This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Simon, J. A. Articles by Hulley, S. B. Search for Related Content PubMed PubMed Citation Articles by Simon, J. A. Articles by Hulley, S. B. Related Collections Cerebrovascular disease/stroke Acute Stroke Syndromes Risk Factors for Stroke

(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)

Joel A. Simon, MD, MPH; Judith Hsia, MD; Jane A. Cauley, DrPH; Cynthia Richards, MD; Fran Harris, MS; Josephine Fong, MS; Elizabeth Barrett-Connor, MD; Stephen B. Hulley, MD, MPH; for the HERS Research Group

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

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
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

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
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 effect^{7 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.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
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 P0.20 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.

	Results

Top Abstract Introduction Methods Results Discussion References

 
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.

View this table: [in this window] [in a new window]   Table 1. Selected Baseline Characteristics of Women in HERS

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).

View this table: [in this window] [in a new window]   Table 2. Risk of Cerebrovascular Disease Events in HERS

View larger version (20K): [in this window] [in a new window]   Figure 1. Kaplan-Meier estimate of cumulative incidence of stroke events. Number of women observed at each year of follow-up and still free from stroke events is provided in parentheses; lines become thinner when this number drops below half of the cohort. Log-rank P value is 0.20.

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.

View this table: [in this window] [in a new window]   Table 3. Predictors of Incident Stroke in HERS

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.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
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 of^{28 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.

	Acknowledgments

 
HERS was supported by a grant from Wyeth-Ayerst Research.

	Footnotes

 
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.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Wilson PWF, 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]
   
2. Hunt K, Vessey M, McPherson K. Mortality in a cohort of long-term users of hormone replacement therapy: an updated analysis. Br J Obstet Gynecol. 1990;97:1080–1086.[Medline] [Order article via Infotrieve]
   
3. Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med. 1991;151:75–78.[Abstract]
   
4. Finucane FF, Madans JH, Bush TL, et al. Decreased risk of stroke among postmenopausal hormone users: results from a national cohort. Arch Intern Med. 1993;153:73–79.[Abstract]
   
5. Falkeborn M, Persson I, Terént A, et al. Hormone replacement therapy and the risk of stroke: follow-up of a population-based cohort in Sweden. Arch Intern Med. 1993;153:1201–1209.[Abstract]
   
6. Schairer C, Adami H-O, Hoover R, et al. Cause-specific mortality in women receiving hormone replacement therapy. Epidemiology. 1997;8:59–65.[Medline] [Order article via Infotrieve]
   
7. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease: ten-year follow-up from the Nurse’s Health Study. N Engl J Med. 1991;325:756–762.[Abstract]
   
8. Lindenstrøm E, Boysen G, Nyboe J. Lifestyle factors and risk of cerebrovascular disease in women: the Copenhagen City Heart Study. Stroke. 1993;24:1468–1472.[Abstract/Free Full Text]
   
9. Folsom AR, Mink PJ, Sellers TA, et al. Hormonal replacement therapy and morbidity and mortality in a prospective study of postmenopausal women. Am J Public Health. 1995;85:1128–1132.[Medline] [Order article via Infotrieve]
   
10. Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med. 1996;335:453–461.[Abstract/Free Full Text]
    
11. Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopausal hormone therapy and mortality. N Engl J Med. 1997;336:1769–1775.[Abstract/Free Full Text]
    
12. Pedersen AT, LidegaardØ, Kreiner S, et al. Hormone replacement therapy and risk of non-fatal stroke. Lancet. 1997;350:1277–1283.[Medline] [Order article via Infotrieve]
    
13. Petitti DB, Sidney S, Quesenberry CP, et al. Ischemic stroke and use of estrogen and estrogen/progestogen as hormone replacement therapy. Stroke. 1998;29:23–28.[Abstract/Free Full Text]
    
14. Fung MM, Barrett-Connor E, et al. Hormone replacement therapy and stroke risk in older women. J Womens Health. 1999;8:359–364.[Medline] [Order article via Infotrieve]
    
15. Grodstein F, Stampfer MJ, Falkeborn M, et al. Postmenopausal hormone therapy and risk of cardiovascular disease and hip fracture in a cohort of Swedish women. Epidemiology. 1999;5:476–480.
    
16. Posthuma WFM, Westendorp RGJ, Vandenbroucke JP. Cardioprotective effect of hormone replacement therapy in postmenopausal women: is the evidence biased? BMJ. 1994;308:308–309.[Abstract/Free Full Text]
    
17. Sturgeon SR, Schairer C, Brinton LA, et al. Evidence of a healthy estrogen user survivor effect. Epidemiology. 1995;6:227–231.[Medline] [Order article via Infotrieve]
    
18. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605–613.[Abstract/Free Full Text]
    
19. Hulley S, Grady D, Vittinghoff E, et al. Hormone replacement therapy for secondary prevention of coronary heart disease. JAMA. 1999;281:796–797. Letter.
    
20. Warlow CP. Epidemiology of stroke. Lancet. 1998;352(suppl III):1–4.
    
21. Sacco RL, Benjamin EJ, Broderick JP, et al. American Heart Association Prevention Conference IV: prevention and rehabilitation of stroke: risk factors. Stroke. 1997;28:1507–1517.[Free Full Text]
    
22. Sacco RL. Risk factors and outcomes for ischemic stroke. Neurology. 1995;45(suppl 1):S10–S14.
    
23. Biller J, Love BB. Diabetes and stroke. Med Clin North Am. 1993;77:95–110.[Medline] [Order article via Infotrieve]
    
24. Shinton R, Beevers G. Meta-analysis of relation between cigarette smoking and stroke. BMJ. 1989;298:789–794.
    
25. Hart RG, Pearce LA, McBride R, et al. Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. Stroke. 1999;30:1223–1229.[Abstract/Free Full Text]
    
26. DiPietro L, Ostfeld AM, Rosner GL. Adiposity and stroke among older adults of low socioeconomic status: the Chicago Stroke Study. Am J Public Health. 1994;84:14–19.[Abstract/Free Full Text]
    
27. Njølstad I, Arnesen E, Lund-Larsen PG. Body height, cardiovascular risk factors, and risk of stroke in middle-aged men and women: a 14-year follow-up of the Finnmark Study. Circulation. 1996;94:2877–2882.[Abstract/Free Full Text]
    
28. Hubert HB, Feinleib M, McNamara PM, et al. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation. 1983;67:968–977.[Abstract/Free Full Text]
    
29. Johnson JL, Heineman EF, Heiss G, et al. Cardiovascular disease risk factor and mortality among black women and white women aged 40–64 years in Evans County, Georgia. Am J Epidemiol. 1986;123:209–220.[Abstract/Free Full Text]
    
30. Comstock GW, Kendrick MA, Livesay VT. Subcutaneous fatness and mortality. Am J Epidemiol. 1966;83:548–563.[Free Full Text]
    
31. Paffenbarger RS Jr, Notkin J, Krueger DE, et al. Chronic disease in former college students, II: methods of study and observations on mortality from coronary heart disease. Am J Public Health. 1966;56:962–971.
    
32. Ostfeld AM, Shekelle RB, Klawans H, et al. Epidemiology of stroke in an elderly welfare population. Am J Epidemiol. 1974;64:450–458.
    
33. Carman WJ, Barrett-Connor E, Sowers M, et al. Higher risk of cardiovascular mortality among lean hypertensive individuals in Tecumseh, Michigan. Circulation. 1994;89:703–711. [Abstract/Free Full Text]
    

This article has been cited by other articles:

				W. Rosamond, K. Flegal, K. Furie, A. Go, K. Greenlund, N. Haase, S. M. Hailpern, M. Ho, V. Howard, B. Kissela, et al. Heart Disease and Stroke Statistics--2008 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Circulation, January 29, 2008; 117(4): e25 - e146. [Full Text] [PDF]

				T. R. Rebbeck, A. B. Troxel, S. Norman, G. Bunin, A. DeMichele, R. Schinnar, J. A. Berlin, and B. L. Strom Pharmacogenetic Modulation of Combined Hormone Replacement Therapy by Progesterone-Metabolism Genotypes in Postmenopausal Breast Cancer Risk Am. J. Epidemiol., December 15, 2007; 166(12): 1392 - 1399. [Abstract] [Full Text] [PDF]

				C. W. Hogue Jr, K. Freedland, T. Hershey, R. Fucetola, A. Nassief, B. Barzilai, B. Thomas, S. Birge, D. Dixon, K. B. Schechtman, et al. Neurocognitive Outcomes Are Not Improved by 17{beta}-Estradiol in Postmenopausal Women Undergoing Cardiac Surgery Stroke, July 1, 2007; 38(7): 2048 - 2054. [Abstract] [Full Text] [PDF]

				L. B. Goldstein Low LDL cholesterol, statins, and brain hemorrhage: Should we worry? Neurology, March 6, 2007; 68(10): 719 - 720. [Full Text] [PDF]

				W. Rosamond, K. Flegal, G. Friday, K. Furie, A. Go, K. Greenlund, N. Haase, M. Ho, V. Howard, B. Kissela, et al. Heart Disease and Stroke Statistics--2007 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Circulation, February 6, 2007; 115(5): e69 - e171. [Full Text] [PDF]

				T. R. Rebbeck, A. B. Troxel, Y. Wang, A. H. Walker, S. Panossian, S. Gallagher, E. G. Shatalova, R. Blanchard, G. Bunin, A. DeMichele, et al. Estrogen sulfation genes, hormone replacement therapy, and endometrial cancer risk. J Natl Cancer Inst, September 20, 2006; 98(18): 1311 - 1320. [Abstract] [Full Text] [PDF]

				C. D. Bushnell, P. Hurn, C. Colton, V. M. Miller, G. del Zoppo, M. S.V. Elkind, B. Stern, D. Herrington, G. Ford-Lynch, P. Gorelick, et al. Advancing the Study of Stroke in Women: Summary and Recommendations for Future Research From an NINDS-Sponsored Multidisciplinary Working Group Stroke, September 1, 2006; 37(9): 2387 - 2399. [Abstract] [Full Text] [PDF]

				L. Sunday, M. M. Tran, D. N. Krause, and S. P. Duckles Estrogen and progestagens differentially modulate vascular proinflammatory factors Am J Physiol Endocrinol Metab, August 1, 2006; 291(2): E261 - E267. [Abstract] [Full Text] [PDF]

				L. B. Goldstein, R. Adams, M. J. Alberts, L. J. Appel, L. M. Brass, C. D. Bushnell, A. Culebras, T. J. DeGraba, P. B. Gorelick, J. R. Guyton, et al. Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline. Circulation, June 20, 2006; 113(24): e873 - e923. [Abstract] [Full Text] [PDF]

				L. B. Goldstein, R. Adams, M. J. Alberts, L. J. Appel, L. M. Brass, C. D. Bushnell, A. Culebras, T. J. DeGraba, P. B. Gorelick, J. R. Guyton, et al. Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline. Stroke, June 1, 2006; 37(6): 1583 - 1633. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				Stroke Obstet. Gynecol., October 1, 2004; 104(4_suppl): 97S - 105S. [Full Text] [PDF]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]