Original Paper

Neuroepidemiology Received: October 8, 2019

Accepted: January 8, 2020
DOI: 10.1159/000505970 Published online: February 11, 2020

Physical Activity, Hormone Therapy Use,

and Stroke Risk among Women in the
California Teachers Study Cohort
Charlie Zhong a Jenna Voutsinas a Joshua Z. Willey b, c Kamakshi Lakshminarayan d
       

James V. Lacey, Jr. a Nadia T. Chung a Daniel Woo e Mitchell S.V. Elkind b, c

       

Sophia S. Wang a  

a Division
of Health Analytics, Department of Computational and Quantitative Medicine, Beckman Research Institute
and the City of Hope, Duarte, CA, USA; b Department of Neurology, Vagelos College of Physicians and Surgeons,
 

New York, NY, USA; c Department of Epidemiology, Mailman School of Public Health, Columbia University,
 

New York, NY, USA; d Division of Epidemiology and Community Health, School of Public Health, University of Minnesota,
 

Minneapolis, MN, USA; e Department of Neurology, University of Cincinnati Medical Center, Cincinnati, OH, USA
 

Keywords proportional hazards models, we estimated the hazard ra-

Stroke epidemiology · Hormone therapy · Women ·
Postmenopausal · Physical activity
Abstract
Background: Postmenopausal hormone therapy (HT) in-
creases the risk of stroke. Here we evaluate whether leisure
time physical activity (LTPA) can change stroke risk in wom-
en using HT, leveraging data from the California Teachers
Study. Methods: Female California educators without a prior
history of stroke (n = 118,294) were followed from 1995
through 2015 for stroke end points. Based on statewide hos-
pitalization data, 4,437 women had ischemic (n = 3,162; In-
ternational Classification of Diseases [ICD]-9 433, 434, 436) or
hemorrhagic (n = 1,275; ICD-9 430–432, excluding 432.1)
stroke. LTPA and HT use were evaluated at 2 time points
(baseline [1995–1996] and 10-year follow-up [2005–2006]).
LTPA was assessed using American Heart Association (AHA)
recommendations (> 150 min/week moderate or > 75 min/
week strenuous physical activity). Using multivariable Cox
tios (HRs) and 95% CIs for the associations between HT use
and concurrent LTPA with incident stroke. Results: Com-
pared to women who never used HT, stroke risk was highest
among women who were current HT users and did not meet
AHA recommendations for LTPA at the time of their HT use:
HRbaseline 1.28 (95% CI 1.13–1.44); HR10-year follow-up 1.17 (95%
CI 0.91–1.50). Based on the baseline questionnaire, current
HT users who met AHA recommendations for LTPA in 1995–
1996 still had elevated stroke risk in the 20-year follow-up
(HR 1.22, 95% CI 1.08–1.37). However, among current HT us-
ers who met AHA recommendations for LTPA at the 2005–
2006 follow-up questionnaire, stroke risk was not elevated
(HR 1.01, 95% CI 0.80–1.29). Evaluation of the 2 time points
in concert further demonstrated that meeting AHA recom-
mendations for LTPA at the most recent follow-up time point
was required to reduce HT-related stroke risk. Conclusion:
Concurrent physical activity may attenuate the short-term
increase in risk of stroke risk associated with HT use.
© 2020 S. Karger AG, Basel
193.51.85.197 - 2/12/2020 2:59:39 PM

© 2020 S. Karger AG, Basel Charlie Zhong

Division of Health Analytics, Department of Computational and
Quantitative Medicine, Beckman Research Institute of the City of Hope
E-Mail karger@karger.com
1500 East Duarte Road, Duarte, CA 91010 (USA)
Université de Paris

www.karger.com/ned
Downloaded by:

E-Mail czhong @ coh.org

 Introduction
More than 610,000 incident strokes and over 140,000
deaths from strokes occur in the United States each year,
making it a leading cause of death [1]. Women are more
likely than men to die from a stroke or to be severely dis-
abled and require medical care following stroke [2]. Be-
cause modifiable risk factors account for a large propor-
tion of the overall stroke burden [3], opportunities exist
for population-based prevention efforts.
Stroke risk doubles among women from pre- to post-
menopause [4]. This doubling of risk can be attributed to
the increase in cardiovascular risk factors that occurs after
menopause. Data from the Women’s Health Initiative, a
randomized trial of 16,608 postmenopausal women, dem-
onstrated a 44% higher risk of ischemic stroke among
women using estrogen plus progestin therapy and a 55%
increased risk of ischemic stroke among estrogen users
alone [5]. A subsequent meta-analysis further confirmed a
~30% increased risk of total stroke, non-fatal stroke, fatal
stroke, and ischemic stroke, but not hemorrhagic stroke,
among hormone therapy (HT) users [6]. Current recom-
mendations are to “limit use of HT to the lowest effective
dose for the shortest amount of time possible” [7] with the
aim to limit HT exposure to short-term use in order to
maximize benefits from HT use and minimize health out-
comes, including cardiovascular end points such as stroke.
In contrast to other known stroke risk factors (e.g., to-
bacco use, body mass index [BMI]), leisure time physical
activity (LTPA) is associated with decreased stroke risk,
making it an important and potentially modifiable pre-
vention strategy for reducing stroke incidence and mor-
tality [8, 9]. We recently reported that meeting American
Heart Association (AHA) recommendations for LTPA
was associated with lower risk of stroke among women,
and largely for ischemic stroke [10]. Here, we evaluate the
concurrent effects of LTPA and HT use on women’s risk
of stroke among participants in the California Teachers
Study (CTS), a prospective cohort study of 133,479 wom-
en continuously followed for stroke and other health out-
comes since 1995–1996. Specifically, we sought to evalu-
ate the difference in stroke risk, by stroke type, among
physically active HT users.
Materials and Methods
Study Population
Details of the CTS have been described previously [11]. Briefly,
the CTS is a prospective cohort study of 133,479 current and for-
mer female public school professionals. Women joined the cohort
2 Neuroepidemiology
DOI: 10.1159/000505970
by completing a mailed baseline questionnaire in 1995–1996,
which collected information on demographics, personal and fam-
ily history of selected diseases and conditions, smoking status, diet,
alcohol consumption, menstrual and reproductive histories,
menopausal HT, adult height, weight, and LTPA.
Analytic cohort. The eligible participants for this analysis were
118,294 women aged 26–99 years old; after exclusion of those who
had a prior stroke (n = 1,810 self-reported; n = 345 identified in
hospitalization records), were not California residents at baseline
(n = 8,649), were younger than 26 or older than 99 years (n =
1,146), or had missing data on race, smoking status, socioeconom-
ic status (SES), or physical activity (n = 3,235). Of those women,
88,923 were either postmenopausal at baseline or became post-
menopausal during follow-up and were included in the baseline
analysis. A total of 34,212 of these postmenopausal women also
had complete LTPA and HT data during a follow-up questionnaire
(2005–2006) and were included in those analyses (Fig. 1).
Stroke Ascertainment
CTS participants diagnosed with a stroke were identified
through linkage with the California Office of Statewide Health
Planning and Development (OSHPD) hospital discharge database
files (http://www.oshpd.ca.gov/) and with mortality data from the
California Department of Public Health and the National Death
Index. Stroke was defined as the first hospitalization with an Inter-
national Classification of Diseases (ICD)-9-CM code in the prin-
cipal diagnosis position of 430, 431, 432.x (excluding 432.1), 433.
x1, 434.xx (excluding 434.x0), 436, 437.1, or 437.9. Ischemic stroke
was defined as hospitalization with ICD-9-CM codes 433.x1, 434.
xx (excluding 434.x0), or 436. Hemorrhagic stroke was defined as
hospitalization with ICD-9-CM codes 430, 431, or 432. Addition-
al strokes not identified through hospitalization records were
identified through mortality data (n = 494). These definitions were
previously validated in the CTS based on expert neurologist re-
views [12]. Follow-up through September 2015 identified 4,437
women who were diagnosed with a stroke; among these, 3,162 had
an ischemic stroke and 1,275 had hemorrhagic stroke.
HT. Menopausal HT use was queried at baseline (1995–1996)
and 2 follow-up questionnaires (2000–2002, 2005–2007); meno-
pausal status, hormone type, formulation, age of first use, duration
of use, and years since last use were ascertained. Based on their
questionnaire responses regarding duration of use coupled with
questionnaire completion date – participants were classified for
each year of follow-up as never, former, current, or unknown user.
To evaluate the effect of LTPA among HT users, we specified HT
simultaneous to the period in which physical activity was ascer-
tained (e.g., 1995–1996 and 2005–2006).
LTPA. LTPA was ascertained at the baseline questionnaire
(1995–1996) and in a follow-up questionnaire (2005–2007) [13].
Mean hours per week was calculated by multiplying the hours per
week by the portion of the year in which the woman was engaged
in that level of activity (moderate activities and strenuous activi-
ties). We categorized these measures by the AHA recommenda-
tions for ideal cardiovascular health (either 150 min per week of
moderate activity or 75 min per week of strenuous activity).
Covariates. Variables considered as potential confounders in-
cluded race/ethnicity (non-Hispanic White, Black, Hispanic,
Asian/Pacific Islander, Other), SES (below median, above median
of California population based on US Census), family history of
stroke in first-degree relatives, BMI (kg/m2), smoking status (nev-
193.51.85.197 - 2/12/2020 2:59:39 PM
Zhong/Voutsinas/Willey/Lakshminarayan/
Lacey, Jr./Chung/Woo/Elkind/Wang
Université de Paris
Downloaded by:
 indication of postmenopausal status and the first of the following
CTS cohort ages: at event (stroke diagnosis), at censoring (e.g., when a par-
(n = 133,479) ticipant moved out of California for > 4 months), at death, or at
the end of follow-up (September 30, 2015). Models included for
Prior stroke
Self-reported (n = 1,810)
the following covariates that had been ascertained in the baseline
OSHPD (n = 345) questionnaire: race/ethnicity, smoking status, alcohol use, SES
(below or above statewide population median), BMI (< 18.5,
n = 131,324 18.5–25, 25–30, or ≥30 kg/m2), total caloric intake (kcal/day),
and presence or absence of a diagnosis of hypertension, diabetes,
Resided outside of California hyperlipidemia, and cardiac disease. Other potential covariates
(n = 8,649) were evaluated but none altered the HR estimates by 10% or
greater and were thus not included in the final models. All statis-
n = 122,675
tical analyses were performed with SAS, version 9.4 (SAS Insti-
tute Inc., Cary, NC, USA).
Age <26 or >99
(n = 1,146)

Results
n = 121,529

Select demographic characteristics and established

Missing data on covariates
(n = 3,235)
Responded to 2005–2006
n = 118,294 questionnaire
(n = 65,321)
Post menopausal Post menopausal
(n = 88,923) (n = 34,212)
Fig. 1. Flowchart of CTS participants eligible at baseline (1995–
1996) and follow-up (2005–2006) with exercise and hormone use.
OSHPD, California Office of Statewide Health Planning and De-
velopment; CTS, California Teachers Study.
er, former, current), alcohol use (never, former, current), and dai-
ly caloric intake (kilocalories); all assessed on baseline question-
naire. Aspirin and NSAID use were also assessed but not found to
confound the main association of interest, between physical activ-
ity, HT use, and stroke. Clinical covariates ascertained by ICD-9-
CM code from the linkage with OSHPD included atrial fibrillation
(427.3x), cardiomyopathy (425.xx), coronary heart disease (410–
414, 429.2), heart failure (428.xx, 402.x1, 403.x2, 404.x1, 404.x3),
atherosclerosis (440.xx), myocardial infarctions (410.xx), diabetes
(250.xx), hyperlipidemia (272.xx), and hypertension (401–405).
Statistical Analysis
Age-stratified multivariable Cox proportional hazards models
were fit to estimate the hazard ratio (HR) and 95% CIs for stroke
overall and for stroke types (ischemic and hemorrhagic) for as-
sociations with physical activity and HT. We stratified by hor-
mone use (current, former, never) and physical activity (meeting
or not meeting the AHA recommendation). In the Cox regres-
sion models, the time scale (in days) was defined by age at first
stroke risk factors are shown in online supplementary Ta-
ble 1 (for all online suppl. material, see www.karger.com/
doi/10.1159/000505970). We note that women who en-
gaged in exercise had higher SES, lower BMI, and less co-
morbidities. However, the distribution of HT use was not
significantly different between those who did and did not
meet exercise recommendations.
Evaluation of HT use and LTPA at study baseline
(1995–1996) yielded increased stroke risk (HRischemic
1.22, 95% CI 1.08–1.38; HRhemorrhagic 1.36, 95% CI 1.05–
1.75) for current HT users regardless of whether they met
AHA guidelines for LTPA or not (Table 1). Among the
participant subset who completed the 2005–2006 survey
with 10 years of follow-up, we found a higher risk of
stroke in former (HR 1.24, 95% CI 1.03–1.50) and current
HT users (HR 1.17, 95% CI 0.91–1.50) who did not meet
AHA recommendations. On the other hand, HT users
who met AHA recommendations had stroke risk similar
to never users (HRformer HT user = 0.93, 95% CI 0.76–1.13;
HRcurrent HT user = 1.01, 95% CI 0.80–1.29). These associa-
tions were consistent for ischemic, but not hemorrhagic
stroke.
We next evaluated whether changes in LTPA measured
at the 10-year follow-up was associated with a differential
risk of stroke among HT users. Current HT users who met
AHA recommendations at both time points (persistently
active) did not have increased risk for stroke (adjusted HR
0.97, 95% CI 0.74–1.28). These persistently active women
who were former HT users also showed no increased
stroke risk (adjusted HR 1.03, 95% CI 0.84–1.27). How-
ever, among former HT users, those who did not meet
AHA guidelines at baseline, but did in 2005–2006 (thus
become more active) had decreased stroke risk (adjusted
193.51.85.197 - 2/12/2020 2:59:39 PM

Physical Activity, HT Use, and Stroke Neuroepidemiology 3

DOI: 10.1159/000505970
Université de Paris
Downloaded by:
Table 1. Main association between HT use and overall stroke, ischemic, and hemorrhagic stroke risk, also stratified by HT use and
leisure time physical activity in the CTS cohort (1995–2015) based on baseline (1995–1996) and 10-year follow-up (2005–2006)
questionnaires

Cohort, n Strokes Ischemic Hemorrhagic

n HR 95% CI n HR 95% CI n HR 95% CI

HT use – overall association

HT use
Never users 25,376 494 1.00α – 362 1.00α – 132 1.00α –
Former users 5,374 393 1.09α 0.94–1.27 298 1.10α 0.93–1.29 95 1.03α 0.71–1.49
Current users 55,046 2,250 1.24α 1.11–1.39 1,632 1.22α 1.08–1.38 618 1.36α 1.05–1.75
Meeting AHA guidelines at baseline questionnaire (1995–1996)
Physical activity*/HT use
Any activity/never users 25,376 484 1.00^ – 362 1.00^ – 132 1.00^ –
Met AHA guidelines/former user 2,711 200 1.11^ 0.93–1.33 146 1.07^ 0.88–1.32 54 1.30^ 0.84–2.00
Did not meet AHA guidelines/former user 2,663 193 1.07^ 0.89–1.29 152 1.13^ 0.92–1.38 41 0.74^ 0.43–1.27
Met AHA guidelines/current user 27,197 1,107 1.22^ 1.08–1.37 802 1.18^ 1.03–1.35 305 1.36^ 1.04–1.80
Did not meet AHA guidelines/current user 27,849 1,143 1.28^ 1.13–1.44 830 1.26^ 1.10–1.44 313 1.36^ 1.03–1.79
Meeting AHA guidelines in follow-up questionnaire (2005–2006)
Physical activity*/HT use
Any activity/never users 7,818 216 1.00^ – 175 1.00^ – 41 1.00^ –
Met AHA guidelines/former user 8,802 222 0.93^ 0.76–1.13 171 0.89^ 0.71–1.11 51 1.09^ 0.72–1.67
Did not meet AHA guidelines/former user 7,122 294 1.24^ 1.03–1.50 257 1.33^ 1.08–1.64 37 0.87^ 0.55–1.39
Met AHA guidelines/current user 5,610 105 1.01^ 0.80–1.29 78 0.96^ 0.73–1.27 27 1.18^ 0.71–1.94
Did not meet AHA guidelines/current user 3,926 97 1.17^ 0.91–1.50 78 1.19^ 0.90–1.57 19 1.09^ 0.62–1.92
Meeting AHA guidelines over 10-year period (1995–1996 and 2005–2006)
Physical activity*/HT use
Any activity/never users 7,818 216 1.00^ – 175 1.00^ – 41 1.00^ –
Met AHA guidelines in 1995–1996 and 2005–2006/former user 5,776 174 1.03^ 0.84–1.27 134 0.98^ 0.77–1.24 40 1.24^ 0.79–1.94
Did not meet AHA guidelines in 1995–1996 but met in
2005–2006/former user 3,026 48 0.69^ 0.50–0.96 37 0.67^ 0.46–0.96 11 0.79^ 0.40–1.54
Met AHA guidelines in 1995–1996 but not 2005–2006/former user 2,275 109 1.27^ 1.00–1.62 93 1.31^ 1.00–1.71 16 1.11^ 0.61–2.02
Did not meet AHA guidelines in 1995–1996 and 2005–2006/former user 4,847 185 1.23^ 1.00–1.52 164 1.35^ 1.07–1.70 21 0.74^ 0.43–1.29
Met AHA guidelines in 1995–1996 and 2005–2006/current user 3,750 71 0.97^ 0.74–1.28 53 0.93^ 0.68–1.27 18 1.13^ 0.64–2.02
Did not meet AHA guidelines in 1995–1996 but
met in 2005–2006/current user 1,860 34 1.11^ 0.76–1.60 25 1.05^ 0.68–1.62 9 1.27^ 0.61–2.64
Met AHA guidelines in 1995–1996 but not 2005–2006/current user 1,216 35 1.23^ 0.85–1.77 29 1.27^ 0.85–1.90 6 1.09^ 0.46–2.59
Did not meet AHA guidelines in 1995–1996 and 2005–2006/current user 2,710 62 1.14^ 0.85–1.53 49 1.15^ 0.83–1.60 13 1.08^ 0.56–2.08

* AHA guidelines – 150 min/week of moderate or 75 min/week of strenuous physical activity.

α Adjusted for age, race, smoking status, alcohol, SES, BMI, hypertension, diabetes, hyperlipidemia – all at baseline.
^ Adjusted for age, race, smoking status, alcohol, calories, SES, BMI, hypertension, diabetes, hyperlipidemia – all at baseline.

Associations significant at a p value of 0.05 are indicated in italics.

HT, hormone therapy; CTS, California Teachers Study; AHA, American Heart Association; SES, socioeconomic status; BMI, body mass index.

HR 0.69, 95% CI 0.50–0.96). Women who became less ac-
tive (adjusted HR 1.27, 95% CI 1.00–1.62) or were not ac-
tive (adjusted HR 1.23, 95% CI 1.00–1.52) had higher
stroke risk. This direction of effect appears to be consis-
tent among current HT users as well. Independent effects
by moderate and strenuous physical activity are shown in
online supplementary Table 2.
Discussion
Physical inactivity may be one of the more readily
modifiable risk factors for women’s health. It is an im-
portant primary prevention strategy for reducing stroke
incidence and mortality [8, 9]. To guide current prac-
tices regarding the known increased stroke risk among
women who use HT [14, 15], we evaluated the role of
physical activity by HT status. LTPA has been associ-
ated with improved markers of cardiovascular disease
risk in older age. In particular, those who stayed active
or became more active had better risk profiles than
those who became less active [16]. Results from the
Framingham Heart Study have also shown reduced risk
for cardiovascular disease in women who have been
more recently physically active [17]. It is still unclear
the exact mechanism behind the increased risk of stroke
from HT use, but it is believed to be related to choles-
terol levels and accelerating atherosclerosis [18], which
can be mediated with physical activity [19]. Our data
show that meeting AHA recommendations for physical
activity concurrent to HT use can attenuate short-term
stroke risk.
193.51.85.197 - 2/12/2020 2:59:39 PM

4 Neuroepidemiology Zhong/Voutsinas/Willey/Lakshminarayan/
DOI: 10.1159/000505970 Lacey, Jr./Chung/Woo/Elkind/Wang
Université de Paris
Downloaded by:
 Strengths of our study include the prospective design
and the large sample size from which to identify stroke
outcomes. Linkage of our data to the California hospi-
talization discharge data also provide reliable case as-
certainment, which was verified by medical record
­review [12]. Study limitations include the lack of infor-
mation on other types of physical activities (e.g., occu-
pational), although we believe these other activities
should be largely similar since the cohort was of similar
occupation (public school teachers and administrators).
HT use prior to enrollment was not ascertained so it is
unknown if a woman reporting HT use at enrollment
was a recent or already a long-term HT user. We did not
have sufficient sample size to further stratify HT, but
results were consistent for various formulations (estro-
gen only, estrogen + progesterone, progesterone only)
and delivery methods (pill, injection, patch, cream) that
were reported in the baseline questionnaire. We also ac-
knowledge the potential for residual confounding re-
garding our broad HT categories. However, we antici-
pate that this would mostly likely result in nondifferen-
tial misclassification at most, or, at worst, diminish the
main associations that might have been expected. That
we still observed increased risk for HT use among this
broad category, however, permitted us to evaluate the
joint effect that LTPA would have. We further acknowl-
edge that physical activity only reflects one way to po-
tentially diminish the HT-stroke association and that
others were beyond the scope of this manuscript, in-
cluding the modification of HT dose and duration.
However, we do note that evaluation of LTPA on other
known stroke risk factors such as smoking and obesity
did not reflect a similar mitigation in risk. Clinical co-
variates were obtained from the California inpatient
hospitalization discharge records (OSHPD) and there-
fore likely represent more severe comorbidities that re-
quired or were noted during hospitalization. Lastly, our
cohort consisted of primarily non-Hispanic White
women (87%), and, while reflecting the California
teacher population in 1995–1996, it does not reflect the
increased racial/ethnic diversity of California today.
However, we note that stroke incidence in our study
population is comparable to age-adjusted incidence
rates published by the AHA for women.
Our study results are particularly relevant for post-
menopausal women as they navigate increased risk for
cardiovascular diseases including stroke. Identifying fac-
tors to manage increased stroke risk during this time pe-
riod is thus critical for stroke prevention efforts. Should
women elect to undergo HT to manage menopause asso-
Physical Activity, HT Use, and Stroke
ciated symptoms, our results suggest that meeting AHA
recommendations for LTPA could help mitigate short-
term stroke risk [4, 20].
Acknowledgments
We are grateful to the women of the CTS for their continued
participation and enthusiasm for the study, to our talented CTS
study staff, Teri Terrusa-Forve, Cynthia Quince, and Michelle
Dich, and to the CTS Steering Committee for their scientific guid-
ance and insight.
Statement of Ethics
The CTS is approved by Institutional Review Boards of the City
of Hope, the University of Southern California, the University of
California at San Francisco, and University of California Irvine,
and by the Committee for the Protection of Human Subjects of the
California Health and Human Services Agency. Informed consent
was obtained at study entry.
Disclosure Statement
Dr. Mitchell S.V. Elkind reports receiving personal compensa-
tion from Merck/Organon for providing expert witness testimo-
ny regarding Nuvaring® and stroke. The other authors declare
that they have no competing interest.
Funding Sources
This work was supported in part by federal funds from the Na-
tional Institute of Neurological Diseases and Stroke under
R21NS075608. The CTS and the research reported in this publica-
tion were supported by the National Cancer Institute of the Nation-
al Institutes of Health under award number U01-CA199277; P30-
CA033572; P30-CA023100; UM1-CA164917; and R01-CA077398.
The content is solely the responsibility of the authors and does not
necessarily represent the official views of the National Cancer Insti-
tute or the National Institutes of Health. The opinions, findings, and
conclusions expressed herein are those of the author(s) and do not
necessarily reflect the official views of the State of California, Depart-
ment of Public Health, the National Cancer Institute, the National
Institutes of Health, or their Contractors and Subcontractors, or the
Regents of the University of California, or any of its programs.
Author Contributions
S.S.W. and J.V.L., Jr. conceived of the study. K.L., M.S.V.E., and
D.W. conducted medical record review. C.Z., J.V., and N.C. con-
ducted data collection and data analysis. All contributed to data
interpretation and manuscript preparation. All authors have read
and approved the submitted manuscript.
193.51.85.197 - 2/12/2020 2:59:39 PM
Neuroepidemiology 5
DOI: 10.1159/000505970
Université de Paris
Downloaded by:
 References
  1 Benjamin EJ, Muntner P, Alonso A, Bitten-
court MS, Callaway CW, Carson AP, et al.;
American Heart Association Council on Epi-
demiology and Prevention Statistics Com-
mittee and Stroke Statistics Subcommittee.
Heart disease and stroke statistics-2019 up-
date: A report from the American heart as-
sociation. Circulation. 2019 Mar;139(10):e56–
528.
  2 Petrea RE, Beiser AS, Seshadri S, Kelly-Hayes
M, Kase CS, Wolf PA. Gender differences in
stroke incidence and poststroke disability in
the Framingham heart study. Stroke. 2009
Apr;40(4):1032–7.
  3 Danaei G, Ding EL, Mozaffarian D, Taylor B,
Rehm J, Murray CJ, et al. The preventable
causes of death in the United States: compar-
ative risk assessment of dietary, lifestyle, and
metabolic risk factors. PLoS Med. 2009 Apr;
6(4):e1000058.
  4 Lisabeth L, Bushnell C. Stroke risk in women:
the role of menopause and hormone therapy.
Lancet Neurol. 2012 Jan;11(1):82–91.
  5 Wassertheil-Smoller S, Hendrix SL, Limacher
M, Heiss G, Kooperberg C, Baird A, et al.;
WHI Investigators. Effect of estrogen plus
progestin on stroke in postmenopausal wom-
en: the Women’s Health Initiative: a random-
ized trial. JAMA. 2003 May;289(20):2673–84.
  6 Bath PM, Gray LJ. Association between hor-
mone replacement therapy and subsequent
stroke: a meta-analysis. BMJ. 2005 Feb;
330(7487):342.
6 Neuroepidemiology
DOI: 10.1159/000505970
  7 American College of Obstetricians and Gyne-
cologists Committee on Gynecologic Practice.
ACOG Committee Opinion No. 420, Novem-
ber 2008: hormone therapy and heart disease.
Obstet Gynecol. 2008 Nov;112(5):1189–92.
  8 Lee CD, Folsom AR, Blair SN. Physical activ-
ity and stroke risk: a meta-analysis. Stroke.
2003 Oct;34(10):2475–81.
 9 Wendel-Vos GC, Schuit AJ, Feskens EJ,
Boshuizen HC, Verschuren WM, Saris WH,
et al. Physical activity and stroke. A meta-
analysis of observational data. Int J Epidemi-
ol. 2004 Aug;33(4):787–98.
10 Willey JZ, Voutsinas J, Sherzai A, Ma H, Ber-
nstein L, Elkind MS, et al. Trajectories in lei-
sure-time physical activity and risk of stroke
in women in the California teachers study.
Stroke. 2017 Sep;48(9):2346–52.
11 Bernstein L, Allen M, Anton-Culver H, Deap-
en D, Horn-Ross PL, Peel D, et al. High breast
cancer incidence rates among California
teachers: results from the California Teachers
Study (United States). Cancer Causes Con-
trol. 2002 Sep;13(7):625–35.
12 Miller EC, Boehme AK, Chung NT, Wang SS,
Lacey JV Jr, Lakshminarayan K, et al. Aspirin
reduces long-term stroke risk in women with
prior hypertensive disorders of pregnancy.
Neurology. 2019 Jan;92(4):e305–16.
13 Dallal CM, Sullivan-Halley J, Ross RK, Wang
Y, Deapen D, Horn-Ross PL, et al. Long-term
recreational physical activity and risk of inva-
sive and in situ breast cancer: the California
teachers study. Arch Intern Med. 2007 Feb;
167(4):408–15.
14 Lobo RA. The risk of stroke in postmenopaus-
al women receiving hormonal therapy. Cli-
macteric. 2009;12 Suppl 1:81–5.
15 Stefanick ML. Postmenopausal hormone
therapy and cardiovascular disease in women.
Nutr Metab Cardiovasc Dis. 2010 Jul; 20(6):
451–8.
16 Elhakeem A, Murray ET, Cooper R, Kuh D,
Whincup P, Hardy R. Leisure-time physical
activity across adulthood and biomarkers of
cardiovascular disease at age 60-64: A pro-
spective cohort study. Atherosclerosis. 2018
Feb;269:279–87.
17 Sherman SE, D’Agostino RB, Silbershatz H,
Kannel WB. Comparison of past versus recent
physical activity in the prevention of prema-
ture death and coronary artery disease. Am
Heart J. 1999 Nov;138(5 Pt 1):900–7.
18 Reslan OM, Khalil RA. Vascular effects of es-
trogenic menopausal hormone therapy. Rev
Recent Clin Trials. 2012 Feb;7(1):47–70.
19 Monda KL, Ballantyne CM, North KE. Longi-
tudinal impact of physical activity on lipid
profiles in middle-aged adults: the Athero-
sclerosis Risk in Communities Study. J Lipid
Res. 2009 Aug;50(8):1685–91.
20 Bushnell C, McCullough L. Stroke prevention
in women: synopsis of the 2014 American
Heart Association/American Stroke Associa-
tion guideline. Ann Intern Med. 2014 Jun;
160(12):853–7.
193.51.85.197 - 2/12/2020 2:59:39 PM
Zhong/Voutsinas/Willey/Lakshminarayan/
Lacey, Jr./Chung/Woo/Elkind/Wang
Université de Paris
Downloaded by: