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Dara G. Jamieson & Maryna Skliut
Published online: 21 May 2010
# Springer Science+Business Media, LLC 2010
Abstract Stroke, a major cause of morbidity and mortality in
the general population, varies in incidence in men and women
of different age groups: more boys than girls have strokes; the
incidence of stroke is greater in men in their 60s and 70s; and
stroke is more common in women after age 80 years. These
differences are attributed to hormonal (sex-related) changes
and variable risk factors in women, as well as lifestyle and
environmental (gender-related) co-morbid conditions. A
woman, who is more likely to have a stroke in her lifetime
than a myocardial infarction, has a different response to
primary and secondary prevention as compared with a man.
Although response to thrombolysis is similar, older age and
more severe strokes in women lead to poorer outcomes in
female stroke survivors.
Stroke risk factors
According to 2010 report from American Heart Association
(AHA), each year about 795,000 people in the United
States have new or recurrent stroke [1••]. The same report
states that approximately 55,000 more women than men
have a stroke each year. Community-based data on a group
of North Americans of European descent indicate that the
lifetime risk of stroke for a middle-aged woman is 1 in 5
and for a middle-aged man the risk is 1 in 6 . The female
predominance is not present in all ages and is expressed
mostly in older women. Boys have more strokes than girls.
In the age group of 65 to 74 years, the male-to-female-
predominance-of-stroke ratio is 1.5. This ratio goes down to
0.76 in the age group of ≥85 years. Women ages 45 to 54
have a likelihood of developing a stroke twice as high as
man in the same age group. The risk of stroke in women
increases with age: there is a fourfold increase in the
likelihood of stroke in women ages 45 to 54 years compared
with the ages of 35 to 44 years . More women than men die
of stroke each year. In the United States, 60.6% of stroke
deaths in 2006 were women. The decline in stroke-related
death is greater in women than in men, with the age adjusted
male-to-female ratio decreasing from 1.1 to 1.03. Common
risk factors for stroke are applied to women as they are to
men, but women carry a significant number of specific risk
factors, including hormonal states like pregnancy and
menopause, predisposition to particular female predominant
diseases with increased stroke risk (such as migraine), and
longevity (resulting in higher risk of atrial fibrillation and
associated stroke risk) [4••]. Age is also an independent
and the strongest risk factor for stroke. It is also a negative
predictive factor for poor outcomes after stroke .
Sex Versus Gender Influences on Stroke Risk in Women
Risk of stroke and response to treatment in women can be
divided into sex (hormonal) and gender (environmental)
D. G. Jamieson (*)
Department of Neurology and Neuroscience,
New York Presbyterian Hospital,
Weill Cornell Medical College of Cornell University,
525 E 68 St., F610,
New York, NY 10065, USA
Department of Neurology, Beth Israel Medical Center,
10 Union Square East, 5D,
New York, NY 10003, USA
Curr Atheroscler Rep (2010) 12:236–243
influences, as noted in Table 1. Hormonal fluctuations that
women experience through their lifetime and conditions
that have higher prevalence in females, such as migraine
headache, exogenous estrogen, and pregnancy, increase a
woman’s risk of stroke. In 2006, the National Institute of
Neurological Disorders and Stroke (NINDS) sponsored a
multidisciplinary working group who published an overview
of our current understanding of the role of estrogen, both
endogenous and exogenous, in stroke risk, as well as
recommendations for future investigation . Multiple
epidemiologic studies, including the Women’s Health Study
(WHS) [6–9, 10•], the Women’s Health Initiative (WHI) [11,
12•, 13, 14], and the Northern Manhattan Stroke Study
(NOMAS) [15, 16] have revealed vascular risk factors
relevant to women.
Sex-Related Influences in Stroke Risk
Estrogen properties, as related to stroke risk, are paradoxical,
with inconsistent translation from laboratory to clinical
observations. Pretreatment with estradiol protects the cortex
from cell death in a middle cerebral artery occlusion in a
rodent model, yet no clinical benefit is conferred by estradiol
treatment of acute ischemic stroke. Although endogenous
estradiol appears to be neuroprotective and may decrease a
woman’s risk of cardiovascular disease, exogenous estrogen
(hormone replacement therapy) actually increases the risk of
coronary heart disease or stroke in older postmenopausal
women. Circulating endogenous estradiol is associated with
increased stroke risk in older postmenopausal women. A
prospective case-control study found that endogenous estradiol
level is an indicator of stroke risk in older postmenopausal
women, especially in those with greater central adiposity.
Potential mediators included atherogenic dyslipidemia, insulin
resistance, and inflammation .
Multiple mechanisms of action may explain the compli-
cated and contradictory effects of endogenous and exogenous
estrogen in stroke risk. Nitric oxide synthase, which is
expressed within the vascular wall, is a target of estrogen
action, with different effects as a function of age. In younger
women estrogen produces a beneficial effect (production of
nitric oxide), but a deleterious product (superoxide) is formed
in older women . Although variations in the estrogen
alpha receptor (ESR1) gene appear to be strongly associated
with risk of ischemic heart disease, an association between
variations in the ESR1 gene and risk of stroke has not been
The role of serum and radiologic markers to predict
vascular risk is unclear and controversial irrespective of
their specificity and patient’s sex. Whether markers, proven
Sex: biological attributes of men or women
Possible neuroprotective effect
Decreased stroke size in animal MCA stroke models
Low premenopausal stroke rates
Antioxidant, antiapoptotic, antiglutamate, increased cGMP
Possible proinflammatory effect
Increased CRP (dose dependent)
Possible increase in cerebral blood flow
Increased eNO, increased prostacyclin, stimulation of angiogenesis
Possible prothrombotic effect
Inherited predisposition for Factor V Leiden and prothrombin gene mutation
Effect on platelet activation
Female conditions with increased stroke risk
Exogenous estrogen treatment
Gender: the behavioral, cultural, or psychological attributes of men or women
Increased life expectancy
Care-giver vs care-receiver
Access to appropriate health care
Table 1 Women: effect of sex
and gender on stroke
cGMP cyclic guanosine
monophosphate, CRP C-reactive
protein, eNO endothelial nitric
oxide, MCA middle cerebral
Curr Atheroscler Rep (2010) 12:236–243 237
or putative, can predict cerebrovascular, as distinct from
general vascular or cardiovascular, risk is uncertain. Although
dyslipidemia is more closely linked to cardiovascular than to
cerebrovascular risk, elevations in total cholesterol, low-
density lipoprotein (LDL) cholesterol, the total cholesterol to
high-density lipoprotein (HDL) cholesterol ratio, and non-
HDL cholesterol were significantly associated with an
increased risk of ischemic stroke in the WHS .
A study following 250 healthy postmenopausal women
found that fibrinogen, carotid lesions, and high-sensitivity
C-reactive protein (hs-CRP) were predictors of vascular
events . However, although there was a correlation with
risk of myocardial infarction (MI), there was no correlation
with ischemic stroke risk. Fibrinogen, along with LDL, has
been correlated with the progression of carotid intima-media
thickness (IMT) in women. The Tromso Study, which used
ultrasonography, showed sex-dependent differences in associ-
ations between measures of carotid atherosclerosis, MI, and
inflammatory markers. Carotid atherosclerosis predicted first-
ever MI in women (absolute risk reduction=3.95; 95% CI,
2.16–7.19) compared with men (absolute risk reduction=1.56;
95% CI, 1.04–2.36). Women and men with carotid plaque had
significantly elevated levels of white blood cells (WBC) and
fibrinogen, but not CRP, with a significant association between
WBC and plaque echogenicity in women [21, 22]. Estrogen
and sex hormone binding globulin have been associated with
a reduction in carotid IMT in healthy postmenopausal
women, indicating a potential marker for reduced vascular
risk, mediated through beneficial effects on lipids.
More specific markers of risk of stroke are being identified.
Hepatocyte growth factor (HGF), a potent angiogenic factor,
plays a role in the development and progression of athero-
sclerotic lesions. Circulating levels of HGF are associated
with an increased risk of incident ischemic stroke, independent
of obesity and other risk factors for cardiovascular disease,
among postmenopausal women aged 50 to 79 years in the
Lipoprotein-associated phospholipase A
appears to be a reliable marker of risk for cardiovascular
events, including ischemic stroke. In the Northern Manhattan
study, stroke patients with Lp-PLA
activity levels in the
highest quartile compared with those in the lowest quartile
had an increased risk of recurrence after first ischemic stroke
. Investigators in the WHI found that among postmen-
opausal women not using hormone replacement therapy,
levels of the biomarker Lp-PLA
in the highest quartile
compared with those in the lowest was independently
associated with a 64% increased risk of ischemic stroke
. The increased risk persisted after adjustment for
traditional cardiovascular risk factors (odds ratio=1.55;
95% CI, 1.05–2.28). There was no association of Lp-PLA
with stroke risk among women using hormone replacement
therapy. Among nonusers of hormone replacement therapy,
the association of Lp-PLA
with stroke risk was strongest in
women who also had elevated hs-CRP. In healthy postmen-
opausal women, hs-CRP also appears to be a strong predictor
of the risk of cardiovascular events .
Intracranial stenosis appears to be a marker for vascular
risk that is especially prescient in women . The
Warfarin-Aspirin Symptomatic Intracranial Disease
(WASID) trial found that women with intracranial stenosis
were at greater risk of stroke or vascular death (28.4% for
women; 16.6% for men) . After accounting for
traditional vascular risk factors and stroke severity, women
had almost a twofold increased risk of stroke compared
with men, and a 1.6-fold increased risk of combined
outcome (stroke or vascular death).
Gender-Related Influences in Stroke Risk
Gender-specific risk factors for women relate to their
lifestyle and environment. Lifestyle issues are recognized
for their important role in risk of cerebrovascular disease
. Kurth et al.  used data from the WHS of almost
38,000 healthy female health professionals aged 45 years
and older to look at lifestyle and weight as risk factors for
stroke. Healthy lifestyle in the WHS was defined as 1)
abstinence for smoking, 2) body mass index (BMI) less
than 22 kg/m
, 3) exercise ≥4 times/week, 4) alcohol
consumption of 4 to 10.5 drinks per week, and 5) diet high
in cereal fiber, folate, omega-3 fatty acids; high polyunsat-
urated to saturated fat ratio; low in trans fat; low in
glycemic load. A composite healthy lifestyle was associated
with a significantly reduced total and ischemic stroke risk,
but not with reduced hemorrhagic stroke risk. The
association was apparent even after controlling for hyper-
tension, diabetes, and elevated cholesterol. Analysis of the
individual components of the healthy life style showed
substantial reduction of stroke risk in nonsmokers and
women with lower BMI. The associations with alcohol
consumption and physical activity were weaker. The healthier
diet paradoxically increased risk of ischemic and hemorrhagic
stroke, but the overall risk outcomes were unchanged with
exclusion of diet data. Data from the Northern Manhattan
study suggest that increased daily total fat intake, especially
above 65 g, significantly increases risk of ischemic stroke in a
predominantly female population .
Obesity is a strong risk factor for ischemic stroke, with a
less clear relationship with hemorrhagic stroke. Markers of
abdominal adiposity are strongly associated with the risk of
ischemic stroke or transient ischemic attack . In the WHS,
there was a statistically significant trend for increased risk of
ischemic stroke with BMI greater than 30 kg/m
association was highly mediated by hypertension, diabetes,
and elevated cholesterol . Women who were current
cigarette smokers had increased risk of stroke irrespective of
238 Curr Atheroscler Rep (2010) 12:236–243
BMI. The association between BMI and hemorrhagic stroke
in women was inconsistent. Physical activity reduces the risk
of stroke. A study of combined work and leisure activity in
men and women confirmed this data, showing about 40%
risk reduction for stroke in the most active group .
Female-Predominant Stroke-Related Conditions
Women’s Lifetime Risk of Stroke
Hormonal influences dictate a woman’s stroke risk throughout
her life. Menarche before age 12 years is associated with
increased vascular risk, cardiac disease events, and overall
mortality, with the association only partly mediated by
increased adiposity. However, the risk of stroke is not
influenced by age of menarche .
Pregnancy increases the immediate and future risk of
ischemic and hemorrhagic stroke. Past pregnancies can
also increase future stroke risk. Multiple deliveries have
been shown to increase a woman’s risk of hemorrhagic
stroke, both intracerebral hemorrhage (ICH) and subarach-
noid hemorrhage (SAH) . The risk of cerebral infarc-
tion or hemorrhagic stroke is greater in the postpartum
period compared with during pregnancy . The excess
risk for either type of stroke during or within 6 weeks after
pregnancy is 8.1 strokes per 100,000 pregnancies (95% CI,
6.4–9.7). In pregnancy, the rate of ICH is equal to or greater
than the rate of ischemic stroke, whereas the incidence of
ischemic stroke is much greater than that of hemorrhagic
stroke in nonpregnant women in the same age range .
Pregnancy-associated ischemic strokes are usually due to
embolism (venous or cardiac thrombus, fat, amniotic fluid,
air, or choriocarcinoma). Cerebral venous thrombosis or
leakage from a vascular malformation can cause peri-partum
ICH. Subarachnoid hemorrhage due to aneurysmal rupture is
a major cause of maternal mortality during pregnancy, with
high fetal mortality as well. Preeclampsia and eclampsia
complicate about 5% to 8% of pregnancies and are important
risk factors for both hemorrhagic and ischemic stroke.
Preeclampsia or eclampsia was found in 24% of women with
cerebral infarction and 14% of women with intracerebral
hemorrhage . Risk of ischemic stroke after pregnancy
and the puerperium is increased in women with a history of
Although the correlation between oral contraceptives and
stroke risk has been debated for decades, the evidence for
an association, independent of traditional vascular risk
factors, is not clear. Meta-analyses of studies published up
to 2002 (with patient data collection up to 1995) reported
variable risk depending on study design . Doses of
estrogen greater than 50 μg were associated with greater
risk than lower doses. The absolute risk was noted to be
low, with only an additional 4.1 ischemic strokes per
100,000 nonsmoking, normotensive women using low-dose
estrogen oral contraceptives. A population based cohort
study in the Netherlands, the Risk of Arterial Thrombosis in
Relation to Oral Contraceptives (RATIO) study, reported
that current oral contraceptive use was associated with a
risk of stroke twice that of nonusers; smoking, hyperten-
sion, hypercholesterolemia, diabetes, and obesity conferred
significantly increased risk in combination with oral
contraception . Thrombophilias, specifically Factor V
Leiden and the G20210A prothrombin gene mutation,
increase the risk of cerebral venous thrombosis in users of
oral contraceptives. Ischemic stroke risk, in association
with oral contraceptives, has also been shown to be
increased in women with Factor V Leiden or methylenete-
trahydrofolate reductase (MTHFR) 677TT polymorphism
The increased stroke risk in postmenopausal woman
appears to be due to a combination of age and hormonal
changes caused by decreasing estrogen levels. Although
estrogen has been shown to be neuroprotective in animal
ischemic stroke models, a neuroprotective effect of human
estrogen supplementation has not been confirmed in clinical
trials. Observational cohort studies of the use of hormone
replacement therapy on stroke risk in postmenopausal
women have shown mixed results . The conflicting
results of these studies could be secondary to the differences in
the age of participants, dose of estrogen used, time of
administration (pre/postmenopausal), preparation form, pre-
morbid conditions, and genetic predisposition . The WHI
showed a 44% increased incidence in ischemic stroke with
estrogen plus progestin treatment of healthy women who
were on average a decade into menopause . The Heart
and Estrogen/Progestin Replacement Study found that in
women with increased risk of vascular events due to
coronary heart disease, hormone replacement therapy offered
no primary protection against ischemic stroke . A study
found that there is an increased risk for the combination of
transient ischemic attack (TIA), ischemic stroke, and
hemorrhagic stroke associated with the use of hormone
replacement therapy, with the greatest increase in risk during
the first year of treatment . Estrogen supplementation has
also not been shown to be of benefit in secondary stroke
Curr Atheroscler Rep (2010) 12:236–243 239
Approximately 21 million American women have migraine
headaches, making it a female-predominant disorder. In the
WHS, migraine with aura was found to increase the risk of
ischemic stroke as well as MI, coronary revascularization,
and angina . Migraines without aura and non-migraine
headaches were not associated with increased vascular risk.
Although migraine with aura appears to confer an increased
vascular risk, migraine without aura may also be associated
with some degree of vascular risk .
Stroke Prevention in Women
Women have different degrees of risk reduction with medical
and surgical therapy for stroke prevention compared with
men. The reasons for this differential response to therapy are
Multiple clinical trials verify the benefit of long-term
antiplatelet therapy in the reduction of recurrent ischemic
stroke in both men and women. However, women may
respond differently to aspirin therapy than men, in primary
prevention. Women appear to benefit from aspirin for
prevention of a first stroke, an effect not as striking in men
[12•, 43, 44]. The pathophysiologic mechanisms for the
perceived clinical difference is not clear, but may reflect
differences in aspirin metabolism or aspirin resistance, as
well as the gender difference in incidence of stroke and MI.
The WHS showed that in women (mean age, 54.6 years),
low-dose aspirin (100 mg every other day) had a protective
effect against a first stroke, but generally offered no
protection against MI and cardiovascular death except in
women aged 65 years and older . Among women in the
placebo group, there was a stroke to MI ratio of 1.4:1
compared with a ratio of 0.4:1 among men in the Physicians’
Health Study . A sex-specific meta-analysis of aspirin
therapy for the primary prevention of cardiovascular events
found that aspirin therapy was associated with a 24%
reduced rate of ischemic stroke, with no apparent effect on
hemorrhagic stroke in women . Analysis of data from
postmenopausal women with stable cardiovascular disease
enrolled in the WHI found aspirin use (with no difference
between 81 mg and 325 mg) was associated with signifi-
cantly lower risk of all-cause mortality [12•]
Carotid Endarterectomy and Carotid Angioplasty with Stenting
Although women with ischemic stroke or TIA are less likely
than men to undergo carotid screening and revascularization,
this difference is largely explained by potential contraindica-
tions to surgery and by sex differences in the severity of
carotid disease . Carotid revascularization is widely used
for primary and secondary stroke prevention in both men and
women. Although data from older studies suggested that
carotid endarterectomy (CEA) for prevention of initial and
recurrent stroke risk reduction in women may have less
benefit than in men, this conclusion has been challenged
. Recent analysis of data from the Oxford Vascular
Study found that lower rates of surgical intervention for
50% to 99% symptomatic carotid stenosis in women could
be explained by sex differences in population-based
incidence . Restenosis rates after carotid surgery are
increased in women compared with men . Smaller vessel
size and increased vessel redundancy in women may
contribute to their increased restenosis risk. Carotid angio-
plasty with stenting is an alternative for CEA. Recent reports
indicate that there are no substantial gender influences on
clinical outcomes or durability of carotid artery revasculari-
zation following CEA or carotid angioplasty with stenting
Acute Stroke Treatment and Outcome
Presentation and outcomes of acute stroke in women are
different compared with men. Women, especially elderly
women, may be less likely to be evaluated within the first 3
hours after symptom onset . Significantly fewer women
(62%) receive imaging within 1 hour of emergency
department arrival than men . Women have more
severe strokes and higher National Institutes of Health
Stroke Scale (NIHSS) scores on presentation [55, 56]. A
recent study of gender differences in acute care showed that
women arrived in the emergency department at equivalent
times and had similar baseline functional status. In this
study, women had similar NIHSS scores as men. Despite
similar baseline characteristics, women had worse out-
comes at 3 and 12 months, leading to the conclusion that
the female sex, or gender-related lack of support systems,
predisposes to poorer outcomes after acute ischemic stroke
Women have worse functional outcome after having a
stroke, possibly related to advanced age and more frequent
co-morbid conditions . Quality of life, in particular
mental health and physical function, has been found to be
lower in women after stroke. This difference persists even
after correction for age and stroke severity. Treatment
differences may also play a role in this gender disparity in
functional outcome. Women are less likely to be given
thrombolytic therapy for acute ischemic stroke, perhaps due
to advanced age at the time of stroke or delay until stroke
symptoms are recognized and treated .
240 Curr Atheroscler Rep (2010) 12:236–243
There does not seen to be a consistent difference in
benefit from thrombolysis based on sex. The recanalization
rate may be higher in women than in men, and women may
be more likely to benefit from the treatment compared with
men . Good functional outcome, as measured by a
favorable Barthel Index and modified Rankin Scale (mRS),
may be more likely for men than women, but women may
be more likely to survive for 3 months [61•]. Equally
favorable clinical outcome (mRS 0–2) and recanalization
rate were seen in both men and women after intra-arterial
tissue plasminogen activator treatment of middle cerebral
artery and internal carotid artery occlusion .
Although men and women may have comparable outcomes
after treatment with tissue plasminogen activator, if untreated,
women have poorer outcomes after acute stroke than men [63,
64]. Women have a higher rate of cardioembolic strokes than
thrombotic and lacunar strokes, with a higher frequency of
atrial fibrillation as the etiology of their ischemic strokes.
Greater mortality due to stroke may occur because women
are older, with more co-morbid medical conditions, at the
time they suffer a more severe stroke [55, 56]. Quality of life,
in particular mental health and physical functioning, has been
found to be lower in women after stroke. This difference was
found to persist even after correction for age and stroke
Stroke is common in women because they have unique risk
factors and they outlive men. The incidence of stroke varies
in men and women of different age groups. The male/
female differences are attributed to hormonal (sex-related)
changes and variable risk factors in women, as well as
women’s lifestyle and environmental (gender-related) co-
morbid conditions. The risk of ischemic and hemorrhagic
stroke is increased in the post-partum period. Women can
reduce ischemic stroke risk by not smoking and staying
thin. A woman is more likely to have a stroke in her
lifetime than an MI, a differential vascular risk that should
direct her life-style modification and medications to reduce
stroke risk. She has a different response to primary and
secondary prevention compared with a man. Aspirin offers
primary prevention against ischemic stroke in women but
not in men. Hormone replacement therapy does not offer
either primary or secondary cerebrovascular protection.
Although response to thrombolysis is similar, older age and
more severe strokes in women lead to poorer outcomes in
female stroke survivors, who may lack a post-stroke support
Disclosure No potential conflicts of interest relevant to this article
were reported other than both authors are women.
Papers of particular interest, published recently, have been
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