreatment assignment produced similar findings.
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Discussion |
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Postmenopausal Hormone Therapy and Stroke
Our main finding was the absence of any significant beneficial or detrimental effect of hormone therapy on the risk of cerebrovascular disease events among postmenopausal women with coronary disease followed up for a mean of 4.1 years. Compared with a stroke incidence rate of 4/1000 person-years among populations of white women aged 45 to 84 years,20 HERS participants had a higher incidence rate. Unlike the pattern observed for myocardial infarction and CHD death in the original HERS report,18 there was no early increase in risk of stroke in the hormone-treated group followed by a later decrease. HERS was not designed to detect differences in the rate of stroke events. However, the 149 women who experienced a stroke event provided enough power to observe a modest protective effect, and the confidence interval of 0.89 to 1.70 makes it unlikely that we missed a true reduction exceeding 11%.
HERS is important because it is the first large randomized clinical trial to examine the effect of hormone therapy on risk of strokes, a predesignated secondary outcome of interest. Our findings concur with many recent observational studies that reported no significant association between postmenopausal hormone therapy and stroke risk.7 8 9 10 11 12 13 14 15 However, some studies examining the relation between postmenopausal hormone therapy and stroke have reported that hormone therapy decreases stroke risk,2 3 4 5 6 and the Framingham Heart Study reported that it increased risk of stroke, at least among smokers.1 Our findings do not support the Framingham observation of an adverse interaction between postmenopausal hormone therapy and stroke among smokers. Because women who use postmenopausal hormone therapy tend to be more health-conscious than nonusers, it is possible that the ostensible beneficial effects of hormone therapy on risk of stroke reported in some observational studies may have resulted from such confounding.
Other Predictors of Stroke
Similar to the findings of others, we found that
increasing age, hypertension, diabetes, and cigarette smoking were
important independent risk factors for stroke
events.21 22 23 24
Black women in HERS experienced an increased risk for stroke events,
even after controlling for other factors. These findings also are
similar to those of other investigators and largely remain
unexplained.21 22
Baseline atrial fibrillation was the strongest predictor of stroke
events. The risk of a thromboembolic stroke in the presence of
untreated atrial fibrillation is 5% per
year.21 Among the 29 women
(1% of HERS participants) identified with atrial fibrillation at
baseline, 55% of whom were given warfarin for anticoagulation, we
found a 6.5-fold increased risk of stroke, independent of
anticoagulation with warfarin and other risk factors. These estimates
concur with those from other studies that range from 6- to
18-fold.22 The risk of
stroke for women with atrial fibrillation did not differ by treatment
assignment, in contrast with the findings of Hart et
al,25 who reported that
postmenopausal hormone therapy conferred a 3-fold additional increased
risk of ischemic stroke in women with atrial fibrillation enrolled in
the Stroke Prevention in Atrial Fibrillation (SPAF) III trial. However,
HERS enrolled so few women with atrial fibrillation that there was
little power to observe such an association.
Although obesity is a less-well-documented risk factor for stroke, it is associated with established stroke risk factors, such as hypertension, diabetes mellitus, and hyperlipidemia, and may therefore be on the causal pathway to stroke.21 Whereas a number of recent studies have found no association between obesity and risk of stroke in women,8 26 27 some earlier studies reported obesity to be a stroke risk factor, either independent of28 29 or as related to hypertension or diabetes.30 31 32 In contrast, we found an inverse association between body mass index and stroke. This finding may have occurred by chance or may possibly reflect residual confounding by other risk factors, such as smoking. Of note, the Tecumseh study33 reported a higher risk of cardiovascular mortality (including stroke) among lean hypertensive individuals even after adjustment for smoking. We controlled for differences in hypertension, but like the Tecumseh investigators, we do not have an explanation for the observation of decreased risk among heavier women.
There were a number of limitations to our study. HERS was restricted to postmenopausal women with CHD, and therefore our findings may not be generalizable to other groups of women. Using data from HERS, we cannot separate the effects of estrogen from those of progestin. Much of the baseline data were obtained by self-report; hence, misclassification of some variables, such as diabetes mellitus, likely occurred. However, the magnitude of the risk for stroke associated with age, diabetes, and atrial fibrillation was similar to risk estimates from other studies. Because the main HERS trial did not collect data on dietary intake, markers of inflammation, or hemostasis, we are unable to comment on several other possible predictors of stroke. However, HERS was a randomized, blinded trial, and it is unlikely that our principal findings regarding the relation of estrogen plus progestin to stroke and TIA were affected by confounding or bias.
In conclusion, HERS is the first large randomized clinical trial to examine the effect of hormone therapy on risk of strokes. Our findings indicate that there is no significant association between postmenopausal hormone therapy and risk of stroke among postmenopausal women followed up for a mean of 4.1 years.
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Acknowledgments |
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HERS was supported by a grant from Wyeth-Ayerst Research.
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Footnotes |
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Dr Cauley has received research funding from Lilly & Co, Wyeth-Ayerst, Roche, and Merck; she has also received honoraria from Merck, Lilly, and Procter & Gamble. Dr Richards is an employee of Wyeth-Ayerst Research. Dr Barrett-Connor has received research support from Wyeth-Ayerst and Lilly.
Received July 5, 2000; revision received September 21, 2000; accepted September 24, 2000.
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R. L. Sacco, R. Adams, G. Albers, M. J. Alberts, O. Benavente, K. Furie, L. B. Goldstein, P. Gorelick, J. Halperin, R. Harbaugh, et al. Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline. Circulation, March 14, 2006; 113(10): e409 - e449. [Abstract] [Full Text] [PDF]
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 G. Han, X. Yu, L. Lu, S. Li, H. Ma, S. Zhu, X. Cui, and R. E. White Estrogen Receptor {alpha} Mediates Acute Potassium Channel Stimulation in Human Coronary Artery Smooth Muscle Cells J. Pharmacol. Exp. Ther., March 1, 2006; 316(3): 1025 - 1030. [Abstract] [Full Text] [PDF]
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 R. N. Lemaitre, N. S. Weiss, N. L. Smith, B. M. Psaty, T. Lumley, E. B. Larson, and S. R. Heckbert Esterified estrogen and conjugated equine estrogen and the risk of incident myocardial infarction and stroke. Arch Intern Med, February 27, 2006; 166(4): 399 - 404. [Abstract] [Full Text] [PDF]
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T. Thom, N. Haase, W. Rosamond, V. J. Howard, J. Rumsfeld, T. Manolio, Z.-J. Zheng, K. Flegal, C. O'Donnell, S. Kittner, et al. Heart Disease and Stroke Statistics--2006 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Circulation, February 14, 2006; 113(6): e85 - e151. [Full Text] [PDF]
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R. L. Sacco, R. Adams, G. Albers, M. J. Alberts, O. Benavente, K. Furie, L. B. Goldstein, P. Gorelick, J. Halperin, R. Harbaugh, et al. Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline. Stroke, February 1, 2006; 37(2): 577 - 617. [Abstract] [Full Text] [PDF]
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R. L. Prentice, R. Langer, M. L. Stefanick, B. V. Howard, M. Pettinger, G. Anderson, D. Barad, J. D. Curb, J. Kotchen, L. Kuller, et al. Combined Postmenopausal Hormone Therapy and Cardiovascular Disease: Toward Resolving the Discrepancy between Observational Studies and the Women's Health Initiative Clinical Trial Am. J. Epidemiol., September 1, 2005; 162(5): 404 - 414. [Abstract] [Full Text] [PDF]
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R. A. Khalil Sex Hormones as Potential Modulators of Vascular Function in Hypertension Hypertension, August 1, 2005; 46(2): 249 - 254. [Abstract] [Full Text] [PDF]
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P. Dick, C. Sherif, S. Sabeti, J. Amighi, E. Minar, and M. Schillinger Gender Differences in Outcome of Conservatively Treated Patients With Asymptomatic High Grade Carotid Stenosis Stroke, June 1, 2005; 36(6): 1178 - 1183. [Abstract] [Full Text] [PDF]
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L. M. Brass Hormone Replacement Therapy and Stroke: Clinical Trials Review Stroke, November 1, 2004; 35(11_suppl_1): 2644 - 2647. [Abstract] [Full Text] [PDF]
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 Asia Pacific Cohort Studies Collaboration Body mass index and cardiovascular disease in the Asia-Pacific Region: an overview of 33 cohorts involving 310 000 participants Int. J. Epidemiol., August 1, 2004; 33(4): 751 - 758. [Abstract] [Full Text] [PDF]
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C. G. Sobey, J. M. Weiler, M. Boujaoude, and O. L. Woodman Effect of Short-Term Phytoestrogen Treatment in Male Rats on Nitric Oxide-Mediated Responses of Carotid and Cerebral Arteries: Comparison with 17{beta}-Estradiol J. Pharmacol. Exp. Ther., July 1, 2004; 310(1): 135 - 140. [Abstract] [Full Text] [PDF]
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 The Women's Health Initiative Steering Committee Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy: The Women's Health Initiative Randomized Controlled Trial JAMA, April 14, 2004; 291(14): 1701 - 1712. [Abstract] [Full Text] [PDF]
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S. B. Hulley and D. Grady The WHI Estrogen-Alone Trial--Do Things Look Any Better? JAMA, April 14, 2004; 291(14): 1769 - 1771. [Full Text] [PDF]
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 A. K. Death, K. C. Y. McGrath, M. A. Sader, S. Nakhla, W. Jessup, D. J. Handelsman, and D. S. Celermajer Dihydrotestosterone Promotes Vascular Cell Adhesion Molecule-1 Expression in Male Human Endothelial Cells via a Nuclear Factor-{kappa}B-Dependent Pathway Endocrinology, April 1, 2004; 145(4): 1889 - 1897. [Abstract] [Full Text] [PDF]
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C. D. Bushnell, L. K. Newby, L. B. Goldstein, F. Lin, K. Yaffe, and J. A. Simon Statin use and stroke outcomes in the Heart and Estrogen-Progestin Replacement Study (HERS) Neurology, March 23, 2004; 62(6): 968 - 970. [Abstract] [Full Text] [PDF]
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 J. M. Orshal and R. A. Khalil Gender, sex hormones, and vascular tone Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2004; 286(2): R233 - R249. [Abstract] [Full Text] [PDF]
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F. Iemolo, A. Martiniuk, D. A. Steinman, and J. D. Spence Sex Differences in Carotid Plaque and Stenosis Stroke, February 1, 2004; 35(2): 477 - 481. [Abstract] [Full Text] [PDF]
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F. L. Wynne, J. A. Payne, A. E. Cain, J. F. Reckelhoff, and R. A. Khalil Age-Related Reduction in Estrogen Receptor-Mediated Mechanisms of Vascular Relaxation in Female Spontaneously Hypertensive Rats Hypertension, February 1, 2004; 43(2): 405 - 412. [Abstract] [Full Text] [PDF]
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 Minerva BMJ, October 6, 2003; 327(7418): E29 - 29. [Full Text] [PDF]
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 E. Barrett-Connor An Epidemiologist Looks at Hormones and Heart Disease in Women J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4031 - 4042. [Full Text] [PDF]
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S. Wassertheil-Smoller, S. Hendrix, M. Limacher, G. Heiss, C. Kooperberg, A. Baird, T. Kotchen, J. D. Curb, H. Black, J. E. Rossouw, et al. Effect of Estrogen Plus Progestin on Stroke in Postmenopausal Women: The Women's Health Initiative: A Randomized Trial JAMA, May 28, 2003; 289(20): 2673 - 2684. [Abstract] [Full Text] [PDF]
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 J. Ren, K. K. Hintz, Z. K. F. Roughead, J. Duan, P. B. Colligan, B. H. Ren, K. J. Lee, and H. Zeng Impact of estrogen replacement on ventricular myocyte contractile function and protein kinase B/Akt activation Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1800 - H1807. [Abstract] [Full Text] [PDF]
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 K. H. Humphries and S. Gill Risks and benefits of hormone replacement therapy: The evidence speaks Can. Med. Assoc. J., April 15, 2003; 168(8): 1001 - 1010. [Abstract] [Full Text] [PDF]
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P. D. Hurn and L. M. Brass Estrogen and Stroke: A Balanced Analysis Stroke, February 1, 2003; 34(2): 338 - 341. [Full Text] [PDF]
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L. B. Goldstein Prevention and Health Services Delivery Stroke, February 1, 2003; 34(2): 367 - 369. [Full Text] [PDF]
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 U.S. Preventive Services Task Force* Postmenopausal Hormone Replacement Therapy for Primary Prevention of Chronic Conditions: Recommendations and Rationale Ann Intern Med, November 19, 2002; 137(10): 834 - 839. [Abstract] [Full Text] [PDF]
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T. B. Clarkson, M. S. Anthony, T. S. Mikkola, and R. W. St Clair Comparison of Tibolone and Conjugated Equine Estrogens Effects on Carotid Artery Atherosclerosis of Postmenopausal Monkeys Stroke, November 1, 2002; 33(11): 2700 - 2703. [Abstract] [Full Text] [PDF]
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R. Liu, S.-H. Yang, E. Perez, K. D. Yi, S. S. Wu, K. Eberst, L. Prokai, K. Prokai-Tatrai, Z. Y. Cai, D. F. Covey, et al. Neuroprotective Effects of a Novel Non-Receptor-Binding Estrogen Analogue: In Vitro and In Vivo Analysis Stroke, October 1, 2002; 33(10): 2485 - 2491. [Abstract] [Full Text] [PDF]
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R. N. Lemaitre, S. R. Heckbert, B. M. Psaty, N. L. Smith, R. C. Kaplan, and W. T. Longstreth Jr Hormone Replacement Therapy and Associated Risk of Stroke in Postmenopausal Women Arch Intern Med, September 23, 2002; 162(17): 1954 - 1960. [Abstract] [Full Text] [PDF]
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A. E. Mullick, J. M. McDonald, G. Melkonian, P. Talbot, K. E. Pinkerton, and J. C. Rutledge Reactive carbonyls from tobacco smoke increase arterial endothelial layer injury Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H591 - H597. [Abstract] [Full Text] [PDF]
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Writing Group for the Women's Health Initiative In Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial JAMA, July 17, 2002; 288(3): 321 - 333. [Abstract] [Full Text] [PDF]
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D. Grady, D. Herrington, V. Bittner, R. Blumenthal, M. Davidson, M. Hlatky, J. Hsia, S. Hulley, A. Herd, S. Khan, et al. Cardiovascular Disease Outcomes During 6.8 Years of Hormone Therapy: Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II) JAMA, July 3, 2002; 288(1): 49 - 57. [Abstract] [Full Text] [PDF]
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D. B. Petitti Hormone Replacement Therapy for Prevention: More Evidence, More Pessimism JAMA, July 3, 2002; 288(1): 99 - 101. [Full Text] [PDF]
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T. Simoncini, G. Varone, L. Fornari, P. Mannella, M. Luisi, F. Labrie, and A. R. Genazzani Genomic and Nongenomic Mechanisms of Nitric Oxide Synthesis Induction in Human Endothelial Cells by a Fourth-Generation Selective Estrogen Receptor Modulator Endocrinology, June 1, 2002; 143(6): 2052 - 2061. [Abstract] [Full Text] [PDF]
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D. Grady A 60-Year-Old Woman Trying to Discontinue Hormone Replacement Therapy JAMA, April 24, 2002; 287(16): 2130 - 2137. [Full Text] [PDF]
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E. Barrett-Connor Looking for the Pony in the HERS Data Circulation, February 26, 2002; 105(8): 902 - 903. [Full Text] [PDF]
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 S. Stork, K. Baumann, C. von Schacky, and P. Angerer The effect of 17{beta}-estradiol on MCP-1 serum levels in postmenopausal women Cardiovasc Res, February 15, 2002; 53(3): 642 - 649. [Abstract] [Full Text] [PDF]
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M. A. Hlatky, D. Boothroyd, E. Vittinghoff, P. Sharp, M. A. Whooley, and for the HERS Research Group Quality-of-Life and Depressive Symptoms in Postmenopausal Women After Receiving Hormone Therapy: Results From the Heart and Estrogen/Progestin Replacement Study (HERS) Trial JAMA, February 6, 2002; 287(5): 591 - 597. [Abstract] [Full Text] [PDF]
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 B. G. Angeja, M. G. Shlipak, A. S. Go, S. C. Johnston, P. D. Frederick, J. G. Canto, H. V. Barron, D. Grady, and for the National Registry of Myocardial Infarction Hormone therapy and the risk of stroke after acute myocardial infarction in postmenopausal women J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1297 - 1301. [Abstract] [Full Text] [PDF]
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 C. M. Viscoli, L. M. Brass, W. N. Kernan, P. M. Sarrel, S. Suissa, and R. I. Horwitz A Clinical Trial of Estrogen-Replacement Therapy after Ischemic Stroke N. Engl. J. Med., October 25, 2001; 345(17): 1243 - 1249. [Abstract] [Full Text] [PDF]
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J. C. LaRosa Prevention and Treatment of Coronary Heart Disease: Who Benefits? Circulation, October 2, 2001; 104(14): 1688 - 1692. [Abstract] [Full Text] [PDF]
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L. Mosca, P. Collins, D. M. Herrington, M. E. Mendelsohn, R. C. Pasternak, R. M. Robertson, K. Schenck-Gustafsson, S. C. Smith Jr, K. A. Taubert, and N. K. Wenger Hormone Replacement Therapy and Cardiovascular Disease: A Statement for Healthcare Professionals From the American Heart Association Circulation, July 24, 2001; 104(4): 499 - 503. [Full Text] [PDF]
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T. Tolbert and S. Oparil Hormone Replacement Therapy and Stroke: Are the Results Surprising? Circulation, February 6, 2001; 103(5): 620 - 622. [Full Text] [PDF]
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