From the Kaiser Permanente Medical Care Program, Southern California
(D.B.P.) and Northern California (S.S., C.P.Q., A.B.).
Methods—In this case-control study, women aged 45 to 74 years
hospitalized with a fatal or nonfatal stroke in any of 10 Northern
California Kaiser Permanente facilities during the period November 1991
to November 1994 were identified as cases. Controls were selected at
random from female Health Plan members. Data regarding use of estrogen
plus progestogen or estrogen alone were obtained in interviews.
Results—The analysis was based on nonproxy responses from
349 cases of ischemic stroke and 349 matched control subjects.
After adjustment for confounders, the odds ratio for ischemic
stroke in current hormone users was 1.03 (95% confidence interval,
0.65 to 1.65). The odds ratios for ischemic stroke in current
hormone users showed no clear trend of increasing or decreasing risk in
relation to duration of hormone use. The odds ratio for
ischemic stroke in past hormone users was 0.84 (95% confidence
interval, 0.54 to 1.32).
Conclusions—In this study postmenopausal hormone use was not
associated with an increase or decrease in the risk of ischemic
stroke, a finding that is consistent with the body of
literature on this topic.
The Women's Health Initiative is a large randomized trial that will
examine the relationship of ERT and HRT with a variety of health
outcomes. The results of this study will not be available for several
years.
Our study was designed to estimate the relative risk of stroke in
relation to current use of ERT and HRT in a population with a
relatively high prevalence of hormone use. The risk of stroke in
relation to duration of use of postmenopausal hormones is also
presented because this is a topic that has not been examined
closely in prior studies.
Case Ascertainment and Classification
Stroke was defined as the new onset of rapidly developing symptoms and
signs of loss of cerebral function with no apparent cause other than
that of vascular origin. Specifically excluded were neurological events
due to subdural hematoma, brain tumor, infection, metabolic
derangement, and multiple sclerosis. Case subjects with a prior history
of cerebrovascular disease based on medical record review at the
time of their event were also excluded.
To establish the stroke diagnosis, records of all potential stroke
events were reviewed by two physicians (D.B.P. and S.S.) with
adjudication of discrepancies in their assessment by a project
neurologist (A.B.). The review used a defined protocol. Strokes were
subclassified as being hemorrhagic or due to ischemic
infarction, also according to a defined protocol that included review
of records by two physicians (D.B.P. and S.S) with adjudication of
discrepancies by a project neurologist. A stroke was considered to
be hemorrhagic if blood was found on CT or MRI scan, if a nontraumatic
lumbar puncture revealed blood and/or xanthochromia, or if
intracerebral blood was found at autopsy, on cerebral
angiography, or at surgery. Remaining strokes were considered
ischemic infarctions.
Control Subjects
Information Sources
Interview questions were asked relative to an index date, which was the
date of symptom onset for case subjects and the same date for the
matched control subjects. The calendar method, in which hormone
replacement use information is gathered by structuring questions in
relation to significant life events, was used to obtain information on
all hormone replacement preparations ever used. A visual aid,
consisting of actual pills for commonly used preparations and a color
chart with a picture of all hormone replacement preparations ever
marketed in the United States, was used to facilitate recall of the
formulation of hormone replacement preparations used currently and in
the past.
Hypertension was defined as a "yes" to a question about use of
medication for high blood pressure. Diabetes was defined as a "yes"
to a question asking about use of insulin or pills for diabetes. A
study subject was defined as a nonsmoker if she answered "no" to
the question, "Have you ever smoked cigarettes?" If she answered
"yes" to this question, she was categorized as a current regular
smoker on the basis of her answer to the question, "On (index date)
were you still smoking regularly?" ("regularly" was defined as at
least five cigarettes per week, almost every week). Body mass index
(kilograms per meter squared) was determined with self-reported height
and weight. Exercise was assessed by self-report. A study subject was
defined as having a prior self-reported history of stroke or TIA if she
stated that a physician had told her she had had a stroke or TIA.
Analysis
The vast majority of hysterectomized women (98%) used ERT, and most
nonhysterectomized women (76%) used HRT. For this reason, estimates of
the ORs for stroke in users of ERT who have not had a hysterectomy and
the ORs for stroke in users of HRT who have had a hysterectomy are
highly unstable statistically. Thus, we excluded from the main
analysis hysterectomized women who used HRT and
nonhysterectomized women who used ERT. Women who used only progestogen
were also excluded from both case and control subjects because the
number of women in this group was very small, and valid estimates of
risk in relation to exposure to progestogen only could not be derived.
These exclusions were applied to both case and control subjects.
Of the women who used ERT, 90% used conjugated equine estrogen; of
these, 81% used 0.625 mg/d. Of women who used HRT, 95% used
medroxyprogesterone acetate. The regimens of HRT
use were varied, and no single regimen had a large number of women. For
these reasons, we did not attempt to assess the ORs for stroke in
relation to specific doses of estrogen, types of progestogen, or
regimens of HRT.
We compared information on hormone use in the 2 years before interview
documented in medical records with information provided by proxies
to assess response bias and found that use of hormones was
substantially underreported by proxy respondents. For this reason,
proxy responses were also excluded from the analysis. We did
not use information from medical records for the analysis
because neither hormone use on a particular date nor lifetime past use
could be ascertained from available medical records.
Analysis
We also performed an analysis that examined the ORs for stroke
in relation to current use of ERT and HRT separately. This
analysis was not matched and adjusted for hysterectomy as well
as other confounders.
Table 2
When we took into account only the matching variables, the OR for
ischemic stroke in current ERT users compared with never
hormone users was 0.81 (95% CI, 0.52 to 1.26); the OR in current HRT
users compared with never hormone users was 0.62 (95% CI, 0.35 to
1.11). The OR for past hormone use compared with never hormone use was
0.77 (95% CI, 0.54 to 1.11).
Table 3
We also did an analysis in which women with hysterectomy who
used HRT and women without hysterectomy who used ERT were not excluded.
There were 374 case subjects and 360 control subjects. After the
adjustment for hysterectomy as well as the variables shown in Table 3
After adjustment for smoking, hypertension, diabetes, body mass index,
ethnicity, and education, the OR for hemorrhagic stroke in current
hormones users compared with never hormone users was 0.33 (95% CI,
0.12 to 0.96), based on 83 case/control sets.
Psaty et al12 summarized the published literature on
hormone use and stroke in 1993 and concluded, based on available data
then, that there was little if any association with stroke. This
conclusion was based on the lack of a consistent relationship
between stroke and hormone use. Grady et al,13 in their
comprehensive literature review on hormone replacement therapy, derived
a summary estimate of the relative risk of stroke in ERT users of 0.96
(95% CI, 0.82 to 1.13) but pointed out there was statistical evidence
of heterogeneity for studies of stroke and ERT. There
were few data on stroke in relation to use of HRT at the time these two
reviews were done.
Recent data on stroke in relationship to current use of both ERT and
HRT come from the Nurse's Health Study.1 This
analysis was based on 285 cases of ischemic stroke and
155 cases of subarachnoid hemorrhage. These two types
of strokes were combined in the analysis because the
relationship between hormone use and risk was the same for both stroke
types. After adjustment for age, age at menopause, body mass index,
diabetes, hypertension, high cholesterol, smoking, past use
of oral contraceptives, parental history of myocardial infarction
before age 60, and type of menopause, the relative risk of all stroke
in current users of ERT compared with never hormone users was 1.27
(95% CI, 0.95 to 1.69); it was 1.09 (95% CI, 0.66 to 1.80) in current
users of HRT compared with never hormone users.
We were able to identify only two other published studies that have
examined the relationship specifically between current postmenopausal
hormone use and stroke.3 4 Both studies addressed only ERT.
In a report based on 11 cases of subarachnoid
hemorrhage and 23 cases of other stroke, Petitti et
al3 reported that the relative risk of subarachnoid
hemorrhage in current users of ERT was 1.6 (95% CI, 0.7 to
3.8), and the relative risk of other stroke (virtually all cases were
ischemic stroke) was 0.9 (95% CI, 0.4 to 1.8) after adjustment
for confounders. Rosenberg et al4 reported an estimated
relative risk of ischemic stroke in current users of ERT of
1.16 (95% CI, 0.75 to 1.77) based on a case-control study of 198
nonfatal ischemic strokes. Other published studies of stroke in
users of hormone replacement therapy have examined ever use of
hormones. Ever use of hormones is difficult to interpret as an exposure
because women ever exposed to hormones are a heterogeneous
group of current and past users, with varying durations of use and
varying periods of time since last use among past users. Consideration
of our results along with the results of other studies of stroke in
relationship to current use of ERT or HRT1 4 5 leads to a
conclusion that current postmenopausal hormone use does not increase or
decrease the risk of ischemic stroke.
It would be useful to have more information on hemorrhagic stroke
before drawing a similar conclusion about the absence of an increased
or decreased risk in current users of ERT and HRT. Although
ischemic and hemorrhagic stroke share in common an association
with hypertension and smoking, the associations of diabetes, body mass
index, and alcohol are different for hemorrhagic and ischemic
stroke. It would be a mistake to generalize the results of studies of
hormone use and ischemic stroke to hemorrhagic stroke. Future
studies of hemorrhagic stroke need to take into account the high
proportion of women who cannot provide information about their hormone
use and the lack of validity of proxy responses about hormone use.
Grodstein et al1 also examined stroke risk in
relation to past hormone use in a way that is comparable to our study.
Their findings are consistent with ours and suggest that any
effect of hormone use on stroke risk does not persist
after cessation of use.
Our study has many limitations. Major concerns are recall bias and
nonresponse bias. To assess these biases as explanations for our
results, we examined information about hormone use in the 2 years
before index date as recorded in medical records of a
systematic sample of all women (case and control subjects) eligible for
the study. To assess recall bias as a possible explanation for our
results, we compared self-reports about current use of hormones from
respondents with medical record information for the same subjects.
The percentages were similar—30% and 32%. Thus, we do not believe
that recall bias explains the findings of our study. To assess
nonresponse in control subjects as a possible explanation for our
results, we compared medical record information on hormone use
within 2 years of the index date for respondent and nonrespondent
control subjects. These percentages were 32% and 34%, respectively.
We conclude that response bias in control subjects does not explain our
findings.
We also used information from the medical record review to assess
the possibility that exclusion of proxy responses among case subjects
might explain our results. The proportion of hormone users within 2
years of the index date, after differences in the age of
ischemic stroke cases in the analysis and
ischemic stroke cases whose medical records were reviewed
are taken into account, was 27% for direct respondents and 22% for
proxy respondents. Since 14% of ischemic stroke cases were
excluded as a result of proxy response, we conclude that excluding
proxies did not bias our findings for this outcome. Concern about bias
due to exclusion of proxy data for cases of hemorrhagic stroke is the
reason we did not present detailed analysis for this
outcome.
Stroke is an important cause of morbidity and mortality in women. Grady
et al13 estimated that a 50-year-old woman has a 20%
lifetime probability of developing a stroke and an 8% lifetime
probability of dying from stroke. If hormone use caused either an
increase or a decrease in the risk of stroke, it would have important
implications for the assessment of the overall effect of hormone use on
life expectancy and quality of life. Our study joins a growing body of
literature that suggests that hormone use does not affect the risk of
ischemic stroke.
Received July 31, 1997;
revision received September 22, 1997;
accepted October 8, 1997.
2.
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.
3.
Petitti DB, Wingerd J, Pellegrin F, Ramcharan S. Risk
of vascular disease in women: smoking, oral contraceptives,
noncontraceptive estrogens, and other factors. JAMA. 1979;242:1150–1154.
4.
Rosenberg SH, Fausone V, Clark R. The role of
estrogens as a risk factor for stroke in postmenopausal women.
West J Med. 1980;133:292–296.[Medline]
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5.
Henderson BE, Paganini-Hill A, Ross RK. Decreased
mortality in users of estrogen replacement therapy. Arch Intern
Med. 1991;151:75–78.
6.
Wilson PWF, Garrison J, 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]
7.
Bush TL, Barrett-Connor E, Cowan LD, Criqui MH,
Wallace RB, Suchindran CM, Tyroler HA, Rifkind BM.
Cardiovascular mortality and noncontraceptive use of
estrogen in women: results from the Lipid Research Clinics Program
Follow-up Study. Circulation. 1987;75:1102–1109.
8.
Pfeffer RI, van Den Nort S. Estrogen use and stroke
risk in postmenopausal women. Am J Epidemiol. 1976;103:445–456.
9.
Hammond CB, Jelovesk FR, Lee KL, Creasman WT, Parker
RT. Effects of long-term estrogen replacement therapy, I:
metabolic effects. Am J Obstet Gynecol. 1979;133:525–536.[Medline]
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10.
Boysen G, Nyboe J, Appleyard M, Sorensen PS, Boas J,
Sommier F, Jensen G, Schnor P. Stroke incidence and risk factors for
stroke in Copenhagen, Denmark. Stroke. 1988;19:1145–1153.
11.
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.
12.
Psaty BM, Heckbert SR, Atkins D, Siscovick DS, Koepsell
TD, Wahl PW, Longstreth WT, Weiss NS, Wagner EH, Prentice R, Furberg
CD. A review of the association of estrogens and progestins with
cardiovascular disease in postmenopausal women.
Arch Intern Med. 1993;153:1421–1427.
13.
Grady D, Rubin SM, Petitti DB, Fox CS, Black D,
Ettinger B, Ernster VL, Cummings SR. Hormone therapy to prevent disease
and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016–1037.
© 1998 American Heart Association, Inc.
Original Contributions
Ischemic Stroke and Use of Estrogen and Estrogen/Progestogen as Hormone Replacement Therapy
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—Information
about the risk of stroke in current postmenopausal hormone users
is limited.
Key Words: cerebral infarction • cerebrovascular disorders • hemorrhagic stroke • stroke, ischemic
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
A number of
epidemiological studies have examined the relationship between stroke
and use of postmenopausal hormones.1 2 3 4 5 6 7 8 9 10 11 We identified only
two studies1 2 presenting data on the postmenopausal
use of combined estrogen and progestogen therapy (HRT). We identified
only three studies1 3 4 presenting information on
stroke risk specifically in relation to current use of estrogen alone
(ERT). Studies of stroke and hormone use are difficult to interpret in
aggregate because of differences in the types of strokes included and
variation in the extent of statistical control for socioeconomic and
demographic variables.
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Overview
This was an epidemiological case-control study. The study was
reviewed and approved by the Institutional Review Board of the Kaiser
Permanente Medical Care Program of Northern California.
An attempt was made to identify all fatal and nonfatal strokes
in women aged 45 to 74 years in 10 medical centers of the Kaiser
Permanente Medical Care Program, Northern California region during the
period November 1991 to November 1994. Start and finish dates differed
by facility. Thus, the number of months of case ascertainment differed
at each facility; it averaged 33.4 months. Sources of case
identification included hospital admission and discharge records,
emergency department logs, and payments for out-of-plan
hospitalizations.
For each case subject, one control subject, matched on birth
year and facility of care, was randomly selected from female members of
the Health Plan. Control subjects who could not be located, declined
interview, or spoke other than English or Spanish were replaced with
control subjects selected at random until one control subject was
obtained for each case subject or two "replacement" control
subjects had been selected.
Eligible case and control subjects were interviewed in person by
trained interviewers using a standardized instrument. If a case subject
had died or was unable to communicate verbally, an attempt was made to
interview a proxy.
The analysis was restricted to postmenopausal women. A
study subject was categorized as postmenopausal if she had undergone
bilateral oophorectomy or she was nonhysterectomized and reported that
she had ceased having menstrual periods. Hysterectomized women who have
undergone a unilateral oophorectomy would not know whether they were
premenopausal or postmenopausal based on menstrual function. For this
reason, we also excluded hysterectomized women less than 55 years of
age because they could not be classified as postmenopausal with
certainty. These exclusions were applied to both case and control
subjects.
The exposure OR was used to estimate relative risk. Conditional
logistic regression was used in the main analysis. For the main
analysis, we defined an exposure variable—current hormone
use—as "yes" for hysterectomized woman who used ERT and
nonhysterectomized woman who used HRT. Because of the way hormone
exposure is defined, the OR for hormone use in the main
analysis pertains to current use of ERT for hysterectomized
women and to current use of HRT for nonhysterectomized women. Duration
(years) of hormone replacement therapy in current hormone users was
examined by replacing the hormone replacement treatment variable
(ERT for hysterectomy, HRT for no hysterectomy) with years of use of
either. In the multivariate analyses, we
adjusted for major established risk factors for ischemic
stroke—cigarette smoking, hypertension, and diabetes—and for prior
history of stroke or TIA. In addition, we adjusted for other
variables that were apparent confounders in these data, including
the variable in the model if there was an appreciable change in the
exposure coefficients with the addition of the potential
confounder.
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
There were 885 possible stroke cases identified by our
surveillance effort during the period of case ascertainment; 758 cases
were confirmed stroke cases. Of these 758 confirmed cases, 550 were
cases of ischemic stroke, 201 were cases of hemorrhagic stroke,
and 7 could not be classified as ischemic or hemorrhagic. Of
the 550 cases of ischemic stroke, exclusions because of patient
or physician refusal, proxy interviews, and other reasons (Table 1
) left 349 case/control sets for the
analysis. The same exclusions for cases of hemorrhagic stroke
left only 83 case/control sets for analysis. Because of the
small number of cases of hemorrhagic stroke that remained after
exclusions, we have chosen not to present detailed data on
hemorrhagic stroke.
View this table:
[in a new window]
Table 1. Summary of Exclusions shows the characteristics of
ischemic stroke case and control subjects along with the
age-adjusted ORs for each characteristic. Age-adjusted ORs were
elevated in relation to smoking, hypertension, diabetes, high body mass
index, low education, low income, and African-American ethnicity. Women
who drank alcohol were at a lower risk of ischemic stroke. The
risk of ischemic stroke in women with high
cholesterol was only slightly elevated.
View this table:
[in a new window]
Table 2. Characteristics of Ischemic Stroke Case and
Control Subjects and OR for Each Characteristic Taking Into Account
Only the Matching Variables shows results adjusted for
established risk factors for ischemic stroke (age,
hypertension, diabetes, smoking, body mass index, prior history of
stroke or TIA) and for socioeconomic variables (education,
ethnicity). Alcohol use did not confound the relationship between
hormone use, and stroke and was not included in the adjustment model.
After adjustment for confounders, the OR for ischemic stroke in
current hormone users compared with never hormone users was 1.03 (95%
CI, 0.65 to 1.65). The adjusted ORs for ischemic stroke in
current hormone users showed no clear trend of increasing or decreasing
risk in relation to duration of hormone use. The adjusted OR for
ischemic stroke in past hormone users was 0.84 (95% CI, 0.54
to 1.32).
View this table:
[in a new window]
Table 3. Adjusted1
ORs for Ischemic Stroke in
Relation to Hormone Use 
, the OR in current users of HRT was 0.60 (95% CI, 0.31 to 1.16). For
current ERT use, the adjusted OR was 1.04 (95% CI, 0.60 to 1.10).
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Our data show no significant increase or decrease in the risk of
ischemic stroke in current users of ERT or HRT. The upper and
lower bounds of the CI provide an assessment of the power of the study.
The study had a 95% chance of detecting a true OR of ischemic
stroke in current hormone users as low as 0.65 and as high as 1.65, and
it does not rule out ORs for ischemic stroke between these two
values. Firm conclusions about hemorrhagic stroke in current users of
ERT and HRT cannot be drawn from our study because the large number of
excluded cases raises concerns about the
representativeness of the subjects available for
analysis.
Selected Abbreviations and Acronyms
CI
=
confidence interval
ERT
=
estrogen replacement therapy
HRT
=
combined estrogen and progestogen replacement therapy
OR
=
odds ratio
TIA
=
transient ischemic attack
Acknowledgments
This research was supported by a grant (R01-HL-47043) from the
National Heart, Lung, and Blood Institute. Teresa Picchi and Luisa
Hamilton oversaw field operations. Kimberly Tolan did the computer
programming for this analysis.
Footnotes
Reprint requests to Dr Diana B. Petitti, Research and Evaluation, SCPMG, 393 E Walnut St, Pasadena, CA 91188.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
1.
Grodstein F, Stampfer MJ, Manson JE, Colditz GA,
Willett WC, Rosner B, Speizer FE, Hennnekens CH. Postmenopausal
estrogen and progestin use and the risk of
cardiovascular disease. N Engl J
Med. 1996;335:453–461.
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 G. G. Geary, D. N. Krause, and S. P. Duckles Estrogen reduces mouse cerebral artery tone through endothelial NOS- and cyclooxygenase-dependent mechanisms Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H511 - H519. [Abstract] [Full Text] [PDF]
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C. Sarti, D. Rastenyte, Z. Cepaitis, and J. Tuomilehto International Trends in Mortality From Stroke, 1968 to 1994 Stroke, July 1, 2000; 31(7): 1588 - 1601. [Abstract] [Full Text] [PDF]
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K. Sampei, S. Goto, N. J. Alkayed, B. J. Crain, K. S. Korach, R. J. Traystman, G. E. Demas, R. J. Nelson, P. D. Hurn, and S. Piper Duckles Stroke in Estrogen Receptor-{alpha}-Deficient Mice • Editorial Comment Stroke, March 1, 2000; 31(3): 738 - 744. [Abstract] [Full Text] [PDF]
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N. J. Alkayed, S. J. Murphy, R. J. Traystman, P. D. Hurn, and V. M. Miller Neuroprotective Effects of Female Gonadal Steroids in Reproductively Senescent Female Rats Editorial Comment Stroke, January 1, 2000; 31(1): 161 - 168. [Abstract] [Full Text] [PDF]
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R. Rusa, N. J. Alkayed, B. J. Crain, R. J. Traystman, A. S. Kimes, E. D. London, J. A. Klaus, P. D. Hurn, and C. Iadecola 17{beta}-Estradiol Reduces Stroke Injury in Estrogen-Deficient Female Animals • Editorial Comment Stroke, August 1, 1999; 30(8): 1665 - 1670. [Abstract] [Full Text] [PDF]
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R. G. Hart, L. A. Pearce, R. McBride, R. M. Rothbart, and R. W. Asinger Factors Associated With Ischemic Stroke During Aspirin Therapy in Atrial Fibrillation : Analysis of 2012 Participants in the SPAF I–III Clinical Trials Stroke, June 1, 1999; 30(6): 1223 - 1229. [Abstract] [Full Text] [PDF]
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C. X. Pan, J. Boal, for the Geriatrics Journal Club, E. Banks, V. Beral, P. J. L. Ong, M. B. Sorensen, C. S. Hayward, C. M. Webb, P. Collins, et al. Hormone Replacement Therapy for Secondary Prevention of Coronary Heart Disease JAMA, March 3, 1999; 281(9): 794 - 797. [Full Text] [PDF]
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M.-G. Bousser Stroke in Women : The 1997 Paul Dudley White International Lecture Circulation, February 2, 1999; 99(4): 463 - 467. [Full Text] [PDF]
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A. Kastrup, J. Dichgans, M. Niemeier, and M. Schabet Changes of Cerebrovascular CO2 Reactivity During Normal Aging Stroke, July 1, 1998; 29(7): 1311 - 1314. [Abstract] [Full Text] [PDF]
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