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. Keywords Stroke . Gender . Sex . Women . Stroke treatment . Stroke risk factors . Pregnancy Introduction 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 [2]. 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 [3]. 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 [2]. 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 e-mail: dgj2001@med.cornell.edu M. Skliut Department of Neurology, Beth Israel Medical Center, 10 Union Square East, 5D, New York, NY 10003, USA e-mail: mskliut@chpnet.org Curr Atheroscler Rep (2010) 12:236243 DOI 10.1007/s11883-010-0118-3 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 womans 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 [5]. Multiple epidemiologic studies, including the Womens Health Study (WHS) [69, 10], the Womens 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 womans 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 [17]. 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 [18]. 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 replicated [19]. The role of serum and radiologic markers to predict vascular risk is unclear and controversial irrespective of their specificity and patients sex. Whether markers, proven Sex: biological attributes of men or women Estrogen 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 Venous thrombosis Inherited predisposition for Factor V Leiden and prothrombin gene mutation Effect on platelet activation Female conditions with increased stroke risk Exogenous estrogen treatment Pregnancy Migraines Gender: the behavioral, cultural, or psychological attributes of men or women Women Lifestyle Increased life expectancy Care-giver vs care-receiver Access to appropriate health care Social isolation 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 artery Curr Atheroscler Rep (2010) 12:236243 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 [6]. 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 [20]. 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, 2.167.19) compared with men (absolute risk reduction=1.56; 95% CI, 1.042.36). 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 WHI [11]. Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) appears to be a reliable marker of risk for cardiovascular events, including ischemic stroke. In the Northern Manhattan study, stroke patients with Lp-PLA 2 activity levels in the highest quartile compared with those in the lowest quartile had an increased risk of recurrence after first ischemic stroke [16]. Investigators in the WHI found that among postmen- opausal women not using hormone replacement therapy, levels of the biomarker Lp-PLA 2 in the highest quartile compared with those in the lowest was independently associated with a 64% increased risk of ischemic stroke [23]. The increased risk persisted after adjustment for traditional cardiovascular risk factors (odds ratio=1.55; 95% CI, 1.052.28). There was no association of Lp-PLA 2 with stroke risk among women using hormone replacement therapy. Among nonusers of hormone replacement therapy, the association of Lp-PLA 2 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 [13]. Intracranial stenosis appears to be a marker for vascular risk that is especially prescient in women [24]. 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) [25]. 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 [26]. Kurth et al. [9] 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 2 , 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 [27]. 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 [28]. In the WHS, there was a statistically significant trend for increased risk of ischemic stroke with BMI greater than 30 kg/m 2 but the association was highly mediated by hypertension, diabetes, and elevated cholesterol [8]. Women who were current cigarette smokers had increased risk of stroke irrespective of 238 Curr Atheroscler Rep (2010) 12:236243 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 [29]. Female-Predominant Stroke-Related Conditions Womens Lifetime Risk of Stroke Hormonal influences dictate a womans 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 [30]. Pregnancy 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 womans risk of hemorrhagic stroke, both intracerebral hemorrhage (ICH) and subarach- noid hemorrhage (SAH) [31]. The risk of cerebral infarc- tion or hemorrhagic stroke is greater in the postpartum period compared with during pregnancy [32]. 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, 6.49.7). 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 [33]. 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 [32]. Risk of ischemic stroke after pregnancy and the puerperium is increased in women with a history of preeclampsia [33]. Oral Contraception 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 [34]. Doses of estrogen greater than 50 g 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 [35]. 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 [36]. Menopause 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 [37]. 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 [38]. 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 [14]. 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 [39]. 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 [40]. Estrogen supplementation has also not been shown to be of benefit in secondary stroke prevention [41]. Curr Atheroscler Rep (2010) 12:236243 239 Migraine 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 [7]. 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 [42]. 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 poorly understood. Antiplatelet Therapy 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 [43]. 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 [44]. 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 [45]. 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] 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 [46]. 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 [47]. 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 [48]. Restenosis rates after carotid surgery are increased in women compared with men [49]. 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 [47, 5052]. 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 [53]. Significantly fewer women (62%) receive imaging within 1 hour of emergency department arrival than men [54]. 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 [57]. Women have worse functional outcome after having a stroke, possibly related to advanced age and more frequent co-morbid conditions [58]. 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 [59]. 240 Curr Atheroscler Rep (2010) 12:236243 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 [60]. 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 02) 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 [62]. 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 severity. Conclusions 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 womens 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. 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